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Human immunodeficiency virus (HIV) load is suppressed during dengue virus infection. The NS5A phosphoprotein of GB virus C (a related flavivirus) inhibits HIV replication in vitro. To determine whether the dengue virus NS5 protein inhibits HIV replication, CD4+ T cell lines expressing this protein were generated. HIV replication in dengue virus NS5-expressing cells decreased by >90% compared with control cells (P<.01), and this was mediated in part by decreased HIV coreceptor (CXCR4) expression and increased production of SDF-1. Thus, the dengue virus NS5 protein inhibits HIV replication in vitro, potentially explaining the reduction in HIV load observed during acute dengue virus infection. Copyright © 2008 Infectious Diseases Society of America [ABSTRACT FROM AUTHOR]

Hepatitis C virus (HCV) particles in serum associate with lipoproteins (LPs), and the low-density lipoprotein receptor (LDLr) has been implicated in virus attachment and entry into cells. To clarify the basis of interactions between virus and LPs, we determined whether HCV interacts with human LPs via its envelope glycoprotein E2. The binding of serum-derived virus-like particles, HCV E2, and HCV E2-LP complexes to CD81 and LDLr was studied. Incubation of HCV E2 protein with human and bovine LPs (very low density, low density, and high density) enhanced the binding of both HCV E2 and LPs to CD4(+) lymphoblastoid (MOLT-4) cells, foreskin fibroblasts, and hepatocytes. The binding of HCV E2 to MOLT-4 cells was not enhanced when it was preincubated with lipid-free apoprotein B, which suggests that E2 interacts with the lipid moiety of human lipoproteins. The LP interaction was specific for HCV E2--incubation of HIV gp120 with LPs did not enhance gp120 binding to MOLT-4 cells. The enhanced HCV E2 binding required expression of both human CD81 and LDLr. These data suggest that HCV E2 associates with LDL and that the resulting complex enhances binding of both ligands to cells, which may contribute to the finding that HCV-infected individuals have significantly lower levels of LDL than control subjects. Copyright © 2006 Infectious Diseases Society of America [ABSTRACT FROM AUTHOR]

Objectives GB virus C (GBV-C) infection is associated with delayed mortality in HIV-infected people in most, but not all, studies. Previous investigations of the effect of GBV-C viraemia on response to antiretroviral therapy (ART) were inconclusive. To determine the effect of GBV-C on ART, we retrospectively analysed plasma samples taken from patients in a prospective randomized clinical trial of ART in HIV-positive Brazilians. Methods GBV-C viraemia was characterized by testing stored serum samples from 175 participants by reverse transcriptase–polymerase chain reaction (RT-PCR). Subjects were randomized to receive indinavir ( n=59), zidovudine and lamivudine ( n=58), or zidovudine, lamivudine and indinavir ( n=58). The effect of GBV-C viraemia on the average change in HIV viral load and CD4 count following initiation of therapy was evaluated in a multiple regression analysis. Results The prevalence of GBV-C viraemia was similar to that observed in previous studies (24%). HIV viral load decreased following ART to a significantly greater extent in patients with GBV-C viraemia (by 0.48 log10 HIV-1 RNA copies/mL, P=0.009, adjusting for age, ART group, and baseline CD4 count). Although there was no significant difference in change in CD4 count between individuals with and without GBV-C viraemia overall, CD4 counts were higher following 48 weeks of therapy in GBV-C viraemic individuals receiving the least potent ART regimen (zidovudine and lamivudine) compared with those without GBV-C infection. Conclusions GBV-C viraemia is associated with an enhanced reduction of HIV viral load in response to ART. In this study of treatment-naive individuals during 48 weeks of follow up, patients with GBV-C viraemia had reductions in HIV viral load that were approximately 0.5 log copies/mL greater than those found in patients without GBV-C viraemia. This is similar to reductions observed with nucleoside reverse transcriptase inhibitors. [ABSTRACT FROM AUTHOR]

Living with HIV can challenge core features of a person's sense of identity and ultimately lead to a diminished sense of self regard. Self-regard has been defined as the extent to which a person experiences an integrated sense of identity. Gay men with HIV may also face struggles related to their identity in deciding whether to disclose or conceal their homosexuality. This study examined whether concealment of homosexuality and a person's sense of self regard would be associated with CD4+ cell count over time among HIV seropositive gay men. 53 HIV seropositive gay men completed questionnaires at one time point. CD4+ cell counts were measured at the time of questionnaire completion and 24 months later. Greater self regard at baseline was associated with higher CD4+ counts at 24 months. The association between baseline self regard and CD4+ count at 24 months was strongest among persons with less concealment of homosexuality. [ABSTRACT FROM AUTHOR]

