218 results on '"O'Connell RJ"'
Search Results
2. Antibody responses to V2 loop are induced by CRF01_A E and not Clade B envelopes
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Karasavvas N, Karnasuta C, Madnote S, Arworn D, Sinangil F, Rerks-Ngarm S, O'Connell RJ, Nitayaphan S, Ngauy V, Kim JH, Michael NL, and de Souza MS
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Immunologic diseases. Allergy ,RC581-607 - Published
- 2012
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3. HIV viraemia during hepatitis B vaccination shortens the duration of protective antibody levels
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O'Bryan, TA, primary, Rini, EA, additional, Okulicz, JF, additional, Messner, O, additional, Ganesan, A, additional, Lalani, T, additional, Bavaro, MF, additional, O'Connell, RJ, additional, Agan, BK, additional, and Landrum, ML, additional
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- 2015
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4. Herpes simplex virus type 2 and HIV infection among US military personnel: implications for health prevention programmes.
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Bautista CT, Singer DE, O'Connell RJ, Crum-Cianflone N, Agan BK, Malia JA, Sanchez JL, Peel SA, Michael NL, and Scott PT
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US military personnel are routinely screened for HIV infection. Herpes simplex virus type 2 (HSV-2) is a risk factor for HIV acquisition. To determine the association between HSV-2 and HIV, a matched case-control study was conducted among US Army and Air Force servicemembers with incident HIV infections (cases) randomly matched with two HIV-uninfected servicemembers (controls) between 2000 and 2004. HSV-2 prevalence was significantly higher among cases (30.3%, 138/456) than among controls (9.7%, 88/912, P < 0.001). HSV-2 was strongly associated with HIV in univariate (odds ratio [OR] = 4.2, 95% confidence interval [CI] = 3.1-5.8) and multiple analyses (adjusted [OR] = 3.9, 95% CI = 2.8-5.6). The population attributable risk percentage of HIV infection due to HSV-2 was 23%. Identifying HSV-2 infections may afford the opportunity to provide targeted behavioural interventions that could decrease the incidence of HIV infections in the US military population; further studies are needed. [ABSTRACT FROM AUTHOR]
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- 2009
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5. The Modified Wilson Osteotomy for Hallux Valgus
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Jaishanker Js, White M, O'Connell Rj, and Keogh P
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Metatarsalgia ,medicine.medical_specialty ,Callosity ,biology ,business.industry ,medicine.medical_treatment ,Forefoot ,General Medicine ,medicine.disease ,Osteotomy ,biology.organism_classification ,Surgery ,body regions ,Valgus ,Orthopedic surgery ,medicine ,Deformity ,Orthopedics and Sports Medicine ,Displacement (orthopedic surgery) ,medicine.symptom ,business - Abstract
The modified Wilson osteotomy for hallux valgus is a double oblique osteotomy through the metatarsal shaft. The distal fragment is displaced laterally and plantarward. The lateral displacement corrects the varus position of the metatarsal, while the plantar displacement prevents the distal fragment from tilting dorsally into a metatarsus elevatus deformity that could produce metatarsalgia. Seventy-four cases of hallux valgus treated by this method were reviewed five years postoperatively. Sixty-six cases (89%) were graded as satisfactory and eight (11%) as unsatisfactory. Roentgenographic analysis in 61 cases showed the operation had reduced the hallux valgus angle by an average of 15 degrees and the intermetatarsal angle by an average of 4 degrees. The operation shortened the first metatarsal by an average of 5 mm. Although this caused callosities on the forefoot, it did not produce metatarsalgia. The operation is technically uncomplicated and yields a high percentage of satisfactory results.
- Published
- 1990
6. Morphine after combat injury and post-traumatic stress disorder.
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O'Connell RJ, Winstead JP, and Matthews JM
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- 2010
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7. Outcomes of highly active antiretroviral therapy in the context of universal access to healthcare: the U.S. Military HIV Natural History Study.
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Marconi VC, Grandits GA, Weintrob AC, Chun H, Landrum ML, Ganesan A, Okulicz JF, Crum-Cianflone N, O'Connell RJ, Lifson A, Wortmann GW, Agan BK, and Infectious Disease Clinical Research Program HIV Working Group
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- 2010
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8. Walking blood banks: screening blood in the battlefield.
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Rentas FJ, Lincoln DA, Jenkins CR, O'Connell RJ, and Gates RG
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- 2010
9. An investigation of bloodborne pathogen transmission due to multipatient sharing of insulin pens.
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Hakre S, Upshaw-Combs DR, Sanders-Buell EE, Scoville SL, Kuper JD, Jagodzinski LL, Bradfield AN, Davison DC, Callis WG, Owens AB, Michael NL, O'Connell RJ, Peel SA, Gardner JW, Thompson ND, Hu DJ, Kim JH, Tovanabutra S, Scott PT, and LaFon SG
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HEPATITIS B transmission , *HEPATITIS C transmission , *HIV infection transmission , *SUBCUTANEOUS injections , *DRUG delivery systems , *CROSS infection , *HEPATITIS B , *HEPATITIS C , *HIV infections , *HYPOGLYCEMIC agents , *INSULIN , *MILITARY hospitals , *RNA , *DISPOSABLE medical devices , *EQUIPMENT & supplies - Abstract
On January 30, 2009, nursing staff at a military hospital in Texas reported that single-patient use insulin pens were used on multiple patients. An investigation was initiated to determine if patient-to-patient bloodbome transmission occurred from the practice. Human immunodeficiency virus (HIV), hepatitis B virus (HBV), and hepatitis C virus (HCV) testing was offered to patients hospitalized from August 2007 to January 2009 and prescribed insulin pen injections. Virus from HCV-infected patients' sera was sequenced and compared for relatedness. An anonymous survey was administered to nurses. Of 2,113 patients prescribed insulin pen injections, 1,501 (71%) underwent testing; 6 (0.4%) were HIV positive, 6 (0.4%) were hepatitis B surface antigen positive, and 56 (3.7%) had HCV antibody. No viral sequences from 10 of 28 patients with newly diagnosed and 12 of 28 patients with preexisting HCV infection were closely related. Of 54 nurses surveyed, 74% reported being trained on insulin pen use, but 24% believed nurses used insulin pens on more than one patient. We found no clear evidence of bloodborne pathogen transmission. Training of hospital staff on correct use of insulin pens should be prioritized and their practices evaluated. Insulin pens should be more clearly labeled for single-patient use. [ABSTRACT FROM AUTHOR]
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- 2012
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10. Broadly neutralizing antibodies and monoclonal V2 antibodies derived from RV305 inhibit capture and replication of HIV-1.
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Kim J, Villar Z, Jobe O, Rerks-Ngarm S, Pitisuttithum P, Nitayaphan S, O'Connell RJ, Ake JA, Vasan S, Rao VB, and Rao M
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- Humans, HIV Infections virology, HIV Infections immunology, AIDS Vaccines immunology, HIV Envelope Protein gp120 immunology, Leukocytes, Mononuclear immunology, Leukocytes, Mononuclear virology, Broadly Neutralizing Antibodies immunology, HIV-1 immunology, Virus Replication, HIV Antibodies immunology, Antibodies, Neutralizing immunology, Antibodies, Monoclonal immunology
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An important approach to stopping the AIDS epidemic is the development of a vaccine that elicits antibodies that block virus capture, the initial interactions of HIV-1 with the target cells, and replication. We utilized a previously developed qRT-PCR-based assay to examine the effects of broadly neutralizing antibodies (bNAbs), plasma from vaccine trials, and monoclonal antibodies (mAbs) on virus capture and replication. A panel of bNAbs inhibited primary HIV-1 replication in PBMCs but not virus capture. Plasma from RV144 and RV305 trial vaccinees demonstrated inhibition of virus capture with the HIV-1 subtype prevalent in Thailand. Several RV305 derived V2-specific mAbs inhibited virus replication. One of these RV305 derived V2-specific mAbs inhibited both virus capture and replication, demonstrating that it is possible to elicit antibodies by vaccination that inhibit virus capture and replication. Induction of a combination of such antibodies may be the key to protection from HIV-1 acquisition., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Published by Elsevier Inc.)
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- 2024
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11. Opportunities for Enhanced Public Health Surveillance via Molecular Detection and Sequencing of Diverse Respiratory Viruses From Self-collected SARS-CoV-2 Antigen Test Swabs.
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Schmidt K, Pollett SD, Richard SA, Hogan V, Hone E, Rothenberg J, Tant R, Wayman M, Friend C, Thapa K, Ulomi L, Davies J, Michel A, Burgess TH, O'Connell RJ, Simons MP, Tilley DH, Fries AC, and Colombo RE
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We sequenced and genotyped severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), influenza, adenovirus, and respiratory syncytial virus, among other pathogens, from residual anterior nasal swabs self-collected for rapid SARS-CoV-2 antigen testing at the US Naval Academy. This is a key proof-of-concept for an acute respiratory infection surveillance approach, which could leverage prevalent SARS-CoV-2 antigen self-testing., Competing Interests: Potential conflicts of interest. All authors: no reported conflicts., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)
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- 2024
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12. Complete genome of the Medicago anthracnose fungus, Colletotrichum destructivum , reveals a mini-chromosome-like region within a core chromosome.
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Lapalu N, Simon A, Lu A, Plaumann PL, Amselem J, Pigné S, Auger A, Koch C, Dallery JF, and O'Connell RJ
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- Synteny, Phylogeny, Medicago sativa microbiology, Colletotrichum genetics, Colletotrichum pathogenicity, Genome, Fungal, Chromosomes, Fungal genetics, Plant Diseases microbiology
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Colletotrichum destructivum ( Cd ) is a phytopathogenic fungus causing significant economic losses on forage legume crops ( Medicago and Trifolium species) worldwide. To gain insights into the genetic basis of fungal virulence and host specificity, we sequenced the genome of an isolate from Medicago sativa using long-read (PacBio) technology. The resulting genome assembly has a total length of 51.7 Mb and comprises ten core chromosomes and two accessory chromosomes, all of which were sequenced from telomere to telomere. A total of 15, 631 gene models were predicted, including genes encoding potentially pathogenicity-related proteins such as candidate-secreted effectors (484), secondary metabolism key enzymes (110) and carbohydrate-active enzymes (619). Synteny analysis revealed extensive structural rearrangements in the genome of Cd relative to the closely related Brassicaceae pathogen, Colletotrichum higginsianum . In addition, a 1.2 Mb species-specific region was detected within the largest core chromosome of Cd that has all the characteristics of fungal accessory chromosomes (transposon-rich, gene-poor, distinct codon usage), providing evidence for exchange between these two genomic compartments. This region was also unique in having undergone extensive intra-chromosomal segmental duplications. Our findings provide insights into the evolution of accessory regions and possible mechanisms for generating genetic diversity in this asexual fungal pathogen.
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- 2024
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13. Infection of Alfalfa Cotyledons by an Incompatible but Not a Compatible Species of Colletotrichum Induces Formation of Paramural Bodies and Secretion of EVs.
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Ghosh S, Regmi KC, Stein B, Chen J, O'Connell RJ, and Innes RW
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Hemibiotrophic fungi in the genus Colletotrichum employ a biotrophic phase invading host epidermal cells followed by a necrotrophic phase spreading through neighboring mesophyll and epidermal cells. We used serial block face scanning electron microscopy (SBF-SEM) to compare subcellular changes that occur in Medicago sativa (alfalfa) cotyledons during infection by Colletotrichum destructivum (compatible on M. sativa ) and C. higginsianum (incompatible on M. sativa ). Three-dimensional reconstruction of serial images revealed that alfalfa epidermal cells infected with C. destructivum undergo massive cytological changes during the first 60 hours following inoculation to accommodate extensive intracellular hyphal growth. Conversely, inoculation with the incompatible species C. higginsianum resulted in no successful penetration events and frequent formation of papilla-like structures and cytoplasmic aggregates beneath attempted fungal penetration sites. Further analysis of the incompatible interaction using focused ion beam-scanning electron microcopy (FIB-SEM) revealed formation of large multivesicular body-like structures that appeared spherical and were not visible in compatible interactions. These structures often fused with the host plasma membrane, giving rise to paramural bodies that appeared to be releasing extracellular vesicles (EVs). Isolation of EVs from the apoplastic space of alfalfa leaves at 60h post inoculation showed significantly more vesicles secreted from alfalfa infected with incompatible fungus compared to compatible fungus, which in turn was more than produced by non-infected plants. Thus, the increased frequency of paramural bodies during incompatible interactions correlated with an increase in EV quantity in apoplastic wash fluids. Together, these results suggest that EVs and paramural bodies contribute to immunity during pathogen attack in alfalfa.
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- 2024
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14. Precision symptom phenotyping identifies early clinical and proteomic predictors of distinct COVID-19 sequelae.
