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1. Multiply spliced HIV RNA is a predictive measure of virus production ex vivo and in vivo following reversal of HIV latency

Author

Jennifer M. Zerbato, Georges Khoury, Wei Zhao, Matthew J. Gartner, Rachel D. Pascoe, Ajantha Rhodes, Ashanti Dantanarayana, Megan Gooey, Jenny Anderson, Peter Bacchetti, Steven G. Deeks, James McMahon, Michael Roche, Thomas A. Rasmussen, Damian FJ Purcell, and Sharon R. Lewin

Subjects
HIV, Multiply-spliced HIV RNA, Reservoir, Shock and kill, Latency reversal, Biomarker, Medicine, Medicine (General), R5-920
Abstract

Background: One strategy being pursued to clear latently infected cells that persist in people living with HIV (PLWH) on antiretroviral therapy (ART) is to activate latent HIV infection with a latency reversing agent (LRA). Surrogate markers that accurately measure virus production following an LRA are needed. Methods: We quantified cell-associated unspliced (US), multiply spliced (MS) and supernatant (SN) HIV RNA by qPCR from total and resting CD4+ T cells isolated from seven PLWH on ART before and after treatment ex vivo with different LRAs, including histone deacetylase inhibitors (HDACi). MS and plasma HIV RNA were also quantified from PLWH on ART (n-11) who received the HDACi panobinostat. Findings: In total and resting CD4+ T cells from PLWH on ART, detection of US RNA was common while detection of MS RNA was infrequent. Primers used to detect MS RNA, in contrast to US RNA, bound sites of the viral genome that are commonly mutated or deleted in PLWH on ART. Following ex vivo stimulation with LRAs, we identified a strong correlation between the fold change increase in SN and MS RNA, but not the fold change increase in SN and US RNA. In PLWH on ART who received panobinostat, MS RNA was significantly higher in samples with detectable compared to non0detectable plasma HIV RNA. Interpretation: Following administration of an LRA, quantification of MS RNA is more likely to reflect an increase in virion production and is therefore a better indicator of meaningful latency reversal. Funding: NHMRC, NIH DARE collaboratory.

Published
2021
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3. Multiply spliced HIV RNA is a predictive measure of virus production ex vivo and in vivo following reversal of HIV latency

Author

Zerbato, Jennifer M, Khoury, Georges, Zhao, Wei, Gartner, Matthew J, Pascoe, Rachel D, Rhodes, Ajantha, Dantanarayana, Ashanti, Gooey, Megan, Anderson, Jenny, Bacchetti, Peter, Deeks, Steven G, McMahon, James, Roche, Michael, Rasmussen, Thomas A, Purcell, Damian FJ, and Lewin, Sharon R

Subjects
Medical Microbiology, Biomedical and Clinical Sciences, Immunology, Clinical Research, Genetics, HIV/AIDS, Sexually Transmitted Infections, Infectious Diseases, 2.2 Factors relating to the physical environment, Aetiology, Infection, Anti-Retroviral Agents, CD4-Positive T-Lymphocytes, Cell Proliferation, HIV Infections, HIV-1, Histone Deacetylase Inhibitors, Humans, Polyhydroxyalkanoates, RNA Splicing, RNA, Viral, Tetradecanoylphorbol Acetate, Virus Latency, Vorinostat, HIV, Multiply-spliced HIV RNA, Reservoir, Shock and kill, Latency reversal, Biomarker, Clinical Sciences, Public Health and Health Services, Clinical sciences, Epidemiology
Abstract

BackgroundOne strategy being pursued to clear latently infected cells that persist in people living with HIV (PLWH) on antiretroviral therapy (ART) is to activate latent HIV infection with a latency reversing agent (LRA). Surrogate markers that accurately measure virus production following an LRA are needed.MethodsWe quantified cell-associated unspliced (US), multiply spliced (MS) and supernatant (SN) HIV RNA by qPCR from total and resting CD4+ T cells isolated from seven PLWH on ART before and after treatment ex vivo with different LRAs, including histone deacetylase inhibitors (HDACi). MS and plasma HIV RNA were also quantified from PLWH on ART (n-11) who received the HDACi panobinostat.FindingsIn total and resting CD4+ T cells from PLWH on ART, detection of US RNA was common while detection of MS RNA was infrequent. Primers used to detect MS RNA, in contrast to US RNA, bound sites of the viral genome that are commonly mutated or deleted in PLWH on ART. Following ex vivo stimulation with LRAs, we identified a strong correlation between the fold change increase in SN and MS RNA, but not the fold change increase in SN and US RNA. In PLWH on ART who received panobinostat, MS RNA was significantly higher in samples with detectable compared to non0detectable plasma HIV RNA.InterpretationFollowing administration of an LRA, quantification of MS RNA is more likely to reflect an increase in virion production and is therefore a better indicator of meaningful latency reversal.FundingNHMRC, NIH DARE collaboratory.

Published
2021

4. Effect of Convalescent Plasma on Organ Support-Free Days in Critically Ill Patients With COVID-19: A Randomized Clinical Trial