Reverse transcription-polymerase chain reaction was used to identify hepatitis C virus (HCV) RNA in peripheral whole blood (WB) and plasma samples from 15 patients with chronic, unexplained hepatitis. These patients were serologically negative for hepatitis A, B, and C and were classified as having chronic non-A, non-B, non-C hepatitis (NANBNC). HCV RNA was repeatedly detected in WB samples from 10 (67%). In contrast, plasma samples from only 5 were intermittently positive. Statistically, HCV RNA detection in WB was significantly more sensitive than in plasma. Nucleic acid hybridization and HCV genotypic analysis confirmed the specificity of the HCV RNA assay. Liver biopsies from these patients suggested histopathologic differences between HCV RNA-positive and -negative groups. These data demonstrate that HCV infection is present in patients with unexplained chronic hepatitis more frequently than previously believed. Additionally, WB HCV RNA detection is more sensitive than plasma assays in identifying antibody-negative HCV infection. [ABSTRACT FROM AUTHOR]

Introduction: Pandemic influenza vaccine development focuses on the hemagglutinin (HA) antigen for potency and immunogenicity. Antibody responses targeting the neuraminidase (NA) antigen, or the HA stalk domain have been implicated in protection against influenza. Responses to the NA and HA-stalk domain following pandemic inactivated influenza are not well characterized in humans., Material and Methods: In a series of clinical trials, we determine the vaccines' NA content and demonstrate that NA inhibition (NAI) antibody responses increase in a dose-dependent manner following a 2-dose priming series with AS03-adjuvanted influenza A(H7N9) inactivated vaccine (A(H7N9) IIV). NAI antibody responses also increase with interval extension of the 2-dose priming series or following a 5-year delayed boost with a heterologous adjuvanted A(H7N9) IIV. Neither concomitant seasonal influenza vaccination given simultaneously or sequentially, nor use of heterologous A(H7N9) IIVs in the 2-dose priming series had an appreciable effect on NAI antibody responses. Anti-HA stalk antibody responses were minimal and not durable., Conclusions: We provide evidence for strategies to improve anti-neuraminidase responses which can be further standardized for pandemic preparedness., Clinical Trial Registry Numbers: NCT03312231, NCT03318315, NCT03589807, NCT03738241., 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., (Copyright © 2025 Elsevier Ltd. All rights reserved.)

RNA N 6 -methyladenosine (m 6 A) modification is important for regulating gene expression and innate immune responses to viral infection. HIV-1 in vitro infection induces a significant increase in m 6 A modification of cellular RNA; however, whether m 6 A levels of cellular RNA are affected by HIV-1 replication or by antiretroviral therapy (ART) in infected individuals remains unknown. Using dot blot or enzyme-linked immunosorbent assay, we measured RNA m 6 A levels of peripheral blood mononuclear cells (PBMCs) from healthy donors or HIV-1-infected individuals with or without ART. Using a reverse transcription-quantitative polymerase chain reaction array, we quantified expression levels of 84 type-I interferon (IFN-I)-responsive genes in PBMCs from some individuals of these three groups. RNA m 6 A levels in PBMCs from HIV-1 viremic patients ( n = 10) were significantly higher ( p ≤ .0001) compared with ART-treated individuals ( n = 22) or 1.5-fold higher compared with healthy donors ( n = 14). However, the increase in RNA m 6 A levels did not correlate with changes in the expression of 10 m 6 A-regulatory genes. We found significant upregulation and downregulation in the expression of several IFN-I-responsive genes from HIV-1 viremic patients ( n = 4) and ART-treated patients ( n = 6) compared with healthy donors ( n = 5), respectively. Our results suggest that post-transcriptional m 6 A modification may contribute to the regulation of IFN-I-responsive gene expression during HIV-1 infection and ART.