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Epsi NJ, Chenoweth JG, Blair PW, Lindholm DA, Ganesan A, Lalani T, Smith A, Mody RM, Jones MU, Colombo RE, Colombo CJ, Schofield C, Ewers EC, Larson DT, Berjohn CM, Maves RC, Fries AC, Chang D, Wyatt A, Scher AI, Byrne C, Rusiecki J, Saunders DL, Livezey J, Malloy A, Bazan S, Maldonado C, Edwards MS, Mende K, Simons MP, O'Connell RJ, Tribble DR, Agan BK, Burgess TH, Pollett SD, and Richard SA
- Abstract
Background: Post-COVID conditions (PCC) are difficult to characterize, diagnose, predict, and treat due to overlapping symptoms and poorly understood pathology. Identifying inflammatory profiles may improve clinical prognostication and trial endpoints., Methods: 1,988 SARS-CoV-2 positive U.S. Military Health System beneficiaries with quantitative post-COVID symptom scores were included in this analysis. Among participants who reported moderate-to-severe symptoms on surveys collected 6-months post-SARS-CoV-2 infection, principal component analysis (PCA) followed by K-means clustering identified distinct clusters of symptoms., Results: Three symptom-based clusters were identified: a sensory cluster (loss of smell and/or taste), a fatigue/difficulty thinking cluster, and a difficulty breathing/exercise intolerance cluster. Individuals within the sensory cluster were all outpatients during their initial COVID-19 presentation. The difficulty breathing cluster had a higher likelihood of obesity and COVID-19 hospitalization compared to those with no/mild symptoms at 6-months post-infection. Multinomial regression linked early post-infection D-dimer and IL-1RA elevation to fatigue/difficulty thinking, and elevated ICAM-1 concentrations to sensory symptoms., Conclusions: We identified three distinct symptom-based PCC phenotypes with specific clinical risk factors and early post-infection inflammatory predictors. With further validation and characterization, this framework may allow more precise classification of PCC cases and potentially improve the diagnosis, prognostication, and treatment of PCC., (Published by Oxford University Press on behalf of Infectious Diseases Society of America 2024.)
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- 2024
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15. Three-Dimensional Ultrastructure of Arabidopsis Cotyledons Infected with Colletotrichum higginsianum .
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Regmi KC, Ghosh S, Koch B, Neumann U, Stein B, O'Connell RJ, and Innes RW
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- Host-Pathogen Interactions, Hyphae ultrastructure, Imaging, Three-Dimensional, Microscopy, Electron, Transmission, Colletotrichum physiology, Colletotrichum ultrastructure, Colletotrichum pathogenicity, Arabidopsis microbiology, Arabidopsis ultrastructure, Cotyledon microbiology, Cotyledon ultrastructure, Plant Diseases microbiology, Microscopy, Electron, Scanning
- Abstract
We used serial block-face scanning electron microscopy (SBF-SEM) to study the host-pathogen interface between Arabidopsis cotyledons and the hemibiotrophic fungus Colletotrichum higginsianum . By combining high-pressure freezing and freeze-substitution with SBF-SEM, followed by segmentation and reconstruction of the imaging volume using the freely accessible software IMOD, we created 3D models of the series of cytological events that occur during the Colletotrichum-Arabidopsis susceptible interaction. We found that the host cell membranes underwent massive expansion to accommodate the rapidly growing intracellular hypha. As the fungal infection proceeded from the biotrophic to the necrotrophic stage, the host cell membranes went through increasing levels of disintegration culminating in host cell death. Intriguingly, we documented autophagosomes in proximity to biotrophic hyphae using transmission electron microscopy (TEM) and a concurrent increase in autophagic flux between early to mid/late biotrophic phase of the infection process. Occasionally, we observed osmiophilic bodies in the vicinity of biotrophic hyphae using TEM only and near necrotrophic hyphae under both TEM and SBF-SEM. Overall, we established a method for obtaining serial SBF-SEM images, each with a lateral ( x-y ) pixel resolution of 10 nm and an axial ( z ) resolution of 40 nm, that can be reconstructed into interactive 3D models using the IMOD. Application of this method to the Colletotrichum-Arabidopsis pathosystem allowed us to more fully understand the spatial arrangement and morphological architecture of the fungal hyphae after they penetrate epidermal cells of Arabidopsis cotyledons and the cytological changes the host cell undergoes as the infection progresses toward necrotrophy. [Formula: see text] Copyright © 2024 The Author(s). This is an open access article distributed under the CC BY 4.0 International license., Competing Interests: The author(s) declare no conflict of interest.
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- 2024
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16. Immune and behavioral correlates of protection against symptomatic post-vaccination SARS-CoV-2 infection.
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Goguet E, Olsen CH, Meyer WA 3rd, Ansari S, Powers JH 3rd, Conner TL, Coggins SA, Wang W, Wang R, Illinik L, Sanchez Edwards M, Jackson-Thompson BM, Hollis-Perry M, Wang G, Alcorta Y, Wong MA, Saunders D, Mohammed R, Balogun B, Kobi P, Kosh L, Bishop-Lilly K, Cer RZ, Arnold CE, Voegtly LJ, Fitzpatrick M, Luquette AE, Malagon F, Ortega O, Parmelee E, Davies J, Lindrose AR, Haines-Hull H, Moser MS, Samuels EC, Rekedal MS, Graydon EK, Malloy AMW, Tribble DR, Burgess TH, Campbell W, Robinson S, Broder CC, O'Connell RJ, Weiss CD, Pollett S, Laing ED, and Mitre E
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- Adult, Humans, SARS-CoV-2, COVID-19 Vaccines, Antibodies, Viral, Immunoglobulin G, COVID-19 prevention & control
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Introduction: We sought to determine pre-infection correlates of protection against SARS-CoV-2 post-vaccine inzfections (PVI) acquired during the first Omicron wave in the United States., Methods: Serum and saliva samples from 176 vaccinated adults were collected from October to December of 2021, immediately before the Omicron wave, and assessed for SARS-CoV-2 Spike-specific IgG and IgA binding antibodies (bAb). Sera were also assessed for bAb using commercial assays, and for neutralization activity against several SARS-CoV-2 variants. PVI duration and severity, as well as risk and precautionary behaviors, were assessed by questionnaires., Results: Serum anti-Spike IgG levels assessed by research assay, neutralization titers against Omicron subvariants, and low home risk scores correlated with protection against PVIs after multivariable regression analysis. Commercial assays did not perform as well as research assay, likely due to their lower dynamic range., Discussion: In the 32 participants that developed PVI, anti-Spike IgG bAbs correlated with lower disease severity and shorter duration of illness., Competing Interests: SP, TB, and DT report that the USU IDCRP, a U.S. Department of Defense DoD Institution, and the HJF were funded under a Cooperative Research and Development Agreement to conduct an unrelated phase III COVID-19 monoclonal antibody immunoprophylaxis trial sponsored by AstraZeneca. The HJF, in support of the USU IDCRP, was funded by the DoD Joint Program Executive Office for Chemical, Biological, Radiological, and Nuclear Defense to augment the conduct of an unrelated phase III vaccine trial sponsored by AstraZeneca. Both trials were part of the USG COVID-19 response. Neither is related to the work presented here. Authors WM and SA were employed by the company Quest Diagnostics. Author JP was employed by company Leidos Biomedical Research, Inc. Authors LV, MF, AL and FM were employed by company Leidos. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Goguet, Olsen, Meyer, Ansari, Powers, Conner, Coggins, Wang, Wang, Illinik, Sanchez Edwards, Jackson-Thompson, Hollis-Perry, Wang, Alcorta, Wong, Saunders, Mohammed, Balogun, Kobi, Kosh, Bishop-Lilly, Cer, Arnold, Voegtly, Fitzpatrick, Luquette, Malagon, Ortega, Parmelee, Davies, Lindrose, Haines-Hull, Moser, Samuels, Rekedal, Graydon, Malloy, Tribble, Burgess, Campbell, Robinson, Broder, O’Connell, Weiss, Pollett, Laing and Mitre.)
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- 2024
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17. Innate immune cell activation after HIV-1 vaccine administration is associated with increased antibody production.
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N'guessan KF, Machmach K, Swafford I, Costanzo MC, Wieczorek L, Kim D, Akapirat S, Polonis VR, Pitisuttithum P, Nitayaphan S, Gurunathan S, Sinangil F, Chariyalertsak S, Ake JA, O'connell RJ, Vasan S, and Paquin-Proulx D
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- Adult, Humans, Antibody Formation, Immunity, Innate, Immunoglobulin G, Vaccination, Double-Blind Method, HIV Infections prevention & control, HIV Seropositivity, HIV-1, Natural Killer T-Cells
- Abstract
The RV144 Thai phase III clinical trial's canarypox-protein HIV vaccine regimen showed modest efficacy in reducing infection. We therefore sought to determine the effects of vaccine administration on innate cell activation and subsequent associations with vaccine-induced immune responses. RV306 was a randomized, double-blind clinical trial in HIV-uninfected Thai adults that tested delayed boosting following the RV144 regimen. PBMC collected from RV306 participants prior to and 3 days after the last boost were used to investigate innate immune cell activation. Our analysis showed an increase in CD38+ mucosal associated invariant T (MAIT) cells, CD38+ invariant natural killer T (iNKT) cells, CD38+ γδ T cells, CD38+, CD69+ and HLA-DR+ NK cells 3 days after vaccine administration. An increase in CD14-CD16+ non-classical monocytes and CD14+CD16+ intermediate monocytes accompanied by a decrease in CD14+CD16- classical monocytes was also associated with vaccine administration. Inclusion of ALVAC-HIV in the boost did not further increase MAIT, iNKT, γδ T, and NK cell activation or increase the proportion of non-classical monocytes. Additionally, NK cell activation 3 days after vaccination was positively associated with antibody titers of HIV Env-specific total IgG and IgG1. Vδ1 T cell activation 3 days after vaccine administration was associated with HIV Env-specific IgG3 titers. Finally, we observed trending associations between MAIT cell activation and Env-specific IgG3 titers and between NK cell activation and TH023 pseudovirus neutralization titers. Our study identifies a potential role for innate cells, specifically NK, MAIT, and γδ T cells, in promoting antibody responses following HIV-1 vaccine administration., Competing Interests: SG is an employee and shareholder of Sanofi Pasteur. FS is an employee of Global Solutions for Infectious Diseases. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 N’guessan, Machmach, Swafford, Costanzo, Wieczorek, Kim, Akapirat, Polonis, Pitisuttithum, Nitayaphan, Gurunathan, Sinangil, Chariyalertsak, Ake, O’connell, Vasan and Paquin-Proulx.)
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- 2024
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18. Decreased Self-reported Physical Fitness Following SARS-CoV-2 Infection and the Impact of Vaccine Boosters in a Cohort Study.
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Richard SA, Scher AI, Rusiecki J, Byrne C, Berjohn CM, Fries AC, Lalani T, Smith AG, Mody RM, Ganesan A, Huprikar N, Colombo RE, Colombo CJ, Schofield C, Lindholm DA, Mende K, Morris MJ, Jones MU, Flanagan R, Larson DT, Ewers EC, Bazan SE, Saunders D, Maves RC, Livezey J, Maldonado CJ, Edwards MS, Rozman JS, O'Connell RJ, Simons MP, Tribble DR, Agan BK, Burgess TH, and Pollett SD
- Abstract
Background: The long-term effects of coronavirus disease 2019 (COVID-19) on physical fitness are unclear, and the impact of vaccination on that relationship is uncertain., Methods: We compared survey responses in a 1-year study of US military service members with (n = 1923) and without (n = 1591) a history of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. We fit Poisson regression models to estimate the association between history of SARS-CoV-2 infection and fitness impairment, adjusting for time since infection, demographics, and baseline health., Results: The participants in this analysis were primarily young adults aged 18-39 years (75%), and 71.5% were male. Participants with a history of SARS-CoV-2 infection were more likely to report difficulty exercising (38.7% vs 18.4%; P < .01), difficulty performing daily activities (30.4% vs 12.7%; P < .01), and decreased fitness test (FT) scores (42.7% vs 26.2%; P < .01) than those without a history of infection. SARS-CoV-2-infected participants were at higher risk of these outcomes after adjusting for other factors (unvaccinated: exercising: adjusted risk ratio [aRR], 3.99; 95% CI, 3.36-4.73; activities: aRR, 5.02; 95% CI, 4.09-6.16; FT affected: aRR, 2.55; 95% CI, 2.19-2.98). Among SARS-CoV-2-positive participants, full vaccination before infection was associated with a lower risk of post-COVID-19 fitness impairment (fully vaccinated: exercise: aRR, 0.81; 95% CI, 0.70-0.95; activities: aRR, 0.76; 95% CI, 0.64-0.91; FT: aRR, 0.87; 95% CI, 0.76-1.00; boosted: exercise: aRR, 0.62; 95% CI, 0.51-0.74; activities: aRR, 0.52; 95% CI, 0.41-0.65; FT: aRR, 0.59; 95% CI, 0.49-0.70)., Conclusions: In this study of generally young, healthy military service members, SARS-CoV-2 infection was associated with lower self-reported fitness and exercise capacity; vaccination and boosting were associated with lower risk of self-reported fitness loss., Competing Interests: Potential conflicts of interest. 1045 S.D.P., T.H.B., J.S.R., and M.P.S. report that the Uniformed Services University (USU) Infectious Diseases Clinical Research Program (IDCRP), a US Department of Defense institution, and the HJF were funded under a Cooperative Research and Development Agreement to conduct an unrelated phase III COVID-19 monoclonal antibody immunoprophylaxis trial sponsored by AstraZeneca. The HJF, in support of the USU IDCRP, was funded by the Department of Defense Joint Program Executive Office for Chemical, Biological, Radiological, and Nuclear Defense to augment the conduct of an unrelated phase III vaccine trial sponsored by AstraZeneca. Both trials were part of the US Government COVID-19 response. Neither is related to the work presented here. R.C.M. receives research support paid to his institution from Sound Pharmaceuticals for an investigational COVID-19 therapeutic unrelated to the work presented here. M.J.M. is a paid speaker for Xarelto (Janssen Pharmaceuticals). All other authors report no potential conflicts., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)
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- 2023
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19. Yeast-based heterologous production of the Colletochlorin family of fungal secondary metabolites.