Author

Writing Committee for the REMAP-CAP Investigators, Estcourt, Lise J, Turgeon, Alexis F, McQuilten, Zoe K, McVerry, Bryan J, Al-Beidh, Farah, Annane, Djillali, Arabi, Yaseen M, Arnold, Donald M, Beane, Abigail, Bégin, Philippe, van Bentum-Puijk, Wilma, Berry, Lindsay R, Bhimani, Zahra, Birchall, Janet E, Bonten, Marc JM, Bradbury, Charlotte A, Brunkhorst, Frank M, Buxton, Meredith, Callum, Jeannie L, Chassé, Michaël, Cheng, Allen C, Cove, Matthew E, Daly, James, Derde, Lennie, Detry, Michelle A, De Jong, Menno, Evans, Amy, Fergusson, Dean A, Fish, Matthew, Fitzgerald, Mark, Foley, Claire, Goossens, Herman, Gordon, Anthony C, Gosbell, Iain B, Green, Cameron, Haniffa, Rashan, Harvala, Heli, Higgins, Alisa M, Hills, Thomas E, Hoad, Veronica C, Horvat, Christopher, Huang, David T, Hudson, Cara L, Ichihara, Nao, Laing, Emma, Lamikanra, Abigail A, Lamontagne, François, Lawler, Patrick R, Linstrum, Kelsey, Litton, Edward, Lorenzi, Elizabeth, MacLennan, Sheila, Marshall, John, McAuley, Daniel F, McDyer, John F, McGlothlin, Anna, McGuinness, Shay, Miflin, Gail, Montgomery, Stephanie, Mouncey, Paul R, Murthy, Srinivas, Nichol, Alistair, Parke, Rachael, Parker, Jane C, Priddee, Nicole, Purcell, Damian FJ, Reyes, Luis F, Richardson, Peter, Robitaille, Nancy, Rowan, Kathryn M, Rynne, Jennifer, Saito, Hiroki, Santos, Marlene, Saunders, Christina T, Serpa Neto, Ary, Seymour, Christopher W, Silversides, Jon A, Tinmouth, Alan A, Triulzi, Darrell J, Turner, Anne M, van de Veerdonk, Frank, Walsh, Timothy S, Wood, Erica M, Berry, Scott, Lewis, Roger J, Menon, David K, McArthur, Colin, Zarychanski, Ryan, Angus, Derek C, Webb, Steve A, Roberts, David J, Shankar-Hari, Manu, Menon, David [0000-0002-3228-9692], Apollo - University of Cambridge Repository, Investigators, Writing Committee for the REMAP-CAP, Writing Comm REMAP-CAP Investigators, Hôpital Raymond Poincaré [AP-HP], Université de Versailles Saint-Quentin-en-Yvelines - UFR Sciences de la santé Simone Veil (UVSQ Santé), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), National Institutes of Health, NIH, National Institute of Child Health and Human Development, NICHD, Pittsburgh Foundation, Breast Cancer Research Foundation, BCRF, Bristol-Myers Squibb, BMS, GlaxoSmithKline, GSK, Medtronic, Baxter International, Manitoba Medical Service Foundation, MMSF, CancerCare Manitoba Foundation, CCMF, Wellcome Trust, WT, University of Manitoba, UM, Health Research Board, HRB: PHRC-20-0147, National Blood Authority, NBA, Llywodraeth Cymru, Translational Breast Cancer Research Consortium, TBCRC, Canadian Institutes of Health Research, IRSC: 158584, CTN 2014-012, Medical Research Council, MRC, National Institute for Health Research, NIHR, Department of Health and Social Care, DH, European Commission, EC: APP194811, National Heart and Lung Institute, NHLI, National Health and Medical Research Council, NHMRC: 2015-06-18, 2016-16-011, APP1101719, APP2002132, Health Research Council of New Zealand, HRC: 16/631, 447335, Monash University, MU, Ministère des Affaires Sociales et de la Santé: 215522, Seventh Framework Programme, FP7, Université Pierre et Marie Curie, UPMC, Innovate UK, Horizon 2020, Pharmaceuticals Bayer, Minderoo Foundation, Dr Fitzgerald reported receiving grants from the PREPARE Network and the European Commission. Dr Gordon reported receiving grants from the National Institute for Health Research and receiving personal fees from 30 Respiratory, GlaxoSmithKline, and Bristol Myers Squibb. Dr Gosbell reported receiving grants from the Australian Red Cross Lifeblood, which is funded by the Australian government. Dr Haniffa reported receiving grants from the Wellcome Trust Innovations Project, the Minderoo Foundation, and the UK Research and Innovation African Critical Care Registry Network. Dr Higgins reported receiving grants from the National Health and Medical Research Council, the Minderoo Foundation, and the National Blood Authority. Dr Hills reported receiving grants from the Health Research Council of New Zealand. Dr Hoad reported receiving grants from the Australian Red Cross Lifeblood, which is funded by the Australian government. Dr Horvat reported receiving grants from the National Institute of Child Health and Human Development. Dr Huang reported receiving grants from the Breast Cancer Research Foundation. Dr Lamontagne reported receiving grants from the Canadian Institutes of Health Research. Dr Lawler reported receiving consulting fees from Novartis, Coronna LLC, and Brigham and Women’s Hospital, receiving royalties from McGraw-Hill Publishing, and receiving grants from the Canadian Institutes of Health Research, the LifeArc Foundation, the National Institutes of Health, the Peter Munk Cardiac Centre, the Ted Rogers Centre for Heart Research, the Thistledown Foundation, and the province of Ontario. Dr Lorenzi reported receiving personal fees from Berry Consultants. Dr Marshall reported receiving personal fees from AM-Pharma (data and safety monitoring board chair) and Critical Care Medicine (associate editor). Dr McAuley reported receiving personal fees from Bayer, GlaxoSmithKline, Boehringer Ingelheim, Novartis, Eli Lilly, Vir Biotechnology, Faron Pharmaceuticals, and Sobi, receiving grants from the National Institute for Health Research, Wellcome Trust, Innovate UK, the Medical Research Council, and the Northern Ireland Health and Social Care Research and Development Division, and holding a patent for an anti-inflammatory treatment that was issued to Queen’s University Belfast. Dr McGlothlin reported receiving grants from the PREPARE Network, the European Commission, and the Global Coalition for Adapative Research. Mr Mouncey reported receiving grants from the European Union, the PREPARE Network, the National Institute for Health Research, and European Union Horizon 2020. Dr Nichol reported receiving grants from the Health Research Board of Ireland and Baxter and receiving personal fees from AM-Pharma. Dr Parke reported receiving grants from Fisher and Paykel Healthcare Ltd. Ms Parker reported receiving grants from Monash University. Mr Richardson reported receiving funding from the Welsh government. Dr Rowan reported receiving grants from the European Commission and the National Institute for Health Research. Dr Saunders reported receiving grants from the PREPARE Network, the European Commission, and the Global Coalition for Adapative Research. Dr Serpa Neto reported receiving personal fees from Drager and Endpoint Health. Dr Tinmouth reported receiving grants and personal fees from the Canadian Blood Services. Ms Turner reported receiving grants from the Health Research Council of New Zealand. Dr van de Veerdonk reported receiving personal fees from Gilead, Sobi, and GlaxoSmithKline. Dr Wood reported receiving grants from the Australian Medical Research Future Fund. Dr S. Berry reported being an employee of Berry Consultants with an ownership role. Dr Lewis reported being an employee of Berry Consultants. Dr Menon reported receiving grants from the National Institute for Health Research. Dr McArthur reported receiving grants from the Health Research Council of New Zealand. Dr Zarychanski reported receiving grants from the Canadian Institutes of Health Research, the University of Manitoba, LifeArc, the Thistledown Foundation, Research Manitoba, the CancerCare