Viruses capable of causing persistent infection have developed sophisticated mechanisms for evading host immunity, and understanding these processes can reveal novel features of the host immune system. One such virus, human pegivirus (HPgV), infects ~15% of the global human population, but little is known about its biology beyond the fact that it does not cause overt disease. We passaged a pegivirus isolate of feral brown rats (RPgV) in immunodeficient laboratory mice to develop a mouse-adapted virus (maPgV) that established persistent high-titer infection in a majority of wild-type laboratory mice. maRPgV viremia was detected in the blood of mice for >300 days without apparent disease, closely recapitulating the hallmarks of HPgV infection in humans. We found a pro-viral role for type-I interferon in chronic infection; a lack of PD-1-mediated tolerance to PgV infection; and multiple mechanisms by which PgV immunity can be achieved by an immunocompetent host. These data indicate that the PgV immune evasion strategy has aspects that are both common and unique among persistent viral infections. The creation of maPgV represents the first PgV infection model in wild-type mice, thus opening the entire toolkit of the mouse host to enable further investigation of this persistent RNA virus infections., Competing Interests: David O’Connor is a founder of Pathogenuity LLC. All other authors have no competing interests to disclose., (Copyright: © 2024 Nennig et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

There is a critical need to understand the effectiveness of serum elicited by different SARS-CoV-2 vaccines against SARS-CoV-2 variants. We describe the generation of reference reagents comprised of post-vaccination sera from recipients of different primary vaccines with or without different vaccine booster regimens in order to allow standardized characterization of SARS-CoV-2 neutralization in vitro. We prepared and pooled serum obtained from donors who received a either primary vaccine series alone, or a vaccination strategy that included primary and boosted immunization using available SARS-CoV-2 mRNA vaccines (BNT162b2, Pfizer and mRNA-1273, Moderna), replication-incompetent adenovirus type 26 vaccine (Ad26.COV2·S, Johnson and Johnson), or recombinant baculovirus-expressed spike protein in a nanoparticle vaccine plus Matrix-M adjuvant (NVX-CoV2373, Novavax). No subjects had a history of clinical SARS-CoV-2 infection, and sera were screened with confirmation that there were no nucleocapsid antibodies detected to suggest natural infection. Twice frozen sera were aliquoted, and serum antibodies were characterized for SARS-CoV-2 spike protein binding (estimated WHO antibody binding units/ml), spike protein competition for ACE-2 binding, and SARS-CoV-2 spike protein pseudotyped lentivirus transduction. These reagents are available for distribution to the research community (BEI Resources), and should allow the direct comparison of antibody neutralization results between different laboratories. Further, these sera are an important tool to evaluate the functional neutralization activity of vaccine-induced antibodies against emerging SARS-CoV-2 variants of concern. IMPORTANCE: The explosion of COVID-19 demonstrated how novel coronaviruses can rapidly spread and evolve following introduction into human hosts. The extent of vaccine- and infection-induced protection against infection and disease severity is reduced over time due to the fall in concentration, and due to emerging variants that have altered antibody binding regions on the viral envelope spike protein. Here, we pooled sera obtained from individuals who were immunized with different SARS-CoV-2 vaccines and who did not have clinical or serologic evidence of prior infection. The sera pools were characterized for direct spike protein binding, blockade of virus-receptor binding, and neutralization of spike protein pseudotyped lentiviruses. These sera pools were aliquoted and are available to allow inter-laboratory comparison of results and to provide a tool to determine the effectiveness of prior vaccines in recognizing and neutralizing emerging variants of concern., Competing Interests: Declaration of competing interest The authors declare no competing interest., (Published by Elsevier B.V.)