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Geistodt-Kiener A, Totozafy JC, Le Goff G, Vergne J, Sakai K, Ouazzani J, Mouille G, Viaud M, O'Connell RJ, and Dallery JF
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- Promoter Regions, Genetic, Saccharomyces cerevisiae genetics, Saccharomyces cerevisiae metabolism, Multigene Family genetics
- Abstract
Transcriptomic studies have revealed that fungal pathogens of plants activate the expression of numerous biosynthetic gene clusters (BGC) exclusively when in presence of a living host plant. The identification and structural elucidation of the corresponding secondary metabolites remain challenging. The aim was to develop a polycistronic system for heterologous expression of fungal BGCs in Saccharomyces cerevisiae. Here we adapted a polycistronic vector for efficient, seamless and cost-effective cloning of biosynthetic genes using in vivo assembly (also called transformation-assisted recombination) directly in Escherichia coli followed by heterologous expression in S. cerevisiae. Two vectors were generated with different auto-inducible yeast promoters and selection markers. The effectiveness of these vectors was validated with fluorescent proteins. As a proof-of-principle, we applied our approach to the Colletochlorin family of molecules. These polyketide secondary metabolites were known from the phytopathogenic fungus Colletotrichum higginsianum but had never been linked to their biosynthetic genes. Considering the requirement for a halogenase, and by applying comparative genomics, we identified a BGC putatively involved in the biosynthesis of Colletochlorins in C. higginsianum. Following the expression of those genes in S. cerevisiae, we could identify the presence of the precursor Orsellinic acid, Colletochlorins and their non-chlorinated counterparts, the Colletorins. In conclusion, the polycistronic vectors described herein were adapted for the host S. cerevisiae and allowed to link the Colletochlorin compound family to their corresponding biosynthetic genes. This system will now enable the production and purification of infection-specific secondary metabolites of fungal phytopathogens. More widely, this system could be applied to any fungal BGC of interest., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)
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- 2023
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20. Transmission of SARS-CoV-2 among recruits in a US Army training environment: a brief report.
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Hakre S, Maljkovic-Berry I, Hang J, Conte MA, Pollio AR, Fung CK, Gandhi J, Peel SA, Lidl GM, Huhtanen ME, Hall TL, Modjarrad K, Friberg HL, O'Connell RJ, and Scott PT
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- Humans, United States epidemiology, SARS-CoV-2, Quarantine, COVID-19 Testing, COVID-19 epidemiology, COVID-19 prevention & control, Military Personnel
- Abstract
Background: In 2020, preventive measures were implemented to mitigate the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) among 600-700 recruits arriving weekly at a basic combat training (BCT) facility in the southern United States. Trainees were sorted into companies and platoons (cocoons) at arrival, tested, quarantined for 14 days with daily temperature and respiratory-symptom monitoring and retested before release into larger groups for training where symptomatic testing was conducted. Nonpharmaceutical measures, such as masking, and social distancing, were maintained throughout quarantine and BCT. We assessed for SARS-CoV-2 transmission in the quarantine milieu., Methods: Nasopharyngeal (NP) swabs were collected at arrival and at the end of quarantine and blood specimens at both timepoints and at the end of BCT. Epidemiological characteristics were analyzed for transmission clusters identified from whole-genome sequencing of NP samples., Results: Among 1403 trainees enrolled from 25 August to 7 October 2020, epidemiological analysis identified three transmission clusters (n = 20 SARS-CoV-2 genomes) during quarantine, which spanned five different cocoons. However, SARS-CoV-2 incidence decreased from 2.7% during quarantine to 1.5% at the end of BCT; prevalence at arrival was 3.3%., Conclusions: These findings suggest layered SARS-CoV-2 mitigation measures implemented during quarantine minimized the risk of further transmission in BCT., (© The Author(s) 2023. Published by Oxford University Press on behalf of Faculty of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
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- 2023
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21. Additional boosting to the RV144 vaccine regimen increased Fc-mediated effector function magnitude but not durability.
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Shubin Z, Stanfield-Oakley S, Puangkaew J, Pitisutthithum P, Nitayaphan S, Gurunathan S, Sinangil F, Chariyalertsak S, Phanuphak N, Ake JA, O'Connell RJ, Vasan S, Akapirat S, Eller MA, Ferrari G, and Paquin-Proulx D
- Subjects
- Adult, Humans, Antibody Formation, HIV Antibodies, Immunoglobulin G, Vaccination, Double-Blind Method, AIDS Vaccines, HIV Infections prevention & control, HIV-1
- Abstract
Objectives: The RV144 vaccine trial resulted in a decreased risk of HIV acquisition that was associated with a nonneutralizing antibody response. The objective of this study was to determine the impact of an additional boost to the RV144 vaccine regimen on antibody effector function and durability., Design: RV306 was a randomized, double-blind late boosting of the RV144 prime-boost regimen in HIV-uninfected Thai adults (NCT01931358). This analysis included study participants who received the RV144 vaccine regimen and received no additional boost (group 1) or were boosted with ALVAC-HIV and AIDSVAX (group 2) or only AIDSVAX alone (group 3) 24 weeks after completing the RV144 series., Methods: Plasma samples from RV306 study participants were used to measure antibody-dependent cellular phagocytosis (ADCP), antibody-dependent neutrophil phagocytosis (ADNP), antibody-dependent complement deposition (ADCD), antibody-dependent cellular cytotoxicity (ADCC), trogocystosis, and gp120-specifc IgG subclasses., Results: Additional boosting increased the magnitude of all Fc-mediated effector functions 2 weeks following the additional boost compared with 2 weeks after completing the RV144 regimen. However, only trogocytosis remained higher 24-26 weeks after the last vaccination for the study participants receiving an additional boost compared with those that did not receive an additional boost. The additional boost increased IgG1 and IgG4 but decreased IgG3 gp-120 specific antibodies compared with 2 weeks after completing the RV144 regimen., Conclusion: Additional boosting of RV144 improved the magnitude but not the durability of some Fc-mediated effector functions that were associated with vaccine efficacy, with trogocytosis being the most durable.
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- 2023
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22. Unique HIV Risk Factors and Prevention Needs for Transgender Women and Cisgender Men Who Have Sex with Men in Bangkok, Thailand.
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Dear N, Francisco L, Pitisutthithum P, Nitayaphan S, Schuetz A, Wansom T, O'Connell RJ, Crowell TA, and Vasan S
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Background: Transgender women (TGW) and cisgender men who have sex with men (cis-MSM) are often grouped together as key populations. We evaluated behavioral and other characteristics that may distinguish TGW from cis-MSM in Bangkok, Thailand., Methods: We enrolled into an 18-month cohort cis-MSM and TGW 18-35 years of age without HIV, who reported anal intercourse plus condomless anal intercourse, multiple partners, transactional sex, and/or sexually transmitted infection. Robust multivariable Poisson regression was used to estimate adjusted prevalence ratios (aPRs) and confidence intervals (95% CIs) for associations with being a TGW. Among TGW, logistic regression with generalized estimating equations was used to estimate adjusted odds ratios (aORs) and 95% CIs for associations with taking hormones and having undergone gender affirmation surgery (GAS)., Results: From 2017 to 2019, 660 cis-MSM and 348 TGW were enrolled. Compared to cis-MSM, TGW were more likely to be attracted to mostly/only men (aPR: 3.79, 95% CI: 1.57-9.13), have a higher monthly income (aPR: 1.25, 95% CI: 1.04-1.50), have lived in their current residence for <1 year (aPR: 1.21, 95% CI: 1.01-1.46), have engaged in sex work (aPR: 1.48, 95% CI: 1.23-1.77), and be less likely to have ever undergone HIV testing (aPR: 0.83, 95% CI: 0.70-0.98). Among TGW, 149 (42.8%) were taking hormones and 33 (9.5%) had undergone GAS. GAS was more common among TGW who ever used methamphetamines (aOR: 1.55, 95% CI: 1.00-2.41) and those >23 years (18-20-year olds aOR: 0.17, 95% CI: 0.05-0.55; 21-23-year olds aOR: 0.36, 95% CI: 0.20-0.65)., Conclusions: TGW and cis-MSM are unique populations; tailored, gender-affirming, differentiated models of HIV prevention and care are necessary to address vulnerabilities specific to each key population., Competing Interests: No competing financial interests exist., (Copyright 2023, Mary Ann Liebert, Inc., publishers.)
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- 2023
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23. Viral vector delivered immunogen focuses HIV-1 antibody specificity and increases durability of the circulating antibody recall response.
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Williams LD, Shen X, Sawant SS, Akapirat S, Dahora LC, Tay MZ, Stanfield-Oakley S, Wills S, Goodman D, Tenney D, Spreng RL, Zhang L, Yates NL, Montefiori DC, Eller MA, Easterhoff D, Hope TJ, Rerks-Ngarm S, Pittisuttithum P, Nitayaphan S, Excler JL, Kim JH, Michael NL, Robb ML, O'Connell RJ, Karasavvas N, Vasan S, Ferrari G, and Tomaras GD
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- Humans, Antibody Formation, Immunization, Secondary methods, Antibody Specificity, HIV Antibodies, HIV Envelope Protein gp120, HIV-1, HIV Infections prevention & control, AIDS Vaccines, HIV Seropositivity
- Abstract
The modestly efficacious HIV-1 vaccine regimen (RV144) conferred 31% vaccine efficacy at 3 years following the four-shot immunization series, coupled with rapid waning of putative immune correlates of decreased infection risk. New strategies to increase magnitude and durability of protective immunity are critically needed. The RV305 HIV-1 clinical trial evaluated the immunological impact of a follow-up boost of HIV-1-uninfected RV144 recipients after 6-8 years with RV144 immunogens (ALVAC-HIV alone, AIDSVAX B/E gp120 alone, or ALVAC-HIV + AIDSVAX B/E gp120). Previous reports demonstrated that this regimen elicited higher binding, antibody Fc function, and cellular responses than the primary RV144 regimen. However, the impact of the canarypox viral vector in driving antibody specificity, breadth, durability and function is unknown. We performed a follow-up analysis of humoral responses elicited in RV305 to determine the impact of the different booster immunogens on HIV-1 epitope specificity, antibody subclass, isotype, and Fc effector functions. Importantly, we observed that the ALVAC vaccine component directly contributed to improved breadth, function, and durability of vaccine-elicited antibody responses. Extended boosts in RV305 increased circulating antibody concentration and coverage of heterologous HIV-1 strains by V1V2-specific antibodies above estimated protective levels observed in RV144. Antibody Fc effector functions, specifically antibody-dependent cellular cytotoxicity and phagocytosis, were boosted to higher levels than was achieved in RV144. V1V2 Env IgG3, a correlate of lower HIV-1 risk, was not increased; plasma Env IgA (specifically IgA1), a correlate of increased HIV-1 risk, was elevated. The quality of the circulating polyclonal antibody response changed with each booster immunization. Remarkably, the ALVAC-HIV booster immunogen induced antibody responses post-second boost, indicating that the viral vector immunogen can be utilized to selectively enhance immune correlates of decreased HIV-1 risk. These results reveal a complex dynamic of HIV-1 immunity post-vaccination that may require careful balancing to achieve protective immunity in the vaccinated population. Trial registration: RV305 clinical trial (ClinicalTrials.gov number, NCT01435135). ClinicalTrials.gov Identifier: NCT00223080., Competing Interests: The authors have declared that no competing interests exist., (Copyright: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.)
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- 2023
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24. ALVAC-HIV and AIDSVAX B/E vaccination induce improved immune responses compared with AIDSVAX B/E vaccination alone.
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Costanzo MC, Paquin-Proulx D, Schuetz A, Akapirat S, Shubin Z, Kim D, Wieczorek L, Polonis VR, Trinh HV, Rao M, Anenia H, Barrera MD, Boeckelman J, Nails B, Thapa P, Zemil M, Sacdalan C, Kroon E, Kaewboon B, Tipsuk S, Jongrakthaitae S, Gurunathan S, Sinangil F, Kim JH, Robb ML, Ake JA, O'Connell RJ, Pitisutthithum P, Nitayaphan S, Chariyalertsak S, Eller MA, Phanuphak N, and Vasan S
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- Humans, HIV Antibodies, Vaccination, Immunity, Humoral, HIV Infections prevention & control, HIV-1
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The RV144 phase III vaccine trial demonstrated that ALVAC-HIV and AIDSVAX B/E administration over 6 months resulted in 31% efficacy in preventing HIV acquisition, while administration of AIDSVAX B/E alone in both VAX003 and VAX004 studies failed to show efficacy. In this study, we aimed to understand the impact of ALVAC-HIV on the development of cellular, humoral, and functional immune responses compared to the administration of AIDSVAX B/E alone. ALVAC-HIV in combination with 3 doses of AIDSVAX B/E significantly increased CD4+ HIV-specific T cell responses, polyfunctionality, and proliferation compared with 3 doses of AIDSVAX B/E alone. Additionally, Env-specific plasmablasts and A244-specific memory B cells were identified with a significantly higher magnitude in the group that received ALVAC-HIV. Subsequently, data revealed increased magnitude of plasma IgG binding to and avidity for HIV Env in participants who received ALVAC-HIV compared with 3 doses of AIDSVAX B/E alone. Lastly, levels of the Fc-mediated effector functions antibody-dependent cellular cytotoxicity, NK cell activation, and trogocytosis were significantly increased in participants who received ALVAC-HIV compared with those receiving AIDSVAX B/E alone. Taken together, these results suggest that ALVAC-HIV plays an essential role in developing cellular and humoral immune responses to protein-boosted regimens relative to protein alone.