Manitoba Foundation, the Victoria General Hospital Foundation, the Peter Munk Cardiac Centre, and the Manitoba Medical Services Foundation. Dr Webb reported receiving grants from the National Health and Medical Research Council and the Minderoo Foundation. Dr Shankar-Hari reported receiving grants from the National Institute for Clinical Research. No other disclosures were reported., nonprofit sponsors: Monash University, Melbourne, Australia (Australasian sponsor), Utrecht Medical Center, Utrecht, the Netherlands (European sponsor), St Michael’s Hospital, Toronto, Ontario, Canada (Canadian sponsor), and the Global Coalition for Adaptive Research, San Francisco, California (US sponsor). This study was additionally funded by grant 602525 FP7-health-2013-innovation-1 from the European Union Platform for European Preparedness Against Reemerging Epidemics, grants APP1101719 and APP1116530 from the Australian National Health and Medical Research Council, grant APP2002132 from the Australian Medical Research Future Fund, grant 16/631 from the New Zealand Health Research Council, grant 447335 from the Canadian Institutes of Health Research COVID-19 Rapid Research, grant 158584 from the Canadian Institutes of Health Research Strategy for Patient-Oriented Research Innovative Clinical Trials Program, grant CTN 2014-012 from the Health Research Board of Ireland, grant PHRC-20-0147 from the French Ministry of Health, and grant 215522 from the Wellcome Trust Innovations Project and funding from the National Institute for Health Research, the Department of Health and Social Care, the EU Programme Emergency Support Instrument, the NHS Blood and Transplant Research and Development Programme, the National Institute for Health Research, the National Institute for Health Research Imperial Biomedical Research Centre, the UPMC Learning While Doing Program, the Translational Breast Cancer Research Consortium, the Pittsburgh Foundation, and the Minderoo Foundation. The Australian government funds the Australian Red Cross Lifeblood for the provision of blood products and services. The collection of plasma in the United Kingdom was funded by European Union SoHo grants from the Department of Health and Social Care. Dr Turgeon is the Canada Research Chair in Critical Care Neurology and Trauma. Dr McQuilten is supported by emerging leader fellowship APP194811 from the National Health and Medical Research Council. Dr Gordon is funded by research professorship 2015-06-18 from the National Institute for Health Research. Dr Shankar-Hari is funded by clinician scientist fellowship 2016-16-011 from the National Institute for Health Research., In Canada, the trial has been funded by the Canadian Institute of Health Research, Strategy for Patient-Oriented Research (CIHR-SPOR) Innovative Clinical Trials Program Grant (no. 158584) for CAD $1,497,200, for the recruitment of 300 patients., The Platform for European Preparedness Against (Re-)emerging Epidemics (PREPARE) consortium is funded by the European Union (FP7-HEALTH-2013-INNOVATION-1, grant number 602525). Within the PREPARE consortium, the trial has funding for the recruitment of approximately 4000 patients., REMAP-CAP was supported in the Netherlands by the Research Collaboration Critical Care the Netherlands (RCC-Net)., Funding sources for the REMAP-CAP trial are specified in the core protocol documents. This domain has received domain-specific funding from the Australian Medical Research Future Fund (MRFF)., reported receiving grants from the National Institute for Health Research and European Union Horizon 2020. Dr Turgeon reported receiving grants from the Canadian Institutes of Health Research. Dr McQuilten reported receiving grants from the Australian Medical Research Future Fund. Dr McVerry reported receiving grants from the Pittsburgh Foundation, the Translational Breast Cancer Research Consortium, UPMC Learning While Doing Program, National Heart, Lung, and Blood Institute, and Bayer Pharmaceuticals and receiving personal fees from Boehringer Ingelheim. Dr Annane reported receiving grants from the French Ministry of Health and Solidarity. Dr Arnold reported receiving grants from the Canadian Institutes of Health Research. Ms Beane reported receiving grants and salary support from Wellcome Trust. Ms Bentum-Puijk reported receiving grants from the European Commission and the European Union. Dr L. Berry reported receiving grants from Berry Consultants. Dr Bradbury reported receiving personal fees from Lilly, Bristol Myers Squibb, Pfizer, Bayer, Amgen, Novartis, Janssen, Portola Advisors, and Ablynx. Dr Buxton reported receiving personal fees from the Breast Cancer Research Foundation, Amgen, and Eisai. Dr Callum reported receiving grants from the Canadian Blood Services and Octapharma. Dr Cove reported receiving grants from National University Health System, receiving consulting fees from Medtronic and Baxter, and holding a US patent for removal of carbon dioxide via dialysis. Dr Daly reported receiving grants from the Australian Red Cross Lifeblood, which is funded by the Australian government. Dr Derde reported receiving grants from University Medical Center Utrecht, being a member of the COVID-19 guideline committee of the Surviving Sepsis Campaign/ European Society of Intensive Care Medicine and European Society of Intensive Care Medicine COVID-19 taskforce, and serving as chair of the Dutch intensivists taskforce acute infectious threats. Dr Detry reported receiving grants from the European Union Platform for European Preparedness Against Reemerging Epidemics (PREPARE) consortium, the Australian National Health and Medical Research Council, the Health Research Council of New Zealand, and the UPMC Learning While Doing Program. Dr De Jong reported receiving personal fees from Roche Scientific, Shionogi Scientific, and Janssen., The current regions are: x Europe, with funding from a European Union FP7 grant (FP7-HEALTH-2013-INNOVATION-1, grant number 602525), to support the enrollment of 4000 participants. This funding terminates in 2021. x Australia and New Zealand. In Australia the project has received funding from a NHMRC Project Grant (APP1101719), to support the enrollment of 2000 participants. This funding terminates in December 2021, although some extension may be feasible. In New Zealand the project has received funding from a HRC Programme Grant (16/631), to support the enrollment of 800 participants. This funding terminates in November 2021. x Canada. In Canada the project has received funding for a CIHR grant (158584), to support the enrollment of 300 participants. This funding terminates in 2022. x United States. In the US, funding has been received from UPMC health system for recruitment internally at all UPMC hospitals (>40) and to support a US regional coordinating center. Philanthropic support is being provided through GCAR. Additional funds are being pursued., The REMAP-CAP platform is supported by the Australian and New Zealand Intensive Care Society Clinical Trials Group, the Canadian Critical Care Trials Group, the Irish Critical Care, European Project: 602525,EC:FP7:HEALTH,FP7-HEALTH-2013-INNOVATION-1,PREPARE(2014), NIHR, National Institute for Health Research, Medical Microbiology and Infection Prevention, AII - Infectious diseases, and Intensive Care Medicine