Background: Live attenuated vaccines alter immune functions and are associated with beneficial outcomes. We previously demonstrated that live attenuated yellow fever virus (YFV) vaccine (LA-YF-Vax) dampens T-cell receptor (TCR) signaling in vitro via an RNA-based mechanism. We examined study participants before and after LA-YF-Vax to assess TCR-mediated functions in vivo., Methods: Serum samples and peripheral blood mononuclear cells (PBMCs) were obtained before and after LA-YF-Vax (with or without additional vaccines) or quadrivalent influenza vaccine. TCR-mediated activation was determined by interleukin 2 release or phosphorylation of the lymphocyte-specific Src kinase. TCR-regulating phosphatase (protein tyrosine phosphatase receptor type E [PTPRE]) expression was also measured., Results: Compared with prevaccination findings, LA-YF-Vax recipient PBMCs demonstrated transient reduction in interleukin 2 release after TCR stimulation and PTPRE levels, unlike in control participants who received quadrivalent influenza vaccine. YFV was detected in 8 of 14 participants after LA-YF-Vax. After incubation of healthy donor PBMCs in serum-derived extracellular vesicles prepared from LA-YF-Vax recipients, TCR signaling and PTPRE levels were reduced after vaccination, even in participants without detectable YFV RNA., Conclusions: LA-YF-Vax reduces TCR functions and PTPRE levels after vaccination. Extracellular vesicles from serum recapitulated this effect in healthy cells. This likely contributes to the reduced immunogenicity for heterologous vaccines after LA-YF-Vax administration. Identification of specific immune mechanisms related to vaccines should contribute to understanding of the "off-target," beneficial effects of live vaccines., 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. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (Published by Oxford University Press on behalf of Infectious Diseases Society of America 2023.)