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- 2023
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25. CusProSe: a customizable protein annotation software with an application to the prediction of fungal secondary metabolism genes.
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Oliveira L, Chevrollier N, Dallery JF, O'Connell RJ, Lebrun MH, Viaud M, and Lespinet O
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- Amino Acid Sequence, Peptide Synthases genetics, Polyketide Synthases genetics, Tryptophan Synthase genetics, Conserved Sequence genetics, Molecular Sequence Annotation methods, Secondary Metabolism genetics, Software, Fungi enzymology, Fungi genetics
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We report here a new application, CustomProteinSearch (CusProSe), whose purpose is to help users to search for proteins of interest based on their domain composition. The application is customizable. It consists of two independent tools, IterHMMBuild and ProSeCDA. IterHMMBuild allows the iterative construction of Hidden Markov Model (HMM) profiles for conserved domains of selected protein sequences, while ProSeCDA scans a proteome of interest against an HMM profile database, and annotates identified proteins using user-defined rules. CusProSe was successfully used to identify, in fungal genomes, genes encoding key enzyme families involved in secondary metabolism, such as polyketide synthases (PKS), non-ribosomal peptide synthetases (NRPS), hybrid PKS-NRPS and dimethylallyl tryptophan synthases (DMATS), as well as to characterize distinct terpene synthases (TS) sub-families. The highly configurable characteristics of this application makes it a generic tool, which allows the user to refine the function of predicted proteins, to extend detection to new enzymes families, and may also be applied to biological systems other than fungi and to other proteins than those involved in secondary metabolism., (© 2023. The Author(s).)
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- 2023
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26. Cross-Cutting Lessons Learned During the COVID-19 Pandemic-the Walter Reed Army Institute of Research Experience.
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Osgood JM, Froude JW, Daye SP, Cabrera OA, Scherer MR, Capaldi VF, Michael NL, Moon JE, Lombardini ED, Peel SA, Peterson KP, Teyhen DS, Murray CK, and O'Connell RJ
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- Humans, Pandemics prevention & control, COVID-19 Vaccines, Academies and Institutes, COVID-19, Military Personnel
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Introduction: At the start of the coronavirus disease 2019 (COVID-19) pandemic, Walter Reed Army Institute of Research (WRAIR) mobilized to rapidly conduct medical research to detect, prevent, and treat the disease in order to minimize the impact of the pandemic on the health and readiness of U.S. Forces. WRAIR's major efforts included the development of the Department of Defense (DoD) COVID-19 vaccine candidate, researching novel drug therapies and monoclonal antibodies, refining and scaling-up diagnostic capabilities, evaluating the impact of viral diversity, assessing the behavioral health of Soldiers, supporting U.S. DoD operational forces overseas, and providing myriad assistance to allied nations. WRAIR personnel have also filled key roles within the whole of government response to the pandemic. WRAIR had to overcome major pandemic-related operational challenges in order to quickly execute a multimillion-dollar portfolio of COVID-19 research. Consequently, the organization learned lessons that could benefit other leaders of medical research organizations preparing for the next pandemic., Materials and Methods: We identified lessons learned using a qualitative thematic analysis of 76 observation/recommendation pairs from across the organization. These lessons learned were organized under the Army's four pillars of readiness (staffing, training, equipping, and leadership development). To this framework, we added organizing and leading to best capture our experiences within the context of pandemic response., Results: The major lessons learned for organizing were: (1) the pandemic created a need to rapidly pivot to new scientific priorities; (2) necessary health and safety precautions disrupted the flow of normal science and put programs at risk of missing milestones; (3) relationships with partners and allies facilitated medical diplomacy and advancement of U.S. national military and economic goals; and (4) a successful response required interoperability within and across multiple organizations. For equipping: (1) existing infrastructure lacked sufficient capacity and technical capability to allow immediate countermeasure development; (2) critical supply chains were strained; and (3) critical information system function and capacity were suddenly insufficient under maximum remote work. For staffing and training: (1) successful telework required rapid shifts in management, engagement, and accountability methods; and (2) organizational policies and processes had to adapt quickly to support remote staffing. For leading and leadership development (1) engaged, hopeful, and empathetic leadership made a difference; and (2) the workforce benefitted from concerted leadership communication that created a shared understanding of shifting priorities as well as new processes and procedures., Conclusions: An effective pandemic response requires comprehensive institutional preparedness that facilitates flexibility and surge capacity. The single most important action leaders of medical research organizations can take to prepare for the next pandemic is to develop a quick-reaction force that would activate under prespecified criteria to manage reprioritization of all science and support activities to address pandemic response priorities at the velocity of relevance., (Published by Oxford University Press on behalf of the Association of Military Surgeons of the United States 2021. This work is written by (a) US Government employee(s) and is in the public domain in the US.)
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- 2023
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27. Virological and Serological Assessment of US Army Trainees Isolated for Coronavirus Disease 2019.
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Hakre S, Lakhal-Naouar I, King DB, Burns JL, Jackson KN, Krauss SW, Chandrasekaran P, McCauley MD, Ober Shepherd BL, McHenry S, Bianchi EJ, Ouellette J, Darden JM, Sanborn AD, Daye SP, Kwon PO, Stubbs J, Brigantti CL, Hall TL, Beagle MH, Pieri JA, Frambes TR, O'Connell RJ, Modjarrad K, Murray CK, Jagodzinski LL, Scott PT, and Peel SA
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- Humans, SARS-CoV-2, COVID-19 Testing, Sensitivity and Specificity, RNA, RNA, Viral genetics, Reverse Transcriptase Polymerase Chain Reaction, COVID-19 diagnosis
- Abstract
Background: Laboratory screening for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a key mitigation measure to avoid the spread of infection among recruits starting basic combat training in a congregate setting. Because viral nucleic acid can be detected persistently after recovery, we evaluated other laboratory markers to distinguish recruits who could proceed with training from those who were infected., Methods: Recruits isolated for coronavirus disease 2019 (COVID-19) were serially tested for SARS-CoV-2 subgenomic ribonucleic acid (sgRNA), and viral load (VL) by reverse-transcriptase polymerase chain reaction (RT-PCR), and for anti- SARS-CoV-2. Cluster and quadratic discriminant analyses of results were performed., Results: Among 229 recruits isolated for COVID-19, those with a RT-PCR cycle threshold >30.49 (sensitivity 95%, specificity 96%) or having sgRNA log10 RNA copies/mL <3.09 (sensitivity and specificity 96%) at entry into isolation were likely SARS-CoV-2 uninfected. Viral load >4.58 log10 RNA copies/mL or anti-SARS-CoV-2 signal-to-cutoff ratio <1.38 (VL: sensitivity and specificity 93%; anti-SARS-CoV-2: sensitivity 83%, specificity 79%) had comparatively lower sensitivity and specificity when used alone for discrimination of infected from uninfected., Conclusions: Orthogonal laboratory assays used in combination with RT-PCR may have utility in determining SARS-CoV-2 infection status for decisions regarding isolation., Competing Interests: Potential conflicts of interest . All authors: No reported conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)
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- 2022
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28. HLA-B∗46 associates with rapid HIV disease progression in Asian cohorts and prominent differences in NK cell phenotype.
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Li SS, Hickey A, Shangguan S, Ehrenberg PK, Geretz A, Butler L, Kundu G, Apps R, Creegan M, Clifford RJ, Pinyakorn S, Eller LA, Luechai P, Gilbert PB, Holtz TH, Chitwarakorn A, Sacdalan C, Kroon E, Phanuphak N, de Souza M, Ananworanich J, O'Connell RJ, Robb ML, Michael NL, Vasan S, and Thomas R
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- Disease Progression, Epitopes, Humans, Killer Cells, Natural, Phenotype, HIV Infections metabolism, HLA-B Antigens genetics, HLA-B Antigens metabolism
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Human leukocyte antigen (HLA) alleles have been linked to HIV disease progression and attributed to differences in cytotoxic T lymphocyte (CTL) epitope representation. These findings are largely based on treatment-naive individuals of European and African ancestry. We assessed HLA associations with HIV-1 outcomes in 1,318 individuals from Thailand and found HLA-B∗46:01 (B∗46) associated with accelerated disease in three independent cohorts. B∗46 had no detectable effect on HIV-specific T cell responses, but this allele is unusual in containing an HLA-C epitope that binds inhibitory receptors on natural killer (NK) cells. Unbiased transcriptomic screens showed increased NK cell activation in people with HIV, without B∗46, and simultaneous single-cell profiling of surface proteins and transcriptomes revealed a NK cell subset primed for increased responses in the absence of B∗46. These findings support a role for NK cells in HIV pathogenesis, revealed by the unique properties of the B∗46 allele common only in Asia., Competing Interests: Declaration of interests The authors declare no competing interests., (Published by Elsevier Inc.)
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- 2022
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29. Factors associated with testing for HIV and other sexually transmitted infections in men who have sex with men and transgender women in Bangkok, Thailand.
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Crowell TA, Nitayaphan S, Sirisopana N, Wansom T, Kitsiripornchai S, Francisco L, Li Q, Dear N, O'Connell RJ, Pitisuttithum P, and Vasan S
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- Adult, Cross-Sectional Studies, Female, Homosexuality, Male, Humans, Male, Sexual Behavior, Thailand epidemiology, Young Adult, HIV Infections diagnosis, HIV Infections epidemiology, HIV Infections therapy, Sexual and Gender Minorities, Sexually Transmitted Diseases diagnosis, Sexually Transmitted Diseases epidemiology, Transgender Persons
- Abstract
Background: Routine screening for HIV and other sexually transmitted infections (STIs) facilitates early diagnosis and treatment, thereby preventing morbidity and onward transmission. We estimated the prevalence of prior HIV/STI testing among men who have sex with men (MSM) and transgender women (TGW) in Bangkok, Thailand, and identified factors associated with prior testing., Methods: Cross-sectional analyses were performed using data collected at enrollment into an HIV incidence cohort. From April to October 2017, MSM and TGW were enrolled if they were aged 18-35 years, reported anal intercourse with a male or TGW partner, and reported behavioral vulnerability to HIV. Participants answered questions about demographics, sexual behaviors, and lifetime HIV/STI testing history. Multivariable robust Poisson regression was used to estimate risk ratios (RRs) and 95% confidence intervals (CIs) for factors potentially associated with prior testing., Results: Among 1,014 participants, 348 (34.3%) were TGW and the median age was 21.6 (interquartile range 20.0-24.8) years. Prior testing for HIV was reported by 421 (41.5%) and for other STIs by 268 (26.4%). HIV testing was more common among participants aged ≥ 22 years (RR 1.37 [95% CI 1.13-1.67]), with college education as compared to secondary or less (RR 1.37 [95% CI 1.08-1.72]), and who met male sexual partners online (RR 1.52 [95% CI 1.24-1.85]), but lower among participants attracted to both men and women as compared to men only (RR 0.64 [95% CI 0.51-0.81]) and who met male sexual partners in bars (RR 0.83 [95% CI 0.72-0.97]). Similar associations were observed with prior testing for other STIs, including increased testing among participants with college education (RR 1.52 [95% CI 1.11-2.09]) and who met male sexual partners online (RR 1.73 [95% CI 1.30-2.31]), but lower among participants attracted to both men and women (RR 0.70 [95% CI 0.51-0.96]) and who met male sexual partners in bars (RR 0.67 [95% CI 0.54-0.83])., Conclusions: Despite behavioral vulnerability, prior testing for HIV and other STIs was uncommon. Online engagement strategies may be effectively reaching Thai MSM and TGW who meet sexual partners online, but new interventions are needed to encourage testing among younger, less educated, and bisexual MSM and TGW., (© 2022. The Author(s).)
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- 2022
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30. The development of extracellular vesicle markers for the fungal phytopathogen Colletotrichum higginsianum.