Subjects
Male, medicine.medical_treatment, [SDV]Life Sciences [q-bio], lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4], 030204 cardiovascular system & hematology, Logistic regression, law.invention, 0302 clinical medicine, Randomized controlled trial, law, Critical Illness/therapy, Vasoconstrictor Agents, 030212 general & internal medicine, Hospital Mortality, Treatment Failure, 11 Medical and Health Sciences, Original Investigation, Mortality rate, General Medicine, Middle Aged, Intensive care unit, Writing Committee for the REMAP-CAP Investigators, 3. Good health, Female, Life Sciences & Biomedicine, COVID-19/therapy, Adult, medicine.medical_specialty, Randomization, Respiration, Artificial/statistics & numerical data, Critical Illness, ABO Blood-Group System, 03 medical and health sciences, Medicine, General & Internal, Internal medicine, General & Internal Medicine, medicine, Humans, Adverse effect, COVID-19 Serotherapy, Aged, Mechanical ventilation, Science & Technology, business.industry, Immunization, Passive, Vasoconstrictor Agents/therapeutic use, COVID-19, Odds ratio, Length of Stay, Respiration, Artificial, Logistic Models, Human medicine, business
Abstract

Importance The evidence for benefit of convalescent plasma for critically ill patients with COVID-19 is inconclusive.Objective To determine whether convalescent plasma would improve outcomes for critically ill adults with COVID-19.Design, Setting, and Participants The ongoing Randomized, Embedded, Multifactorial, Adaptive Platform Trial for Community-Acquired Pneumonia (REMAP-CAP) enrolled and randomized 4763 adults with suspected or confirmed COVID-19 between March 9, 2020, and January 18, 2021, within at least 1 domain; 2011 critically ill adults were randomized to open-label interventions in the immunoglobulin domain at 129 sites in 4 countries. Follow-up ended on April 19, 2021.Interventions The immunoglobulin domain randomized participants to receive 2 units of high-titer, ABO-compatible convalescent plasma (total volume of 550 mL ± 150 mL) within 48 hours of randomization (n = 1084) or no convalescent plasma (n = 916).Main Outcomes and Measures The primary ordinal end point was organ support–free days (days alive and free of intensive care unit–based organ support) up to day 21 (range, −1 to 21 days; patients who died were assigned –1 day). The primary analysis was an adjusted bayesian cumulative logistic model. Superiority was defined as the posterior probability of an odds ratio (OR) greater than 1 (threshold for trial conclusion of superiority >99%). Futility was defined as the posterior probability of an OR less than 1.2 (threshold for trial conclusion of futility >95%). An OR greater than 1 represented improved survival, more organ support–free days, or both. The prespecified secondary outcomes included in-hospital survival; 28-day survival; 90-day survival; respiratory support–free days; cardiovascular support–free days; progression to invasive mechanical ventilation, extracorporeal mechanical oxygenation, or death; intensive care unit length of stay; hospital length of stay; World Health Organization ordinal scale score at day 14; venous thromboembolic events at 90 days; and serious adverse events.Results Among the 2011 participants who were randomized (median age, 61 [IQR, 52 to 70] years and 645/1998 [32.3%] women), 1990 (99%) completed the trial. The convalescent plasma intervention was stopped after the prespecified criterion for futility was met. The median number of organ support–free days was 0 (IQR, –1 to 16) in the convalescent plasma group and 3 (IQR, –1 to 16) in the no convalescent plasma group. The in-hospital mortality rate was 37.3% (401/1075) for the convalescent plasma group and 38.4% (347/904) for the no convalescent plasma group and the median number of days alive and free of organ support was 14 (IQR, 3 to 18) and 14 (IQR, 7 to 18), respectively. The median-adjusted OR was 0.97 (95% credible interval, 0.83 to 1.15) and the posterior probability of futility (OR Conclusions and Relevance Among critically ill adults with confirmed COVID-19, treatment with 2 units of high-titer, ABO-compatible convalescent plasma had a low likelihood of providing improvement in the number of organ support–free days.Trial Registration ClinicalTrials.gov Identifier: NCT02735707

Published
2021
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5. Multiply spliced HIV RNA is a predictive measure of virus production ex vivo and in vivo following reversal of HIV latency