Background: Human infections with the avian influenza A(H7N9) virus were first reported in China in 2013 and continued to occur in annual waves. In the 2016/2017 fifth wave, Yangtze River Delta (YRD) lineage viruses, which differed antigenically from those of earlier waves, predominated., Methods: In this phase 2 double-blinded trial we randomized 720 adults ≥ 19 years of age to receive two injections of a YRD lineage inactivated A/Hong Kong/125/2017 fifth-wave H7N9 vaccine, given 21 days apart, at doses of 3.75, 7.5, and 15 µg of hemagglutinin (HA) with AS03A adjuvant and at doses of 15 and 45 µg of HA without adjuvant., Results: Two doses of adjuvanted vaccine were required to induce HA inhibition (HI) antibody titers ≥ 40 in most participants. After two doses of the 15 µg H7N9 formulation, given with or without AS03 adjuvant, the proportion achieving a HI titer ≥ 40 against the vaccine strain at 21 days after the second vaccination was 65 % (95 % CI, 57 %-73 %) and 0 % (95 % CI, 0 %-4%), respectively. Among those who received two doses of the 15 µg adjuvanted formulation the proportion with HI titer ≥ 40 at 21 days after the second vaccination was 76 % (95 % CI, 66 %-84 %) in those 19-64 years of age and 49 % (95 % CI, 37 %-62 %) in those ≥ 65 years of age. Responses to the adjuvanted vaccine formulations did not vary by HA content. Antibody responses declined over time and responses against drifted H7N9 strains were diminished. Overall, the vaccines were well tolerated but, as expected, adjuvanted vaccines were associated with more frequent solicited systemic and local adverse events., Conclusions: AS03 adjuvant improved the immune responses to an inactivated fifth-wave H7N9 influenza vaccine, particularly in younger adults, but invoked lower responses to drifted H7N9 strains. These findings may inform future influenza pandemic preparedness strategies., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [LAJ reports funding support to her institution from Pfizer for the conduct of a clinical trial of an investigational influenza vaccine. NGR is a paid safety consultant for ICON and EMMES, serves on the advisory boards for GSK, Moderna, Sanofi, and Seqirus and her institution received funds for the conduct of research from Sanofi, Lilly, Merck, Quidel, and Pfizer. MJM reported potential competing interests: laboratory research and clinical trials contract funding with Lilly, Pfizer, and Sanofi; personal fees for Scientific Advisory Board service from Merck, Meissa Vaccines, Inc. and Pfizer. EBW has received funding support from Pfizer, Moderna, Sequiris, Najit Technologies Inc, and Clinetic for the conduct of clinical trials and clinical research and has served as an advisor to Vaxcyte and consultant to ILiAD biotechnologies. CAR.’s institution has received funds to conduct clinical research unrelated to this manuscript from BioFire Inc, GSK, MedImmune, Micron, Janssen, Merck, Moderna, Novavax, PaxVax, Pfizer, Regeneron, Sanofi-Pasteur. She is co-inventor of patented RSV vaccine technology unrelated to this manuscript, which has been licensed to Meissa Vaccines, Inc.]., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Human pegivirus (HPgV) is a single-stranded RNA virus​ that is closely related to hepatitis C virus (HCV)​. HPgV has also been shown to infect patients with human immunodeficiency virus (HIV). The mechanisms and disease outcomes of HPgV infections are largely unknown, although it has been implicated in both cancer and neurological diseases. There are no established therapies for HPgV., Objectives: To estimate the prevalence of HPgV in a cohort of HCV/HIV co-infected patients undergoing treatment for HCV with direct acting antivirals (DAA) and investigate the effect of DAA therapy on HPgV infection., Study Design: RNA was extracted from plasma samples collected at time points before, during, and after DAA. HPgV RNA abundance was quantified by droplet digital PCR assays targeting the NS5A and 5'UTR domains and confirmed by RT-qPCR. Clinical, demographic and treatment data were analysed., Results: HPgV RNA was detected and quantified in 26 of 100 patients' plasma (26%) before starting DAA. Patients with detectable HPgV were more likely to be male, had higher peak HIV plasma levels, and a history of injection drug use. Patients receiving sofosbuvir/ledipasvir (n = 9) displayed significantly lower HPgV levels at time of DAA completion and had lower post-DAA HPgV rebound​ levels compared to patients receiving sofosbuvir/velpatasvir (n = 11) although both regimens significantly reduced viremia directly following DAA completion. Sustained suppression of HPgV was ​also observed among patients (n = 2) receiving pegylated-interferon., Conclusions: HPgV RNA ​was frequently detected in HCV/HIV co-infected patients and ​was​ supressed by DAA and pegylated interferon therapies with sofosbuvir-ledipasvir showing greatest antiviral activity. These findings suggest potential treatment strategies for HPgV infections​., Competing Interests: Declaration of Competing Interest All authors have no competing interests to declare., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Inflammasome activation is increased in people with human immunodeficiency virus (PWH), but its relationship with coronary plaque is poorly understood in this setting., Methods: In a large human immunodeficiency virus cardiovascular prevention cohort, relationships between caspase-1, interleukin (IL)-1β, and IL-18 and coronary plaque indices were assessed by multivariate logistic regression., Results: Higher IL-18 and IL-1β were associated with Leaman score, an integrative measure of plaque burden and composition., Conclusions: As Leaman score >5 is associated with cardiovascular events in the general population, future work is needed to determine how the inflammasome relates to events and whether strategies to reduce its activation affect events or plaque progression among PWH., Competing Interests: Potential conflicts of interest. SRS reports grant support through his institution from NIH/NIAID. THS reports grant support through her institution from NIH/NIAID and NIH/National Institute of Allergy and Infectious Diseases outside the submitted work. THB reports equity in Excision BioTherapeutics and serves on their Scientific Advisory Board, outside the submitted work. JTS reports grant support through his institution from NIH/NIAID, the US Department of Veterans Affairs, HRSA (Ryan White HIV/AIDS Program), and Abbvie, DSMB service for Transposon Therapeutics, Inc., and honoraria for lectures at Iowa State University, all outside the submitted work. JLC reports honoraria for presentations for Gilead, MSD, and Janssen and advisory board membership for ViiV Healthcare and Gilead Sciences, all outside the submitted work. JT reports funding by Deutsche Forschungsgesellschaft ([DFG], German Research Foundation), speakers bureau for Siemens Healthcare GmbH and Bayer AG, reviewer for Universimed Cross Media Content GmbH, and consultant for Core Lab Black Forrest GmbH, all outside the submitted work. JSC reports consulting fees from Merck, outside the submitted work. MVZ reports grant support through her institution from NIH/NIAID and Gilead Sciences, Inc. relevant to the conduct of the study, as well as grants from NIH/NIAID and NIH/National Heart, Lung, and Blood Institute (NHLBI) outside the submitted work. CM reports institutional research support by Lilly and honoraria from ViiV Healthcare and Gilead Sciences for advisory board membership, all outside the submitted work. CJF reports grant support through his institution from Gilead Sciences, ViiV Healthcare, GSK, Janssen, Abbvie, Merck, Amgen, and Cytodyn; personal fees from Theratechnologies and ViiV for consulting and participation on Advisory Board unrelated to REPRIEVE; and DSMB Chair for Intrepid Study, all outside the submitted work. JAA reports institutional research support for clinical trials from Atea, Emergent Biosolutions, Frontier Technologies, Gilead Sciences, GlaxoSmithKline, Janssen, Merck, Pfizer, Regeneron, and ViiV Healthcare and personal fees for advisory boards from GlaxoSmithKline/ViiV and Merck; and participation on DSMB for Kintor Pharmaceuticals, all outside the submitted work. HJR reports grants from NIH/NHLBI and Kowa Pharmaceuticals during the conduct of the study, as well as grants from NIH/NIAID, NIH/NHLBI, NIH/National Institute of Diabetes and Digestive and Kidney Diseases, and NIH/National Institute on Aging, outside the submitted work. MTL reports grant support through his institution from Kowa Pharmaceuticals America, Inc., for the conduct of the study. He also reports grant support from MedImmune/AstraZeneca and personal fees from PQBypass, outside of the current work. SKG reports grant support through his institution from NIH, Kowa Pharmaceuticals America, Inc., Gilead Sciences, Inc., and ViiV Healthcare for the conduct of the study; personal fees from Theratechnologies and ViiV; and service on the Scientific Advisory Board of Marathon Asset Management, all outside the submitted work. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Viral vector-mediated gene therapies have the potential to treat many human diseases; however, host immune responses against the vector and/or the transgene pose a safety risk to the patients and can negatively impact product efficacy. Thus, novel strategies to reduce vector immunogenicity are critical for the advancement of these therapies. T cell activation (TCA) is required for the development of immune responses during gene therapy. We hypothesized that modulation of TCA by incorporating a novel viral immunomodulatory factor into a viral vector may reduce unwanted TCA and immune responses during gene therapy. To test this hypothesis, we identified an immunomodulatory domain of the hepatitis C virus (HCV) NS protein 5A (NS5A) protein and studied the effect of viral vectors expressing NS5A peptide on TCA. Lentiviral vector-mediated expression of a short 20-mer peptide derived from the NS5A protein in human T cells was sufficient to inhibit TCA. Synthetic 20-mer NS5A peptide also inhibited TCA in primary human T cells. Mechanistically, the NS5A protein interacted with Lck and inhibited proximal TCR signaling. Importantly, NS5A peptide expression did not cause global T cell signaling dysfunction as distal T cell signaling was not inhibited. Finally, recombinant adeno-associated virus (AAV) vector expressing the 20-mer NS5A peptide reduced both the recall antigen and the TCR-mediated activation of human T cells and did not cause global T cell signaling dysfunction. Together, these data suggest that expression of a 20-mer NS5A peptide by an AAV vector may reduce unwanted TCA and may contribute to lower vector immunogenicity during gene therapy., (© 2021. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.)