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Rutter BD, Chu TT, Dallery JF, Zajt KK, O'Connell RJ, and Innes RW
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- Plant Diseases microbiology, Arabidopsis microbiology, Arabidopsis Proteins metabolism, Colletotrichum, Extracellular Vesicles
- Abstract
Fungal phytopathogens secrete extracellular vesicles (EVs) associated with enzymes and phytotoxic metabolites. While these vesicles are thought to promote infection, defining the true contents and functions of fungal EVs, as well as suitable protein markers, is an ongoing process. To expand our understanding of fungal EVs and their possible roles during infection, we purified EVs from the hemibiotrophic phytopathogen Colletotrichum higginsianum, the causative agent of anthracnose disease in multiple plant species, including Arabidopsis thaliana. EVs were purified in large numbers from the supernatant of protoplasts but not the supernatant of intact mycelial cultures. We purified two separate populations of EVs, each associated with over 700 detected proteins, including proteins involved in vesicle transport, cell wall biogenesis and the synthesis of secondary metabolites. We selected two SNARE proteins (Snc1 and Sso2) and one 14-3-3 protein (Bmh1) as potential EV markers and generated transgenic strains expressing fluorescent fusions. Each marker was confirmed to be protected inside EVs. Fluorescence microscopy was used to examine the localization of each marker during infection on Arabidopsis leaves. These findings further our understanding of EVs in fungal phytopathogens and will help build an experimental system to study EV interkingdom communication between plants and fungi., (© 2022 The Authors. Journal of Extracellular Vesicles published by Wiley Periodicals, LLC on behalf of the International Society for Extracellular Vesicles.)
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- 2022
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31. Clinical signs and symptoms associated with acute HIV infection from an intensely monitored cohort on 2 continents.
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Letizia AG, Eller LA, Bryant C, Dawson P, Nitayaphan S, Kosgei J, Kibuuka H, Maganga L, Kroon E, Sriplienchan S, Michael NL, O'Connell RJ, Kim JH, and Robb ML
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- Algorithms, Cohort Studies, Female, Humans, Kenya epidemiology, Male, Risk Factors, Sensitivity and Specificity, Tanzania epidemiology, Thailand epidemiology, Uganda epidemiology, HIV Infections complications, HIV Infections diagnosis, HIV Infections epidemiology
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Abstract: Define the clinical presentation of acute human immunodeficiency virus infection (AHI) among men and women from 2 continents to create a clinical scoring algorithm.Comparison of incident sign and symptom between those with and without AHI.At-risk human immunodeficiency virus (HIV) negative men and women in Thailand, Kenya, Tanzania, and Uganda underwent twice-weekly testing for HIV. Newly diagnosed participants were evaluated twice weekly for 21 days after infection.Of the 3345 participants enrolled, 56 African females and 36 biological males from Thailand were diagnosed with AHI. Four hundred fifty-two of their encounters were compared to 18,281 HIV negative encounters. Due to a high degree of heterogeneity among incident symptoms, 2 unique subgroups based upon geography and sex were created. Among Thai males, the signs and symptoms with the greatest odds ratio (OR) between AHI and uninfected participants were nausea (OR 16.0, 95% confidence interval [CI] 3.9-60.2, P < .001) and lymphatic abnormalities (OR 11.8, 95% CI 4.2-49.0, P < .001); and among African females were pain behind the eyes (OR 44.4, 95% CI 12.0-158.0, P < .0001) and fatigue (OR 22.7, 95% CI 11.3-44.3, P < .001). The Thai male scoring algorithm had a 66% sensitivity and 84% specificity while the African female algorithm had a sensitivity of 27% and specificity of 98%.The different incident symptoms during AHI necessitated creating 2 different scoring algorithms that can guide diagnostic testing among a particular sex in the appropriate geographic setting. Further research on risk exposure, sex, and demographic specific models is warranted., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)
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- 2022
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32. Plant SYP12 syntaxins mediate an evolutionarily conserved general immunity to filamentous pathogens.
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Rubiato HM, Liu M, O'Connell RJ, and Nielsen ME
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- Arabidopsis genetics, Arabidopsis Proteins genetics, Colletotrichum, Evolution, Molecular, Gene Expression Regulation, Plant, Genetic Predisposition to Disease, Marchantia, Phytophthora infestans, Plant Diseases genetics, Qa-SNARE Proteins genetics, Arabidopsis metabolism, Arabidopsis Proteins metabolism, Plant Diseases immunology, Plant Diseases microbiology, Plant Immunity genetics, Qa-SNARE Proteins metabolism
- Abstract
Filamentous fungal and oomycete plant pathogens that invade by direct penetration through the leaf epidermal cell wall cause devastating plant diseases. Plant preinvasive immunity toward nonadapted filamentous pathogens is highly effective and durable. Pre- and postinvasive immunity correlates with the formation of evolutionarily conserved and cell-autonomous cell wall structures, named papillae and encasements, respectively. Yet, it is still unresolved how papillae/encasements are formed and whether these defense structures prevent pathogen ingress. Here, we show that in Arabidopsis the two closely related members of the SYP12 clade of syntaxins (PEN1 and SYP122) are indispensable for the formation of papillae and encasements. Moreover, loss-of-function mutants were hampered in preinvasive immunity toward a range of phylogenetically distant nonadapted filamentous pathogens, underlining the versatility and efficacy of this defense. Complementation studies using SYP12s from the early diverging land plant, Marchantia polymorpha , showed that the SYP12 clade immunity function has survived 470 million years of independent evolution. These results suggest that ancestral land plants evolved the SYP12 clade to provide a broad and durable preinvasive immunity to facilitate their life on land and pave the way to a better understanding of how adapted pathogens overcome this ubiquitous plant defense strategy., Competing Interests: HR, ML, RO, MN No competing interests declared, (© 2022, Rubiato et al.)
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- 2022
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33. Identification of Copper-Containing Oxidoreductases in the Secretomes of Three Colletotrichum Species with a Focus on Copper Radical Oxidases for the Biocatalytic Production of Fatty Aldehydes.
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Ribeaucourt D, Saker S, Navarro D, Bissaro B, Drula E, Correia LO, Haon M, Grisel S, Lapalu N, Henrissat B, O'Connell RJ, Lambert F, Lafond M, and Berrin JG
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- Alcohols, Aldehydes, Fungal Proteins genetics, Fungal Proteins metabolism, Oxidoreductases genetics, Secretome, Colletotrichum enzymology, Colletotrichum genetics, Copper, Fatty Acids biosynthesis, Oxidoreductases metabolism
- Abstract
Copper radical alcohol oxidases (CRO-AlcOx), which have been recently discovered among fungal phytopathogens, are attractive for the production of fragrant fatty aldehydes. With the initial objective to investigate the secretion of CRO-AlcOx by natural fungal strains, we undertook time course analyses of the secretomes of three Colletotrichum species (C. graminicola, C. tabacum, and C. destructivum) using proteomics. The addition of a copper-manganese-ethanol mixture in the absence of any plant-biomass mimicking compounds to Colletotrichum cultures unexpectedly induced the secretion of up to 400 proteins, 29 to 52% of which were carbohydrate-active enzymes (CAZymes), including a wide diversity of copper-containing oxidoreductases from the auxiliary activities (AA) class (AA1, AA3, AA5, AA7, AA9, AA11, AA12, AA13, and AA16). Under these specific conditions, while a CRO-glyoxal oxidase from the AA5_1 subfamily was among the most abundantly secreted proteins, the targeted AA5_2 CRO-AlcOx were secreted at lower levels, suggesting heterologous expression as a more promising strategy for CRO-AlcOx production and utilization. C. tabacum and C. destructivum CRO-AlcOx were thus expressed in Pichia pastoris, and their preference toward both aromatic and aliphatic primary alcohols was assessed. The CRO-AlcOx from C. destructivum was further investigated in applied settings, revealing a full conversion of C
6 and C8 alcohols into their corresponding fragrant aldehydes. IMPORTANCE In the context of the industrial shift toward greener processes, the biocatalytic production of aldehydes is of utmost interest owing to their importance for their use as flavor and fragrance ingredients. Copper radical alcohol oxidases (CRO-AlcOx) have the potential to become platform enzymes for the oxidation of alcohols to aldehydes. However, the secretion of CRO-AlcOx by natural fungal strains has never been explored, while the use of crude fungal secretomes is an appealing approach for industrial applications to alleviate various costs pertaining to biocatalyst production. While investigating this primary objective, the secretomics studies revealed unexpected results showing that under the oxidative stress conditions we probed, Colletotrichum species can secrete a broad diversity of copper-containing enzymes (laccases, sugar oxidoreductases, and lytic polysaccharide monooxygenases [LPMOs]) usually assigned to "plant cell wall degradation," despite the absence of any plant-biomass mimicking compound. However, in these conditions, only small amounts of CRO-AlcOx were secreted, pointing out recombinant expression as the most promising path for their biocatalytic application.- Published
- 2021
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34. Risk Factors for HIV sero-conversion in a high incidence cohort of men who have sex with men and transgender women in Bangkok, Thailand.
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Wansom T, Muangnoicharoen S, Nitayaphan S, Kitsiripornchai S, Crowell TA, Francisco L, Gilbert P, Rwakasyaguri D, Dhitavat J, Li Q, King D, Robb ML, Smith K, Heger EA, Akapirat S, Pitisuttithum P, O'Connell RJ, and Vasan S
- Abstract
Background: We measured Human Immunodeficiency (HIV) incidence, retention, and assessed risk factors for seroconversion among two previously unreported cohorts of men who have sex with men (MSM) and Transgender Women (TGW) in Bangkok, Thailand between 2017 and 2019., Methods: We conducted an 18-month prospective cohort study of HIV-uninfected Thai cisgender men and TGW aged between 18 and 35 years who reported sex with men in the past six months and at least one additional risk factor for HIV infection. HIV and syphilis testing and computer-based behavioral questionnaires were administered at each visit. We utilized Poisson regression to calculate HIV incidence rates. A survival random forest model identified the most predictive risk factors for HIV sero-conversion and then used in a survival regression tree model to elucidate hazard ratios for individuals with groups of selected risk factors. Cox proportional hazards (pH) regression evaluated the strength of association between individual covariates and risk of sero-conversion., Findings: From April 2017-October 2019, 1,184 participants were screened, 167 were found ineligible, and 1,017 enrolled. Over the 18-month study, visit retention was 93·4% (95% CI 91·6%-94·8%) and HIV incidence was 3·73 per 100 person-years (95% CI 2·79-5·87). Utilizing survival regression tree modeling, those who were 18-20 years of age, reported sexual attraction to mostly or only men, and had five or more lifetime sexual partners were 4·9 times more likely to seroconvert compared to other cohort participants. Factors associated with HIV incidence utilizing Cox pH regression included sexual attraction to mostly or only men (adjusted hazard ratio (aHR) 14·9 (95% CI 20·1-107·9), younger age (18-19 years, aHR 10·88 (95% CI 4·12-28·7), five or greater lifetime sexual partners (aHR 2·0, 95%CI 1·1-3·6), inconsistent condom use with casual partners (aHR 2·43, 95% CI 1·3-4·5), and prior HIV testing (adjusted HR 2·0, 95% CI 1·1-3·5)., Interpretation: Interpretation HIV incidence remains high among Bangkok-based MSM and TGW. These key populations expressed high interest in participating in efficacy evaluation of future prevention strategies and had high retention in this 18 month study., Funding: Funding US National Institute of Allergy and Infectious Diseases (NIAID), Division of AIDS Interagency Agreements (DAIDS) and U.S. Department of the Army., Competing Interests: None., (© 2021 Henry M. Jackson Foundation for the Advancement of Military Medicine.)
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- 2021
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35. RV144 vaccine imprinting constrained HIV-1 evolution following breakthrough infection.
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Lewitus E, Sanders-Buell E, Bose M, O'Sullivan AM, Poltavee K, Li Y, Bai H, Mdluli T, Donofrio G, Slike B, Zhao H, Wong K, Chen L, Miller S, Lee J, Ahani B, Lepore S, Muhammad S, Grande R, Tran U, Dussupt V, Mendez-Rivera L, Nitayaphan S, Kaewkungwal J, Pitisuttithum P, Rerks-Ngarm S, O'Connell RJ, Janes H, Gilbert PB, Gramzinski R, Vasan S, Robb ML, Michael NL, Krebs SJ, Herbeck JT, Edlefsen PT, Mullins JI, Kim JH, Tovanabutra S, and Rolland M
- Abstract
The scale of the HIV-1 epidemic underscores the need for a vaccine. The multitude of circulating HIV-1 strains together with HIV-1's high evolvability hints that HIV-1 could adapt to a future vaccine. Here, we wanted to investigate the effect of vaccination on the evolution of the virus post-breakthrough infection. We analyzed 2,635 HIV-1 env sequences sampled up to a year post-diagnosis from 110 vaccine and placebo participants who became infected in the RV144 vaccine efficacy trial. We showed that the Env signature sites that were previously identified to distinguish vaccine and placebo participants were maintained over time. In addition, fewer sites were under diversifying selection in the vaccine group than in the placebo group. These results indicate that HIV-1 would possibly adapt to a vaccine upon its roll-out., (© The Author(s) 2021. Published by Oxford University Press.)
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- 2021
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36. Efficacy of a Broadly Neutralizing SARS-CoV-2 Ferritin Nanoparticle Vaccine in Nonhuman Primates.