Author

Zerbato, Jennifer M., primary, Khoury, Georges, additional, Zhao, Wei, additional, Gartner, Matthew J., additional, Pascoe, Rachel D., additional, Rhodes, Ajantha, additional, Dantanarayana, Ashanti, additional, Gooey, Megan, additional, Anderson, Jenny, additional, Bacchetti, Peter, additional, Deeks, Steven G., additional, McMahon, James, additional, Roche, Michael, additional, Rasmussen, Thomas A., additional, Purcell, Damian FJ, additional, and Lewin, Sharon R., additional

Published
2021
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6. Influenza, but not SARS‐CoV‐2, infection induces a rapid interferon response that wanes with age and diminished tissue‐resident memory CD8 + T cells

Author

Nguyen, Thi HO, primary, McAuley, Julie L, additional, Kim, Youry, additional, Zheng, Ming ZM, additional, Gherardin, Nicholas A, additional, Godfrey, Dale I, additional, Purcell, Damian FJ, additional, Sullivan, Lucy C, additional, Westall, Glen P, additional, Reading, Patrick C, additional, Kedzierska, Katherine, additional, and Wakim, Linda M, additional

Published
2021
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8. Induction of humoral and cellular immune responses against the HIV-1 envelope protein using γ-retroviral virus-like particles

Author

Purcell Damian FJ, Center Robert J, Pedersen Finn S, Bahrami Shervin, Melchjorsen Jesper, Wheatley Adam, Kirkegaard Tea, Ostergaard Lars, Duch Mogens, and Tolstrup Martin

Subjects
HIV-1 envelope protein, Virus-like particles, γ-retroviruses, immunity, Infectious and parasitic diseases, RC109-216
Abstract

Abstract This study evaluates the immunogenicity of the HIV envelope protein (env) in mice presented either attached to γ-retroviral virus-like-particles (VLPs), associated with cell-derived microsomes or as solubilized recombinant protein (gp160). The magnitude and polyfunctionality of the cellular immune response was enhanced when delivering HIV env in the VLP or microsome form compared to recombinant gp160. Humoral responses measured by antibody titres were comparable across the groups and low levels of antibody neutralization were observed. Lastly, we identified stronger IgG2a class switching in the two particle-delivered antigen vaccinations modalities compared to recombinant gp160.

Published
2011
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9. Evolution of DC-SIGN use revealed by fitness studies of R5 HIV-1 variants emerging during AIDS progression

Author

Karlsson Anders, Purcell Damian FJ, Churchill Melissa J, Sterjovski Jasminka, Kuylenstierna Carlotta, Repits Johanna, Borggren Marie, Albert Jan, Gorry Paul R, and Jansson Marianne

Subjects
Immunologic diseases. Allergy, RC581-607
Abstract

Abstract Background At early stages of infection CCR5 is the predominant HIV-1 coreceptor, but in approximately 50% of those infected CXCR4-using viruses emerge with disease progression. This coreceptor switch is correlated with an accelerated progression. However, those that maintain virus exclusively restricted to CCR5 (R5) also develop AIDS. We have previously reported that R5 variants in these "non-switch virus" patients evolve during disease progression towards a more replicative phenotype exhibiting altered CCR5 coreceptor interactions. DC-SIGN is a C-type lectin expressed by dendritic cells that HIV-1 may bind and utilize for enhanced infection of T cells in trans. To further explore the evolution of the R5 phenotype we analyzed sequential R5 isolates obtained before and after AIDS onset, i.e. at the chronic stage and during end-stage disease, with regard to efficiency of DC-SIGN use in trans-infections. Results Results from binding and trans-infection assays showed that R5 viruses emerging during end-stage AIDS disease displayed reduced ability to use DC-SIGN. To better understand viral determinants underlying altered DC-SIGN usage by R5 viruses, we cloned and sequenced the HIV-1 env gene. We found that end-stage R5 viruses lacked potential N-linked glycosylation sites (PNGS) in the gp120 V2 and V4 regions, which were present in the majority of the chronic stage R5 variants. One of these sites, amino acid position 160 (aa160) in the V2 region, also correlated with efficient use of DC-SIGN for binding and trans-infections. In fitness assays, where head-to-head competitions between chronic stage and AIDS R5 viruses were setup in parallel direct and DC-SIGN-mediated infections, results were further supported. Competitions revealed that R5 viruses obtained before AIDS onset, containing the V2 PNGS at aa160, were selected for in the trans-infection. Whereas, in agreement with our previous studies, the opposite was seen in direct target cell infections where end-stage viruses out-competed the chronic stage viruses. Conclusion Results of our study suggest R5 virus variants with diverse fitness for direct and DC-SIGN-mediated trans-infections evolve within infected individuals at end-stage disease. In addition, our results point to the importance of a glycosylation site within the gp120 V2 region for efficient DC-SIGN use of HIV-1 R5 viruses.

Published
2008
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10. HIV-1 infection induces changes in expression of cellular splicing factors that regulate alternative viral splicing and virus production in macrophages

Author

Purcell Damian FJ, Jans David A, Howard Jane L, O'Brien Kate, Tan Chun H, Nasr-Esfahani Somayeh, Dowling Dinushka, Stoltzfus C Martin, and Sonza Secondo