Coinfections are more common in patients with cystic fibrosis and bronchiectasis. Infiltrates on imaging studies are seen more commonly in patients with coinfections, but coinfections did not affect treatment outcomes of pulmonary Mycobacterium avium complex., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Two groups identified a novel human flavivirus in the mid-1990s. One group named the virus hepatitis G virus (HGV) and the other named it GB Virus type C (GBV-C). Sequence analyses found these two isolates to be the same virus, and subsequent studies found that the virus does not cause hepatitis despite sharing genome organization with hepatitis C virus. Although HGV/GBV-C infection is common and may cause persistent infection in humans, the virus does not appear to directly cause any other known disease state. Thus, the virus was renamed "human pegivirus 1" (HPgV-1) for "persistent G" virus. HPgV-1 is found primarily in lymphocytes and not hepatocytes, and several studies found HPgV-1 infection associated with prolonged survival in people living with HIV. Co-infection of human lymphocytes with HPgV-1 and HIV inhibits HIV replication. Although three viral proteins directly inhibit HIV replication in vitro , the major effects of HPgV-1 leading to reduced HIV-related mortality appear to result from a global reduction in immune activation. HPgV-1 specifically interferes with T cell receptor signaling (TCR) by reducing proximal activation of the lymphocyte specific Src kinase LCK. Although TCR signaling is reduced, T cell activation is not abolished and with sufficient stimulus, T cell functions are enabled. Consequently, HPgV-1 is not associated with immune suppression. The HPgV-1 immunomodulatory effects are associated with beneficial outcomes in other diseases including Ebola virus infection and possibly graft-versus-host-disease following stem cell transplantation. Better understanding of HPgV-1 immune escape and mechanisms of inflammation may identify novel therapies for immune-based diseases., Competing Interests: The author JS has patents related to the use of GB virus C in the potential treatment of HIV-1 infection., (Copyright © 2022 Stapleton.)