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Joyce MG, King HAD, Naouar IE, Ahmed A, Peachman KK, Cincotta CM, Subra C, Chen RE, Thomas PV, Chen WH, Sankhala RS, Hajduczki A, Martinez EJ, Peterson CE, Chang WC, Choe M, Smith C, Lee PJ, Headley JA, Taddese MG, Elyard HA, Cook A, Anderson A, McGuckin-Wuertz K, Dong M, Swafford I, Case JB, Currier JR, Lal KG, O'Connell RJ, Molnar S, Nair MS, Dussupt V, Daye SP, Zeng X, Barkei EK, Staples HM, Alfson K, Carrion R, Krebs SJ, Paquin-Proulx D, Karasavva N, Polonis VR, Jagodzinski LL, Amare MF, Vasan S, Scott PT, Huang Y, Ho DD, de Val N, Diamond MS, Lewis MG, Rao M, Matyas GR, Gromowski GD, Peel SA, Michael NL, Bolton DL, and Modjarrad K
- Abstract
The emergence of novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants stresses the continued need for next-generation vaccines that confer broad protection against coronavirus disease 2019 (COVID-19). We developed and evaluated an adjuvanted SARS-CoV-2 Spike Ferritin Nanoparticle (SpFN) vaccine in nonhuman primates (NHPs). High-dose (50 µ g) SpFN vaccine, given twice within a 28 day interval, induced a Th1-biased CD4 T cell helper response and a peak neutralizing antibody geometric mean titer of 52,773 against wild-type virus, with activity against SARS-CoV-1 and minimal decrement against variants of concern. Vaccinated animals mounted an anamnestic response upon high-dose SARS-CoV-2 respiratory challenge that translated into rapid elimination of replicating virus in their upper and lower airways and lung parenchyma. SpFN's potent and broad immunogenicity profile and resulting efficacy in NHPs supports its utility as a candidate platform for SARS-like betacoronaviruses., One-Sentence Summary: A SARS-CoV-2 Spike protein ferritin nanoparticle vaccine, co-formulated with a liposomal adjuvant, elicits broad neutralizing antibody responses that exceed those observed for other major vaccines and rapidly protects against respiratory infection and disease in the upper and lower airways and lung tissue of nonhuman primates.
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- 2021
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37. Protein-based, but not viral vector alone, HIV vaccine boosting drives an IgG1-biased polyfunctional humoral immune response.
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Fischinger S, Shin S, Boudreau CM, Ackerman M, Rerks-Ngarm S, Pitisuttithum P, Nitayaphan S, Kim JH, Robb ML, Michael NL, O'Connell RJ, Vasan S, Streeck H, and Alter G
- Subjects
- Antibody-Dependent Cell Cytotoxicity immunology, HIV Antigens immunology, HIV Infections immunology, Humans, Immunity, Humoral immunology, Immunization, Secondary methods, AIDS Vaccines immunology, HIV Antibodies immunology, HIV Infections prevention & control, HIV-1 immunology
- Abstract
The RV144 HIV-1 vaccine trial results showed moderate reduction in viral infections among vaccinees as well as induction of antibody-dependent cellular cytotoxicity and vaccine-specific IgG and IgG3 responses directed at variable loop regions 1 and 2 of the HIV envelope protein. However, with the recent failure of the HVTN 702 clinical trial, comprehensive profiling of humoral immune responses may provide insight for these disappointing results. One of the changes included in the HVTN 702 study was the addition of a late boost, aimed at augmenting peak immunity and durability. The companion vaccine trial RV305 was designed to permit the evaluation of the immunologic impact of late boosting with either the boosting protein antigen alone, the canarypox viral vector ALVAC alone, or a combination of both. Although previous data showed elevated levels of IgG antibodies in both boosting arms, regardless of ALVAC-HIV vector incorporation, the effect on shaping antibody effector function remains unclear. Thus, here we analyzed the antibody and functional profile induced by RV305 boosting regimens and found that although IgG1 levels increased in both arms that included protein boosting, IgG3 levels were reduced compared with the original RV144 vaccine strategy. Most functional responses increased upon protein boosting, regardless of the viral vector-priming agent incorporation. These data suggest that the addition of a late protein boost alone is sufficient to increase functionally potent vaccine-specific antibodies previously associated with reduced risk of infection with HIV.
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- 2020
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38. Inhibition of jasmonate-mediated plant defences by the fungal metabolite higginsianin B.
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Dallery JF, Zimmer M, Halder V, Suliman M, Pigné S, Le Goff G, Gianniou DD, Trougakos IP, Ouazzani J, Gasperini D, and O'Connell RJ
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- Colletotrichum, Cyclopentanes, Gene Expression Regulation, Plant, Oxylipins, Arabidopsis genetics, Arabidopsis metabolism, Arabidopsis Proteins genetics, Arabidopsis Proteins metabolism, Diterpenes
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Infection of Arabidopsis thaliana by the ascomycete fungus Colletotrichum higginsianum is characterized by an early symptomless biotrophic phase followed by a destructive necrotrophic phase. The fungal genome contains 77 secondary metabolism-related biosynthetic gene clusters, whose expression during the infection process is tightly regulated. Deleting CclA, a chromatin regulator involved in the repression of some biosynthetic gene clusters through H3K4 trimethylation, allowed overproduction of three families of terpenoids and isolation of 12 different molecules. These natural products were tested in combination with methyl jasmonate, an elicitor of jasmonate responses, for their capacity to alter defence gene induction in Arabidopsis. Higginsianin B inhibited methyl jasmonate-triggered expression of the defence reporter VSP1p:GUS, suggesting it may block bioactive jasmonoyl isoleucine (JA-Ile) synthesis or signalling in planta. Using the JA-Ile sensor Jas9-VENUS, we found that higginsianin B, but not three other structurally related molecules, suppressed JA-Ile signalling by preventing the degradation of JAZ proteins, the repressors of jasmonate responses. Higginsianin B likely blocks the 26S proteasome-dependent degradation of JAZ proteins because it inhibited chymotrypsin- and caspase-like protease activities. The inhibition of target degradation by higginsianin B also extended to auxin signalling, as higginsianin B treatment reduced auxin-dependent expression of DR5p:GUS. Overall, our data indicate that specific fungal secondary metabolites can act similarly to protein effectors to subvert plant immune and developmental responses., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Society for Experimental Biology.)
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- 2020
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39. Late boosting of the RV144 regimen with AIDSVAX B/E and ALVAC-HIV in HIV-uninfected Thai volunteers: a double-blind, randomised controlled trial.
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Pitisuttithum P, Nitayaphan S, Chariyalertsak S, Kaewkungwal J, Dawson P, Dhitavat J, Phonrat B, Akapirat S, Karasavvas N, Wieczorek L, Polonis V, Eller MA, Pegu P, Kim D, Schuetz A, Jongrakthaitae S, Zhou Y, Sinangil F, Phogat S, Diazgranados CA, Tartaglia J, Heger E, Smith K, Michael NL, Excler JL, Robb ML, Kim JH, O'Connell RJ, and Vasan S
- Subjects
- AIDS Vaccines immunology, Adult, Double-Blind Method, Female, HIV genetics, HIV immunology, HIV Infections virology, Humans, Immunization, Secondary, Male, Thailand, Young Adult, AIDS Vaccines administration & dosage, HIV Infections prevention & control
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Background: The RV144 phase 3 vaccine trial in Thailand demonstrated that ALVAC-HIV (vCP1521) and AIDSVAX B/E administration over 6 months resulted in a 31% efficacy in preventing HIV acquisition. In this trial, we assessed the immunological effect of an additional vaccine boost to the RV144 regimen at varying intervals between the priming vaccine series and the boost., Methods: RV306 is a double-blind, placebo-controlled, randomised clinical trial done at three clinical sites in Thailand. Eligible volunteers were HIV-uninfected individuals aged 20-40 years who were at low risk for HIV infection and in good health. A randomisation schedule was centrally generated with fixed sized strata for Research Institute for Health Sciences Chiang Mai and combined Bangkok clinics. Participants were randomly assigned to one of five groups and then further randomly assigned to either vaccine or placebo. All participants received the primary RV144 vaccine series at months 0, 1, 3, and 6. Group 1 received no additional boost, group 2 received additional AIDSVAX B/E and ALVAC-HIV (vCP1521) or placebo at month 12, group 3 received AIDSVAX B/E alone or placebo at month 12, group 4a received AIDSVAX B/E and ALVAC-HIV or placebo at month 15, and group 4b received AIDSVAX B/E and ALVAC-HIV or placebo at month 18. Primary outcomes were safety and tolerability of these vaccination regimens and cellular and humoral immune responses compared between the RV144 series alone and regimens with late boosts at different timepoints. Safety and tolerability outcomes were assessed by evaluating local and systemic reactogenicity and adverse events in all participants. This trial is registered at ClinicalTrials.gov (NCT01931358); clinical follow-up is now complete., Findings: Between Oct 28, 2013, and April 29, 2014, 367 participants were enrolled, of whom 27 were assigned active vaccination in group 1, 102 in group 2, 101 in group 3, 52 in group 4a, 51 in group 4b, and 34 combined placebo across all the groups. No vaccine-related serious adverse events were recorded. Occurrence and severity of local and systemic reactogenicity were similar across active groups. Groups with late boosts (groups 2, 3, 4a, and 4b) had increased peak plasma IgG-binding antibody levels against gp70 V1V2 relative to group 1 vaccine recipients with no late boost (gp70 V1V2 92TH023 adjusted p<0·02 for each; gp70 V1V2 CaseA2 adjusted p<0·0001 for each). Boosting at month 12 (groups 2 and 3) did not increase gp120 responses compared with the peak responses after the RV144 priming regimen at month 6; however, boosting at month 15 (group 4a) improved responses to gp120 A244gD- D11 (p=0·0003), and boosting at month 18 (group 4b) improved responses to both gp120 A244gD- D11 (p<0·0001) and gp120 MNgD- D11 (p=0·0016). Plasma IgG responses were significantly lower among vaccine recipients boosted at month 12 (pooled groups 2 + 3) than at month 15 (group 4a; adjusted p<0·0001 for each, except for gp70 V1V2 CaseA2, p=0·0142) and at month 18 (group 4b; all adjusted p<0·001). Boosting at month 18 versus month 15 resulted in a significantly higher plasma IgG response to gp120 antigens (all adjusted p<0·01) but not gp70 V1V2 antigens. CD4 functionality and polyfunctionality scores after stimulation with HIV-1 Env peptides (92TH023) increased with delayed boosting. Groups with late boosts had increased functionality and polyfunctionality scores relative to vaccine recipients with no late boost (all adjusted p<0·05, except for the polyfunctionality score in group 1 vs group 4b, p<0·01)., Interpretation: Taken together, these results suggest that additional boosting of the RV144 regimen with longer intervals between the primary vaccination series and late boost improved immune responses and might improve the efficacy of preventing HIV acquisition., Funding: US National Institute of Allergy and Infectious Diseases and US Department of the Army., (Copyright © 2020 Elsevier Ltd. All rights reserved.)
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- 2020
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40. Boosting with AIDSVAX B/E Enhances Env Constant Region 1 and 2 Antibody-Dependent Cellular Cytotoxicity Breadth and Potency.
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Easterhoff D, Pollara J, Luo K, Tolbert WD, Young B, Mielke D, Jha S, O'Connell RJ, Vasan S, Kim J, Michael NL, Excler JL, Robb ML, Rerks-Ngarm S, Kaewkungwal J, Pitisuttithum P, Nitayaphan S, Sinangil F, Tartaglia J, Phogat S, Kepler TB, Alam SM, Wiehe K, Saunders KO, Montefiori DC, Tomaras GD, Moody MA, Pazgier M, Haynes BF, and Ferrari G
- Subjects
- Antibodies, Monoclonal immunology, Antibody Formation immunology, Antibody Specificity immunology, Antibody-Dependent Cell Cytotoxicity immunology, Epitopes immunology, HIV Antibodies immunology, HIV Antibodies ultrastructure, HIV Envelope Protein gp120 ultrastructure, HIV Infections immunology, HIV-1 immunology, Humans, Immunization, Secondary methods, Immunoglobulin G immunology, AIDS Vaccines immunology, HIV Envelope Protein gp120 immunology
- Abstract
Induction of protective antibodies is a critical goal of HIV-1 vaccine development. One strategy is to induce nonneutralizing antibodies (NNAbs) that kill virus-infected cells, as these antibody specificities have been implicated in slowing HIV-1 disease progression and in protection. HIV-1 Env constant region 1 and 2 (C1C2) monoclonal antibodies (MAbs) frequently mediate potent antibody-dependent cellular cytotoxicity (ADCC), making them an important vaccine target. Here, we explore the effect of delayed and repetitive boosting of RV144 vaccine recipients with AIDSVAX B/E on the C1C2-specific MAb repertoire. It was found that boosting increased clonal lineage-specific ADCC breadth and potency. A ligand crystal structure of a vaccine-induced broad and potent ADCC-mediating C1C2-specific MAb showed that it bound a highly conserved Env gp120 epitope. Thus, boosting to affinity mature these types of IgG C1C2-specific antibody responses may be one method by which to make an improved HIV vaccine with higher efficacy than that seen in the RV144 trial. IMPORTANCE Over one million people become infected with HIV-1 each year, making the development of an efficacious HIV-1 vaccine an important unmet medical need. The RV144 human HIV-1 vaccine regimen is the only HIV-1 clinical trial to date to demonstrate vaccine efficacy. An area of focus has been on identifying ways by which to improve upon RV144 vaccine efficacy. The RV305 HIV-1 vaccine regimen was a follow-up boost of RV144 vaccine recipients that occurred 6 to 8 years after the conclusion of RV144. Our study focused on the effect of delayed boosting in humans on the vaccine-induced Env constant region 1 and 2 (C1C2)-specific antibody repertoire. It was found that boosting with an HIV-1 Env vaccine increased C1C2-specific antibody-dependent cellular cytotoxicity potency and breadth., (Copyright © 2020 Easterhoff et al.)