Subjects
Immunologic diseases. Allergy, RC581-607
Abstract

Abstract Background Macrophages are important targets and long-lived reservoirs of HIV-1, which are not cleared of infection by currently available treatments. In the primary monocyte-derived macrophage model of infection, replication is initially productive followed by a decline in virion output over ensuing weeks, coincident with a decrease in the levels of the essential viral transactivator protein Tat. We investigated two possible mechanisms in macrophages for regulation of viral replication, which appears to be primarily regulated at the level of tat mRNA: 1) differential mRNA stability, used by cells and some viruses for the rapid regulation of gene expression and 2) control of HIV-1 alternative splicing, which is essential for optimal viral replication. Results Following termination of transcription at increasing times after infection in macrophages, we found that tat mRNA did indeed decay more rapidly than rev or nef mRNA, but with similar kinetics throughout infection. In addition, tat mRNA decayed at least as rapidly in peripheral blood lymphocytes. Expression of cellular splicing factors in uninfected and infected macrophage cultures from the same donor showed an inverse pattern over time between enhancing factors (members of the SR family of RNA binding proteins) and inhibitory factors (members of the hnRNP family). While levels of the SR protein SC35 were greatly up-regulated in the first week or two after infection, hnRNPs of the A/B and H groups were down-regulated. Around the peak of virus production in each culture, SC35 expression declined to levels in uninfected cells or lower, while the hnRNPs increased to control levels or above. We also found evidence for increased cytoplasmic expression of SC35 following long-term infection. Conclusion While no evidence of differential regulation of tat mRNA decay was found in macrophages following HIV-1 infection, changes in the balance of cellular splicing factors which regulate alternative viral pre-mRNA splicing were observed. These changes correlated with changes in Tat expression and virus production and could play an important role in viral persistence in macrophages. This mechanism could provide a novel target for control of infection in this critical cell type, which would be necessary for eventual eradication of the virus from infected individuals.

Published
2008
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11. Asn 362 in gp120 contributes to enhanced fusogenicity by CCR5-restricted HIV-1 envelope glycoprotein variants from patients with AIDS

Author

Wang Bin, Saksena Nitin, Purcell Damian FJ, Dunfee Rebecca L, Roche Michael J, Gray Lachlan R, Ellett Anne, Churchill Melissa J, Sterjovski Jasminka, Sonza Secondo, Wesselingh Steven L, Karlsson Ingrid, Fenyo Eva-Maria, Gabuzda Dana, Cunningham Anthony L, and Gorry Paul R

Subjects
Immunologic diseases. Allergy, RC581-607
Abstract

Abstract Background CCR5-restricted (R5) human immunodeficiency virus type 1 (HIV-1) variants cause CD4+ T-cell loss in the majority of individuals who progress to AIDS, but mechanisms underlying the pathogenicity of R5 strains are poorly understood. To better understand envelope glycoprotein (Env) determinants contributing to pathogenicity of R5 viruses, we characterized 37 full-length R5 Envs from cross-sectional and longitudinal R5 viruses isolated from blood of patients with asymptomatic infection or AIDS, referred to as pre-AIDS (PA) and AIDS (A) R5 Envs, respectively. Results Compared to PA-R5 Envs, A-R5 Envs had enhanced fusogenicity in quantitative cell-cell fusion assays, and reduced sensitivity to inhibition by the fusion inhibitor T-20. Sequence analysis identified the presence of Asn 362 (N362), a potential N-linked glycosylation site immediately N-terminal to CD4-binding site (CD4bs) residues in the C3 region of gp120, more frequently in A-R5 Envs than PA-R5 Envs. N362 was associated with enhanced fusogenicity, faster entry kinetics, and increased sensitivity of Env-pseudotyped reporter viruses to neutralization by the CD4bs-directed Env mAb IgG1b12. Mutagenesis studies showed N362 contributes to enhanced fusogenicity of most A-R5 Envs. Molecular models indicate N362 is located adjacent to the CD4 binding loop of gp120, and suggest N362 may enhance fusogenicity by promoting greater exposure of the CD4bs and/or stabilizing the CD4-bound Env structure. Conclusion Enhanced fusogenicity is a phenotype of the A-R5 Envs studied, which was associated with the presence of N362, enhanced HIV-1 entry kinetics and increased CD4bs exposure in gp120. N362 contributes to fusogenicity of R5 Envs in a strain dependent manner. Our studies suggest enhanced fusogenicity of A-R5 Envs may contribute to CD4+ T-cell loss in subjects who progress to AIDS whilst harbouring R5 HIV-1 variants. N362 may contribute to this effect in some individuals.

Published
2007
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12. Influenza, but not SARS‐CoV‐2, infection induces a rapid interferon response that wanes with age and diminished tissue‐resident memory CD8+ T cells.

Author

Nguyen, Thi HO, McAuley, Julie L, Kim, Youry, Zheng, Ming ZM, Gherardin, Nicholas A, Godfrey, Dale I, Purcell, Damian FJ, Sullivan, Lucy C, Westall, Glen P, Reading, Patrick C, Kedzierska, Katherine, and Wakim, Linda M

Subjects
T cells, SARS-CoV-2, TYPE I interferons, INFLUENZA, OLDER people
Abstract

Older individuals exhibit a diminished ability to respond to and clear respiratory pathogens and, as such, experience a higher rate of lung infections with a higher mortality rate. It is unclear why respiratory pathogens impact older people disproportionately. Using human lung tissue from donors aged 22–68 years, we assessed how the immune cell landscape in lungs changes throughout life and investigated how these immune cells respond following in vitro exposure to influenza virus and SARS‐CoV‐2, two clinically relevant respiratory viruses. While the frequency of most immune cell subsets profiled in the human lung remained stable with age, memory CD8+ T cells declined, with the tissue‐resident memory (Trm) CD8+ T‐cell subset being most susceptible to age‐associated attrition. Infection of lung tissue with influenza virus resulted in an age‐associated attenuation in the antiviral immune response, with aged donors producing less type I interferon (IFN), GM‐CSF and IFNγ, the latter correlated with a reduction of IFNγ‐producing memory CD8+ T cells. In contrast, irrespective of donor age, exposure of human lung cells to SARS‐CoV‐2, a pathogen for which all donors were immunologically naïve, did not trigger activation of local immune cells and did not result in the induction of an early IFN response. Our findings show that the attrition of tissue‐bound pathogen‐specific Trm in the lung that occurs with advanced age, or their absence in immunologically naïve individuals, results in a diminished early antiviral immune response which creates a window of opportunity for respiratory pathogens to gain a greater foothold. [ABSTRACT FROM AUTHOR]

Published
2021
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13. No adverse safety or virological changes two years following vorinostat in HIV-infected individuals on antiretroviral therapy