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- 2020
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41. HIV vaccine delayed boosting increases Env variable region 2-specific antibody effector functions.
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Easterhoff D, Pollara J, Luo K, Janus B, Gohain N, Williams LD, Tay MZ, Monroe A, Peachman K, Choe M, Min S, Lusso P, Zhang P, Go EP, Desaire H, Bonsignori M, Hwang KK, Beck C, Kakalis M, O'Connell RJ, Vasan S, Kim JH, Michael NL, Excler JL, Robb ML, Rerks-Ngarm S, Kaewkungwal J, Pitisuttithum P, Nitayaphan S, Sinangil F, Tartaglia J, Phogat S, Wiehe K, Saunders KO, Montefiori DC, Tomaras GD, Moody MA, Arthos J, Rao M, Joyce MG, Ofek G, Ferrari G, and Haynes BF
- Subjects
- AIDS Vaccines chemistry, Antibodies, Monoclonal chemistry, Antibodies, Monoclonal genetics, Antibodies, Monoclonal immunology, Antibody-Dependent Cell Cytotoxicity, Clinical Trials as Topic, Epitopes genetics, Epitopes immunology, HIV Antibodies chemistry, HIV Antibodies genetics, HIV Infections immunology, HIV Infections prevention & control, HIV-1 immunology, Humans, Immunization, Secondary, Models, Molecular, Mutation, Protein Conformation, Viral Vaccines, X-Ray Diffraction, env Gene Products, Human Immunodeficiency Virus genetics, env Gene Products, Human Immunodeficiency Virus immunology, AIDS Vaccines immunology, HIV Antibodies immunology, Immunoglobulin Variable Region genetics, Immunoglobulin Variable Region immunology
- Abstract
In the RV144 HIV-1 phase III trial, vaccine efficacy directly correlated with the magnitude of the variable region 2-specific (V2-specific) IgG antibody response, and in the presence of low plasma IgA levels, with the magnitude of plasma antibody-dependent cellular cytotoxicity. Reenrollment of RV144 vaccinees in the RV305 trial offered the opportunity to define the function, maturation, and persistence of vaccine-induced V2-specific and other mAb responses after boosting. We show that the RV144 vaccine regimen induced persistent V2 and other HIV-1 envelope-specific memory B cell clonal lineages that could be identified throughout the approximately 11-year vaccination period. Subsequent boosts increased somatic hypermutation, a critical requirement for antibody affinity maturation. Characterization of 22 vaccine-induced V2-specific mAbs with epitope specificities distinct from previously characterized RV144 V2-specific mAbs CH58 and CH59 found increased in vitro antibody-mediated effector functions. Thus, when inducing non-neutralizing antibodies, one method by which to improve HIV-1 vaccine efficacy may be through late boosting to diversify the V2-specific response to increase the breadth of antibody-mediated anti-HIV-1 effector functions.
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- 2020
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42. Impact of analytical treatment interruption on the central nervous system in a simian-HIV model.
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Hsu DC, Silsorn D, Inthawong D, Kuncharin Y, Sopanaporn J, Im-Erbsin R, Chumpolkulwong K, O'connell RJ, Michael NL, Ege CA, and Vasan S
- Subjects
- Animals, Biomarkers blood, Biomarkers cerebrospinal fluid, Drug Administration Schedule, HIV-1 genetics, Macaca mulatta, Plasma virology, Simian Acquired Immunodeficiency Syndrome drug therapy, Simian Acquired Immunodeficiency Syndrome virology, Simian Immunodeficiency Virus pathogenicity, T-Lymphocytes virology, Viral Load, Anti-Retroviral Agents therapeutic use, Central Nervous System virology, HIV-1 isolation & purification, Simian Acquired Immunodeficiency Syndrome immunology, Simian Immunodeficiency Virus immunology
- Abstract
Objective(s): Analytical treatment interruption (ATI) studies are often used to evaluate potential HIV cure strategies. This study was conducted to determine the impact of ATI on simian-HIV (SHIV) infection in the central nervous system., Design: Animal study., Methods: Nine rhesus macaques were inoculated with SHIV-1157ipd3N4. Antiretroviral therapy (ART) was administered from week 2 to 18. At week 18, four animals were euthanized (no-ATI-group) and five underwent ATI (ATI-group) and were euthanized at 12 weeks post viral rebound. Plasma and cerebrospinal fluid (CSF) SHIV-RNA, markers of inflammation and brain CD3+, CD68+/CD163+ and RNA+ cells were measured., Results: All nine animals were SHIV-infected, with median pre-ART plasma and CSF SHIV-RNA of 6.2 and 3.6 log10copies/ml. Plasma and CSF IL-15, monocyte chemoattractant protein-1, IFN-γ-induced protein-10 and neopterin increased postinfection. ART initiation was associated with rapid and complete suppression of plasma viremia and reductions in plasma and CSF IL-15, IFN-γ-induced protein-10, neopterin and CSF monocyte chemoattractant protein-1. Median time to plasma viral rebound was 21 days post-ATI. At 12 weeks postrebound, CSF SHIV-RNA was undetectable and no increases in plasma and CSF markers of inflammation were found. Higher numbers of CD3+ and CD68+/CD163+ cells were seen in the brains of 3/5 and 1/5 animals, respectively, in the ATI-group when compared with no-ATI-group. SHIV-RNA+ cells were not identified in the brain in either group post-ATI., Conclusion: ATI in macaques that initiated ART during early SHIV-1157ipd3N4 infection was associated with mild, localized T-cell infiltrate in the brain without detectable SHIV-RNA in the brain or CSF, or elevation in CSF soluble markers of inflammation.
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- 2019
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43. Broad-specificity GH131 β-glucanases are a hallmark of fungi and oomycetes that colonize plants.
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Anasontzis GE, Lebrun MH, Haon M, Champion C, Kohler A, Lenfant N, Martin F, O'Connell RJ, Riley R, Grigoriev IV, Henrissat B, Berrin JG, and Rosso MN
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- Ascomycota enzymology, Ascomycota genetics, Cell Wall metabolism, Fungi genetics, Gene Transfer, Horizontal, Glycoside Hydrolases genetics, Oomycetes genetics, Symbiosis, Fungi enzymology, Glycoside Hydrolases metabolism, Oomycetes enzymology, Plants microbiology
- Abstract
Plant-tissue-colonizing fungi fine-tune the deconstruction of plant-cell walls (PCW) using different sets of enzymes according to their lifestyle. However, some of these enzymes are conserved among fungi with dissimilar lifestyles. We identified genes from Glycoside Hydrolase family GH131 as commonly expressed during plant-tissue colonization by saprobic, pathogenic and symbiotic fungi. By searching all the publicly available genomes, we found that GH131-coding genes were widely distributed in the Dikarya subkingdom, except in Taphrinomycotina and Saccharomycotina, and in phytopathogenic Oomycetes, but neither other eukaryotes nor prokaryotes. The presence of GH131 in a species was correlated with its association with plants as symbiont, pathogen or saprobe. We propose that GH131-family expansions and horizontal-gene transfers contributed to this adaptation. We analysed the biochemical activities of GH131 enzymes whose genes were upregulated during plant-tissue colonization in a saprobe (Pycnoporus sanguineus), a plant symbiont (Laccaria bicolor) and three hemibiotrophic-plant pathogens (Colletotrichum higginsianum, C. graminicola, Zymoseptoria tritici). These enzymes were all active on substrates with β-1,4, β-1,3 and mixed β-1,4/1,3 glucosidic linkages. Combined with a cellobiohydrolase, GH131 enzymes enhanced cellulose degradation. We propose that secreted GH131 enzymes unlock the PCW barrier and allow further deconstruction by other enzymes during plant tissue colonization by symbionts, pathogens and saprobes., (© 2019 Society for Applied Microbiology and John Wiley & Sons Ltd.)
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- 2019
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44. H3K4 trimethylation by CclA regulates pathogenicity and the production of three families of terpenoid secondary metabolites in Colletotrichum higginsianum.
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Dallery JF, Adelin É, Le Goff G, Pigné S, Auger A, Ouazzani J, and O'Connell RJ
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- Arabidopsis microbiology, Colletotrichum genetics, Methylation, Mutation genetics, Plant Diseases microbiology, Plant Leaves microbiology, Virulence, Colletotrichum metabolism, Colletotrichum pathogenicity, Diterpenes metabolism, Histones metabolism
- Abstract
The role of histone 3 lysine 4 (H3K4) methylation is poorly understood in plant pathogenic fungi. Here, we analysed the function of CclA, a subunit of the COMPASS complex mediating H3K4 methylation, in the brassica anthracnose pathogen Colletotrichum higginsianum. We show that CclA is required for full genome-wide H3K4 trimethylation. The deletion of cclA strongly reduced mycelial growth, asexual sporulation and spore germination but did not impair the morphogenesis of specialized infection structures (appressoria and biotrophic hyphae). Virulence of the ΔcclA mutant on plants was strongly attenuated, associated with a marked reduction in appressorial penetration ability on both plants and inert cellophane membranes. The secondary metabolite profile of the ΔcclA mutant was greatly enriched compared to that of the wild type, with three different families of terpenoid compounds being overproduced by the mutant, namely the colletochlorins, higginsianins and sclerosporide. These included five novel molecules that were produced exclusively by the ΔcclA mutant: colletorin D, colletorin D acid, higginsianin C, 13-epi-higginsianin C and sclerosporide. Taken together, our findings indicate that H3K4 trimethylation plays a critical role in regulating fungal growth, development, pathogenicity and secondary metabolism in C. higginsianum., (© 2019 Institut National de la Recherche Agronomique. Molecular Plant Pathology published by British Society for Plant Pathology and John Wiley & Sons Ltd.)
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- 2019
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45. Safety and efficacy of VRC01 broadly neutralising antibodies in adults with acutely treated HIV (RV397): a phase 2, randomised, double-blind, placebo-controlled trial.
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Crowell TA, Colby DJ, Pinyakorn S, Sacdalan C, Pagliuzza A, Intasan J, Benjapornpong K, Tangnaree K, Chomchey N, Kroon E, de Souza MS, Tovanabutra S, Rolland M, Eller MA, Paquin-Proulx D, Bolton DL, Tokarev A, Thomas R, Takata H, Trautmann L, Krebs SJ, Modjarrad K, McDermott AB, Bailer RT, Doria-Rose N, Patel B, Gorelick RJ, Fullmer BA, Schuetz A, Grandin PV, O'Connell RJ, Ledgerwood JE, Graham BS, Tressler R, Mascola JR, Chomont N, Michael NL, Robb ML, Phanuphak N, and Ananworanich J
- Subjects
- Adult, Antibodies, Monoclonal immunology, Antibodies, Monoclonal pharmacology, Antibodies, Neutralizing immunology, Antibodies, Neutralizing therapeutic use, Antibodies, Viral immunology, Antibodies, Viral therapeutic use, Antiretroviral Therapy, Highly Active, Broadly Neutralizing Antibodies immunology, Broadly Neutralizing Antibodies pharmacology, CD4 Lymphocyte Count, CD4-Positive T-Lymphocytes, Female, HIV Antibodies immunology, HIV Antibodies pharmacology, HIV Infections immunology, HIV Infections virology, Humans, Male, Middle Aged, Treatment Outcome, Viral Load, Young Adult, Antibodies, Monoclonal drug effects, Broadly Neutralizing Antibodies drug effects, HIV Antibodies drug effects, HIV Infections drug therapy, HIV-1 immunology
- Abstract
Background: HIV-1-specific broadly neutralising antibodies such as VRC01 could promote HIV remission by halting viral replication and clearing infected cells. We investigated whether VRC01 could promote sustained viral control off antiretroviral therapy (ART) in adults who initiated ART during acute HIV infection., Methods: We did a randomised, double-blind, placebo-controlled trial at the Thai Red Cross AIDS Research Centre in Bangkok, Thailand. Eligible participants were aged 20-50 years, had initiated ART during acute infection (ie, Fiebig stages I-III), had been taking ART for more than 24 months, had fewer than 50 HIV-1 RNA copies per mL on three consecutive measurements, had more than 400 CD4 cells per μL, had fewer than ten copies of integrated HIV-1 DNA per 10
6 peripheral blood mononuclear cells, and were in generally good health. Eligible participants were randomly assigned (3:1) based on computer-generated lists with a blocking factor of 4 to receive VRC01 (40 mg/kg) or placebo (saline) intravenously every 3 weeks for up to 24 weeks during analytic interruption of ART, followed by continued observation off all therapies. Randomisation was stratified by Fiebig stage (I vs II vs III) at HIV diagnosis. Participants were monitored closely and resumed ART if 1000 or more HIV-1 RNA copies were detected per mL of plasma. The primary outcomes were the frequency of serious adverse events and the proportion of participants with fewer than 50 HIV-1 RNA copies per mL 24 weeks after treatment interruption. Efficacy analyses included all participants who received at least one full dose of study product, and safety analyses included all participants exposed to any study product. The trial was registered with ClinicalTrials.gov, number NCT02664415. This trial is completed., Findings: Between Aug 8, 2016, and Jan 9, 2017, 19 men were randomly assigned, 14 to the VRC01 group and five to the placebo group. One participant in the VRC01 group received a partial infusion without undergoing treatment interruption. The other 18 participants all received at least one full study infusion and underwent ART interruption. No serious adverse events were reported in either group. Only one participant in the VRC01 group achieved the primary efficacy endpoint of viral suppression 24 weeks after ART interruption. The other 17 restarted ART because of a confirmed recording of 1000 or more HIV-1 RNA copies per mL before 24 weeks., Interpretation: VRC01 monotherapy in individuals who initiated ART during acute HIV infection was well tolerated but did not significantly increase the number of participants with viral suppression 24 weeks after ART interruption. Further development of VRC01 and other immunotherapies for HIV will probably occur as part of combination regimens that include several treatments directed against unique therapeutic targets., Funding: US Department of the Army, US National Institutes of Health, and the Thai Red Cross AIDS Research Centre., (Copyright © 2019 Elsevier Ltd. All rights reserved.)- Published
- 2019
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46. Deleting a Chromatin Remodeling Gene Increases the Diversity of Secondary Metabolites Produced by Colletotrichum higginsianum.
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Dallery JF, Le Goff G, Adelin E, Iorga BI, Pigné S, O'Connell RJ, and Ouazzani J
- Subjects
- Carbon-13 Magnetic Resonance Spectroscopy, Chromatography, High Pressure Liquid, Colletotrichum genetics, Genes, Fungal, Proton Magnetic Resonance Spectroscopy, Chromatin Assembly and Disassembly genetics, Colletotrichum metabolism, Gene Deletion
- Abstract
Colletotrichum higginsianum is the causal agent of crucifer anthracnose disease, responsible for important economic losses in Brassica crops. A mutant lacking the CclA subunit of the COMPASS complex was expected to undergo chromatin decondensation and the activation of cryptic secondary metabolite biosynthetic gene clusters. Liquid-state fermentation of the Δ cclA mutant coupled with in situ solid-phase extraction led to the production of three families of compounds, namely, colletorin and colletochlorin derivatives with two new representatives, colletorin D (1) and colletorin D acid (2), the diterpenoid α-pyrone higginsianin family with two new analogues, higginsianin C (3) and 13- epi-higginsianin C (4), and sclerosporide (5) coupling a sclerosporin moiety with dimethoxy inositol.
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- 2019
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47. Molecular epidemiology of a primarily MSM acute HIV-1 cohort in Bangkok, Thailand and connections within networks of transmission in Asia.
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Chang D, Sanders-Buell E, Bose M, O'Sullivan AM, Pham P, Kroon E, Colby DJ, Sirijatuphat R, Billings E, Pinyakorn S, Chomchey N, Rutvisuttinunt W, Kijak G, de Souza M, Excler JL, Phanuphak P, Phanuphak N, O'Connell RJ, Kim JH, Robb ML, Michael NL, Ananworanich J, and Tovanabutra S
- Subjects
- Cohort Studies, Genetic Variation, HIV Seropositivity epidemiology, Humans, Longitudinal Studies, Male, Phylogeny, Prospective Studies, Thailand epidemiology, HIV Infections epidemiology, HIV Infections virology, HIV-1 genetics, Homosexuality, Male, Molecular Epidemiology
- Abstract
Introduction: Thailand plays a substantial role in global HIV-1 transmission of CRF01_AE. Worldwide, men who have sex with men (MSM) are at elevated risk for HIV-1 infection. Hence, understanding HIV-1 diversity in a primarily Thai MSM cohort with acute infection, and its connections to the broader HIV-1 transmission network in Asia is crucial for research and development of HIV-1 vaccines, treatment and cure., Methods: Subtypes and diversity of infecting viruses from individuals sampled from 2009 to 2015 within the RV254/SEARCH 010 cohort were assessed by multiregion hybridization assay (MHAbce), multiregion subtype-specific PCR assay (MSSPbce) and full-length single-genome sequencing (SGS). Phylogenetic analysis was performed by maximum likelihood. Pairwise genetic distances of envelope gp160 sequences obtained from the cohort and from Asia (Los Alamos National Laboratory HIV Database) were calculated to identify potential transmission networks., Results: MHAbce/MSSPbce results identified 81.6% CRF01_AE infecting strains in RV254. CRF01_AE/B recombinants and subtype B were found at 7.3% and 2.8% respectively. Western subtype B strains outnumbered Thai B' strains. Phylogenetic analysis revealed one C, one CRF01_AE/CRF02_AG recombinant and one CRF01_AE/B/C recombinant. Asian network analysis identified one hundred and twenty-three clusters, including five clusters of RV254 participants. None of the RV254 sequences clustered with non-RV254 sequences. The largest international cluster involved 15 CRF01_AE strains from China and Vietnam. The remaining clusters were mostly intracountry connections, of which 31.7% included Thai nodes and 43.1% included Chinese nodes., Conclusion: While the majority of strains in Thailand are CRF01_AE and subtype B, emergence of unique recombinant forms (URFs) are found in a moderate fraction of new HIV-1 infections. Approaches to vaccine design and immunotherapeutics will need to monitor and consider the expanding proportion of recombinants and the increasing genetic diversity in the region. Identified HIV-1 transmission networks indicate ongoing spread of HIV-1 among MSM. As HIV-1 epidemics continue to expand in other Asian countries, transmission network analyses can inform strategies for prevention, intervention, treatment and cure., (© 2018 Henry M. Jackson Foundation for the Advancement of Military Medicine Inc. Journal of the International AIDS Society published by John Wiley & Sons Ltd on behalf of the International AIDS Society.)
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- 2018
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48. The US Military Commitment to Vaccine Development: A Century of Successes and Challenges.
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Ratto-Kim S, Yoon IK, Paris RM, Excler JL, Kim JH, and O'Connell RJ
- Abstract
The US military has been a leading proponent of vaccine development since its founding. General George Washington ordered the entire American army to be variolated against smallpox after recognizing the serious threat that it posed to military operations. He did this on the recommendation from Dr. John Morgan, the physician-in-chief of the American army, who wrote a treatise on variolation in 1776. Although cases of smallpox still occurred, they were far fewer than expected, and it is believed that the vaccination program contributed to victory in the War of Independence. Effective military force requires personnel who are healthy and combat ready for worldwide deployment. Given the geography of US military operations, military personnel should also be protected against diseases that are endemic in potential areas of conflict. For this reason, and unknown to many, the US military has strongly supported vaccine research and development. Four categories of communicable infectious diseases threaten military personnel: (1) diseases that spread easily in densely populated areas (respiratory and dysenteric diseases); (2) vector-borne diseases (disease carried by mosquitoes and other insects); (3) sexually transmitted diseases (hepatitis, HIV, and gonorrhea); and (4) diseases associated with biological warfare. For each category, the US military has supported research that has provided the basis for many of the vaccines available today. Although preventive measures and the development of drugs have provided some relief from the burden of malaria, dengue, and HIV, the US military continues to fund research and development of prophylactic vaccines that will contribute to force health protection and global health. In the past few years, newly recognized infections with Zika, severe acute respiratory syndrome, Middle East respiratory syndrome viruses have pushed the US military to fund research and fast track clinical trials to quickly and effectively develop vaccines for emerging diseases. With US military personnel present in every region of the globe, one of the most cost-effective ways to maintain military effectiveness is to develop vaccines against prioritized threats to military members' health.
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- 2018
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49. Central Nervous System Inflammation and Infection during Early, Nonaccelerated Simian-Human Immunodeficiency Virus Infection in Rhesus Macaques.
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Hsu DC, Sunyakumthorn P, Wegner M, Schuetz A, Silsorn D, Estes JD, Deleage C, Tomusange K, Lakhashe SK, Ruprecht RM, Lombardini E, Im-Erbsin R, Kuncharin Y, Phuang-Ngern Y, Inthawong D, Chuenarom W, Burke R, Robb ML, Ndhlovu LC, Ananworanich J, Valcour V, O'Connell RJ, Spudich S, Michael NL, and Vasan S
- Subjects
- Animals, Antigens, CD metabolism, Antigens, Differentiation, Myelomonocytic metabolism, Brain pathology, Brain virology, CD4 Lymphocyte Count, Cells, Cultured, Disease Models, Animal, HIV-1 immunology, HIV-1 pathogenicity, Humans, Macaca mulatta, Meninges pathology, Meninges virology, Microglia immunology, Parenchymal Tissue pathology, Parenchymal Tissue virology, RNA, Viral blood, RNA, Viral cerebrospinal fluid, RNA, Viral genetics, Receptors, Cell Surface metabolism, Simian Acquired Immunodeficiency Syndrome pathology, Simian Acquired Immunodeficiency Syndrome virology, Simian Immunodeficiency Virus pathogenicity, Viral Load immunology, Brain immunology, CD4-Positive T-Lymphocytes immunology, Macrophages immunology, Meninges immunology, Monocytes immunology, Parenchymal Tissue immunology, Simian Acquired Immunodeficiency Syndrome immunology, Simian Immunodeficiency Virus immunology
- Abstract
Studies utilizing highly pathogenic simian immunodeficiency virus (SIV) and simian-human immunodeficiency virus (SHIV) have largely focused on the immunopathology of the central nervous system (CNS) during end-stage neurological AIDS and SIV encephalitis. However, this may not model pathophysiology in earlier stages of infection. In this nonaccelerated SHIV model, plasma SHIV RNA levels and peripheral blood and colonic CD4
+ T cell counts mirrored early human immunodeficiency virus (HIV) infection in humans. At 12 weeks postinfection, cerebrospinal fluid (CSF) detection of SHIV RNA and elevations in IP-10 and MCP-1 reflected a discrete neurovirologic process. Immunohistochemical staining revealed a diffuse, low-level CD3+ CD4- cellular infiltrate in the brain parenchyma without a concomitant increase in CD68/CD163+ monocytes, macrophages, and activated microglial cells. Rare SHIV-infected cells in the brain parenchyma and meninges were identified by RNAScope in situ hybridization. In the meninges, there was also a trend toward increased CD4+ infiltration in SHIV-infected animals but no differences in CD68/CD163+ cells between SHIV-infected and uninfected control animals. These data suggest that in a model that closely recapitulates human disease, CNS inflammation and SHIV in CSF are predominantly mediated by T cell-mediated processes during early infection in both brain parenchyma and meninges. Because SHIV expresses an HIV rather than SIV envelope, this model could inform studies to understand potential HIV cure strategies targeting the HIV envelope. IMPORTANCE Animal models of the neurologic effects of HIV are needed because brain pathology is difficult to assess in humans. Many current models focus on the effects of late-stage disease utilizing SIV. In the era of antiretroviral therapy, manifestations of late-stage HIV are less common. Furthermore, new interventions, such as monoclonal antibodies and therapeutic vaccinations, target HIV envelope. We therefore describe a new model of central nervous system involvement in rhesus macaques infected with SHIV expressing HIV envelope in earlier, less aggressive stages of disease. Here, we demonstrate that SHIV mimics the early clinical course in humans and that early neurologic inflammation is characterized by predominantly T cell-mediated inflammation accompanied by SHIV infection in the brain and meninges. This model can be utilized to assess the effect of novel therapies targeted to HIV envelope on reducing brain inflammation before end-stage disease., (Copyright © 2018 Hsu et al.)- Published
- 2018
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50. Subcellular Localization Screening of Colletotrichum higginsianum Effector Candidates Identifies Fungal Proteins Targeted to Plant Peroxisomes, Golgi Bodies, and Microtubules.
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Robin GP, Kleemann J, Neumann U, Cabre L, Dallery JF, Lapalu N, and O'Connell RJ
- Abstract
The genome of the hemibiotrophic anthracnose fungus, Colletotrichum higginsianum , encodes a large inventory of putative secreted effector proteins that are sequentially expressed at different stages of plant infection, namely appressorium-mediated penetration, biotrophy and necrotrophy. However, the destinations to which these proteins are addressed inside plant cells are unknown. In the present study, we selected 61 putative effector genes that are highly induced in appressoria and/or biotrophic hyphae. We then used Agrobacterium -mediated transformation to transiently express them as N -terminal fusions with fluorescent proteins in cells of Nicotiana benthamiana for imaging by confocal microscopy. Plant compartments labeled by the fusion proteins in N. benthamiana were validated by co-localization with specific organelle markers, by transient expression of the proteins in the true host plant, Arabidopsis thaliana , and by transmission electron microscopy-immunogold labeling. Among those proteins for which specific subcellular localizations could be verified, nine were imported into plant nuclei, three were imported into the matrix of peroxisomes, three decorated cortical microtubule arrays and one labeled Golgi stacks. Two peroxisome-targeted proteins harbored canonical C -terminal tripeptide signals for peroxisome import via the PTS1 (peroxisomal targeting signal 1) pathway, and we showed that these signals are essential for their peroxisome localization. Our findings provide valuable information about which host processes are potentially manipulated by this pathogen, and also reveal plant peroxisomes, microtubules, and Golgi as novel targets for fungal effectors.
- Published
- 2018
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