Author

MOTA, Talia M, RASMUSSEN, Thomas A, RHODES, Ajantha, TENNAKOON, Surekha, DANTANARAYANA, Ashanti, WIGHTMAN, Fiona, HAGENAUER, Michelle, RONEY, Janine, SPELMAN, Tim, PURCELL, Damian FJ, McMAHON, James, HOY, Jennifer F, PRINCE, H. Miles, ELLIOTT, Julian H, and LEWIN, Sharon R

Subjects
Vorinostat, Drug-Related Side Effects and Adverse Reactions, CD4-CD8 Ratio, Antineoplastic Agents, HIV Infections, Viral Load, Hydroxamic Acids, Article, CD4 Lymphocyte Count, Histone Deacetylase Inhibitors, Treatment Outcome, Anti-Retroviral Agents, Neoplasms, Journal Article, Humans, Drug Interactions, Longitudinal Studies, Prospective Studies
Abstract

OBJECTIVE: To determine the long term effects of vorinostat on safety and virological parameters in HIV-infected individuals on suppressive antiretroviral therapy (ART).DESIGN: Prospective longitudinal observational extended follow up of 20 HIV-infected individuals on ART previously enrolled in a clinical trial of daily vorinostat 400 mg for 14 days. Extended follow up included visits at 6, 12, 18 and 24 months post enrolment in the initial clinical trial.METHODS: Cell-associated unspliced (CA-US) HIV RNA, total HIV DNA and plasma HIV RNA were quantified by PCR and, CD4+ and CD8+ T cells quantified by flow cytometry. Changes over time in each parameter were assessed using Wilcoxon matched pair signed-rank test and Generalised Estimating Equations for trend modelling.RESULTS: We recorded a total of 31 adverse events (26 grade 1 and 5 grade 2) in all study participants (n = 20). There were no significant changes in the number of CD4+ or CD8+ T cells or plasma HIV RNA over time. In 12 participants for whom baseline samples were available, there were no significant changes in total HIV DNA, CA-US HIV RNA, plasma RNA, or CD4 and CD8+ T cells at 6, 12, 18 or 24 months.CONCLUSIONS: Extended follow up for 24 months did not reveal any long-term toxicity or changes in markers of HIV persistence or transcription in participants on ART who had received 14 days of vorinostat.

Published
2017
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19. Asn 362 in gp120 contributes to enhanced fusogenicity by CCR5-restricted HIV-1 envelope glycoprotein variants from patients with AIDS

Author

Sterjovski, Jasminka, primary, Churchill, Melissa J, additional, Ellett, Anne, additional, Gray, Lachlan R, additional, Roche, Michael J, additional, Dunfee, Rebecca L, additional, Purcell, Damian FJ, additional, Saksena, Nitin, additional, Wang, Bin, additional, Sonza, Secondo, additional, Wesselingh, Steven L, additional, Karlsson, Ingrid, additional, Fenyo, Eva-Maria, additional, Gabuzda, Dana, additional, Cunningham, Anthony L, additional, and Gorry, Paul R, additional

Published
2007
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20. Transcriptional activity of blood-and cerebrospinal fluid–derivednef/long-terminal repeat sequences isolated from a slow progressor infected withnef-deleted human immunodeficiency virus type 1 (HIV-1) who developed HIV-associated dementia

Author

Churchill, Melissa J, primary, Figueiredo, Anna, additional, Cowley, Daniel, additional, Gray, Lachlan, additional, Purcell, Damian FJ, additional, Sullivan, John S, additional, McPhee, Dale A, additional, Wesselingh, Steven L, additional, Brew, Bruce J, additional, and Gorry, Paul R, additional

Published
2006
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21. Use of laser capture microdissection to detect integrated HIV-1 DNA in macrophages and astrocytes from autopsy brain tissues

Author

Churchill, Melissa J, primary, Gorry, Paul R, additional, Cowley, Daniel, additional, Lal, Luxshimi, additional, Sonza, Secondo, additional, Purcell, Damian FJ, additional, Thompson, Katherine A, additional, Gabuzda, Dana, additional, McArthur, Justin C, additional, Pardo, Carlos A, additional, and Wesselingh, Steven L, additional

Published
2006
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24. MYB Elongation Is Regulated by the Nucleic Acid Binding of NFκB p50 to the Intronic Stem-Loop Region

Author

S Gerondakis, Secondo Sonza, Robert G. Ramsay, Honor J. Hugo, Paul A. Ramsland, Xu Huiling, Alina Cures, Damian F. J. Purcell, Thomas J. Gonda, Lloyd Pereira, Jordane Malaterre, Pereira, Lloyd A, Hugo, Honor J, Malaterre, Jordane, Huiling, Xu, Sonza, Secondo, Cures, Alina, Purcell, Damian FJ, Ramsland, Paul A, Gerondakis, Steven, Gonda, Thomas J, and Ramsay, Robert G

Subjects
animal structures, Genes, myb, lcsh:Medicine, Biology, Rel homology domain, Transcriptional regulation, Humans, MYB, Nucleic acid structure, lcsh:Science, P-TEFb, protein Myb, Multidisciplinary, lcsh:R, Inverted Repeat Sequences, fungi, Intron, NF-kappa B p50 Subunit, RNA, Stem-loop, Molecular biology, Introns, DNA-Binding Proteins, Mutation, HIV-1, RNA, Viral, lcsh:Q, Research Article
Abstract

MYB transcriptional elongation is regulated by an attenuator sequence within intron 1 that has been proposed to encode a RNA stem loop (SLR) followed by a polyU tract. We report that NFekBp50 can bind the SLR polyU RNA and promote MYB transcriptional elongation together with NFekBp65. We identified a conserved lysine-rich motif within the Rel homology domain (RHD) of NFekBp50, mutation of which abrogated the interaction of NFekBp50 with the SLR polyU and impaired NFekBp50 mediated MYB elongation. We observed that the TAR RNA-binding region of Tat is homologous to the NFekBp50 RHD lysine-rich motif, a finding consistent with HIV Tat acting as an effector of MYB transcriptional elongation in an SLR dependent manner. Furthermore, we identify the DNA binding activity of NFekBp50 as a key component required for the SLR polyU mediated regulation of MYB. Collectively these results suggest that the MYB SLR polyU provides a platform for proteins to regulate MYB and reveals novel nucleic acid binding properties of NFekBp50 required for MYB regulation. Refereed/Peer-reviewed

Published
2015
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25. Simultaneous evaluation of antibodies that inhibit SARS-CoV-2 variants via multiplex assay.

Author

Lopez E, Haycroft ER, Adair A, Mordant FL, O'Neill MT, Pymm P, Redmond SJ, Lee WS, Gherardin NA, Wheatley AK, Juno JA, Selva KJ, Davis SK, Grimley SL, Harty L, Purcell DF, Subbarao K, Godfrey DI, Kent SJ, Tham WH, and Chung AW

Subjects
Angiotensin-Converting Enzyme 2 metabolism, High-Throughput Screening Assays, Humans, Immune Evasion, Mutation, Antibodies, Neutralizing immunology, Antibodies, Viral immunology, SARS-CoV-2 immunology
Abstract

The SARS-CoV-2 receptor binding domain (RBD) is both the principal target of neutralizing antibodies and one of the most rapidly evolving domains, which can result in the emergence of immune escape mutations, limiting the effectiveness of vaccines and antibody therapeutics. To facilitate surveillance, we developed a rapid, high-throughput, multiplex assay able to assess the inhibitory response of antibodies to 24 RBD natural variants simultaneously. We demonstrate how this assay can be implemented as a rapid surrogate assay for functional cell-based serological methods to measure the SARS-CoV-2 neutralizing capacity of antibodies at the angiotensin-converting enzyme 2-RBD (ACE2-RBD) interface. We describe the enhanced affinity of RBD variants N439K, S477N, Q493L, S494P, and N501Y to the ACE2 receptor and demonstrate the ability of this assay to bridge a major gap for SARS-CoV-2 research, informing selection of complementary monoclonal antibody candidates and the rapid identification of immune escape to emerging RBD variants following vaccination or natural infection.

Published
2021
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26. ED fracture pain management in children.

Author

Gourde J and Damian FJ

Subjects
Analgesics, Opioid therapeutic use, Child, Child, Preschool, Dose-Response Relationship, Drug, Drug Administration Schedule, Education, Continuing, Emergency Medical Services methods, Emergency Service, Hospital statistics & numerical data, Female, Fractures, Bone diagnostic imaging, Fractures, Bone therapy, Humans, Infusions, Intravenous, Male, Musculoskeletal Pain etiology, Pain Management trends, Radiography, Treatment Outcome, Analgesics administration & dosage, Fractures, Bone complications, Musculoskeletal Pain drug therapy, Pain Management standards, Pain Measurement drug effects
Published
2012
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27. Care of the suicidal pediatric patient in the ED: a case study.

Author

Schmid AM, Truog AW, and Damian FJ

Subjects
Adolescent, Asperger Syndrome psychology, Behavior Control methods, Bullying psychology, Child, Child, Preschool, Female, Humans, Male, Nurse-Patient Relations, Organizational Case Studies, Risk Factors, Algorithms, Asperger Syndrome nursing, Dangerous Behavior, Safety Management, Suicide, Attempted psychology, Triage methods
Abstract

Overview: The suicide rate among children and adolescents has increased worldwide over the past few decades, and many who attempt suicide are first seen at EDs. At Childrens Hospital Boston (CHB), an algorithm-the Risk of Suicidality Clinical Practice Algorithm-has been developed to ensure evidence-based care supported by best practice guidelines. The authors of this article provide an overview of pediatric suicide and suicide attempts; describe screening, assessment, and interventions used at CHB; and discuss the nursing implications. An illustrative case study is also provided., Keywords: algorithm, Asperger's syndrome, attempted suicide, bullying, emergency, emergency department, patient safety, pediatrics, pediatric suicide, suicide, suicide screening, triage.

Published
2011
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28. Transcriptional activity of blood-and cerebrospinal fluid-derived nef/long-terminal repeat sequences isolated from a slow progressor infected with nef-deleted human immunodeficiency virus type 1 (HIV-1) who developed HIV-associated dementia.

Author

Churchill MJ, Figueiredo A, Cowley D, Gray L, Purcell DF, Sullivan JS, McPhee DA, Wesselingh SL, Brew BJ, and Gorry PR

Subjects
Gene Deletion, Gene Expression Regulation, Viral, Gene Products, nef blood, Gene Products, nef cerebrospinal fluid, Gene Products, tat genetics, HIV-1 pathogenicity, Humans, Viral Load, Virulence, nef Gene Products, Human Immunodeficiency Virus, tat Gene Products, Human Immunodeficiency Virus, AIDS Dementia Complex virology, Gene Products, nef genetics, HIV Long Terminal Repeat genetics, HIV-1 genetics, Transcriptional Activation
Abstract

The authors studied the transcriptional activity of blood-and cerebrospinal fluid (CSF)-derived nef/long-terminal repeat (LTR) sequences isolated from a slow progressor infected with nef-deleted human immunodeficiency virus type 1 (HIV-1) who developed HIV-associated dementia (HIVD). The transcriptional activity of CSF-derived nef/LTR clones isolated during HIVD was up to 4.5-fold higher than blood-derived clones isolated before and during HIVD when tested under basal, phorbol 12-myristate 13-acetate-(PMA-), and Tat-activated conditions, and was associated with the presence of duplicated nuclear factor (NF)-kappaB and specificity factor-1 (Sp-1) binding sites coupled with a truncated nef sequence, increased replication capacity, and high CSF viral load. Thus, nef and LTR mutations that augment transcription may contribute to neuropathogenesis of nef-deleted HIV-1.

Published
2006
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