The pathogenesis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is not completely understood. SARS-CoV-2 infection frequently causes significant immune function consequences including reduced T cell numbers and enhanced T cell exhaustion that contribute to disease severity. The extent to which T cell effects are directly mediated through infection or indirectly result from infection of respiratory-associated cells is unclear. We show that primary human T cells express sufficient levels of angiotensin converting enzyme 2 (ACE-2), the SARS-CoV-2 receptor, to mediate viral binding and entry into T cells. We further show that T cells exposed to SARS-CoV-2 particles demonstrate reduced proliferation and apoptosis compared to uninfected controls, indicating that direct interaction of SARS-CoV-2 with T cells may alter T cell growth, activation, and survival. Regulation of T cell activation and/or turnover by SARS-CoV-2 may contribute to impaired T cell function observed in patients with severe disease., (Published by Oxford University Press for the Infectious Diseases Society of America 2021.)

Air pollution particulate matter (PM) is associated with SARS-CoV-2 infection and severity, although mechanistic studies are lacking. We tested whether airway surface liquid (ASL) from primary human airway epithelial cells is antiviral against SARS-CoV-2 and human alphacoronavirus 229E (CoV-229E) (responsible for common colds), and whether PM (urban, indoor air pollution [IAP], volcanic ash) affected ASL antiviral activity. ASL inactivated SARS-CoV-2 and CoV-229E. Independently, urban PM also decreased SARS-CoV-2 and CoV-229E infection, and IAP PM decreased CoV-229E infection. However, in combination, urban PM impaired ASL's antiviral activity against both viruses, and the same effect occurred for IAP PM and ash against SARS-CoV-2, suggesting that PM may enhance SARS-CoV-2 infection., (© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: Extracellular vesicles (EVs) are regulators of cell-cell interactions and mediators of horizontal transfer of bioactive molecules between cells. EV-mediated cell-cell interactions play roles in physiological and pathophysiological processes, which maybe modulated by exposure to pathogens and cocaine use. However, the effect of pathogens and cocaine use on EV composition and function are not fully understood., Results: Here, we used systems biology and multi-omics analysis to show that HIV infection (HIV +) and cocaine (COC) use (COC +) promote the release of semen-derived EVs (SEV) with dysregulated extracellular proteome (exProtein), miRNAome (exmiR), and exmiR networks. Integrating SEV proteome and miRNAome revealed a significant decrease in the enrichment of disease-associated, brain-enriched, and HIV-associated miR-128-3p (miR-128) in HIV + COC + SEV with a concomitant increase in miR-128 targets-PEAK1 and RND3/RhoE. Using two-dimensional-substrate single cell haptotaxis, we observed that in the presence of HIV + COC + SEV, contact guidance provided by the extracellular matrix (ECM, collagen type 1) network facilitated far-ranging haptotactic cues that guided monocytes over longer distances. Functionalizing SEV with a miR-128 mimic revealed that the strategic changes in monocyte haptotaxis are in large part the result of SEV-associated miR-128., Conclusions: We propose that compositionally and functionally distinct HIV + COC + and HIV-COC- SEVs and their exmiR networks may provide cells relevant but divergent haptotactic guidance in the absence of chemotactic cues, under both physiological and pathophysiological conditions., (© 2021. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Human pegivirus (HPgV) infects peripheral leukocytes but was recently shown to be a neurotropic virus associated with leukoencephalitis in humans. In the present study, we investigated the neural cell tropism of HPgV as well as its effects on host immune responses. HPgV wild type (WT) and a mutant virus with a deletion in the HPgV NS2 gene (ΔNS2) were able to productively infect human astrocytes and microglia but not neurons or an oligodendrocyte-derived cell line. Of note, the ΔNS2 virus replicated better than WT pegivirus in astrocytes, with both viruses being able to subsequently infect and spread in fresh human astrocyte cultures. Infection of human glia by HPgV WT and ΔNS2 viruses resulted in suppression of peroxisome-associated genes, including PEX11B , ABCD1 , PEX7 , ABCD3 , PEX3 , and PEX5L , during peak viral production, which was accompanied by reduced expression of IFNB , IRF3 , IRF1 , and MAVS , particularly in ΔNS2-infected cells. These data were consistent with analyses of brain tissue from patients infected with HPgV in which we observed suppression of peroxisome and type I interferon gene transcripts, including PEX11B , ABCD3 , IRF1 , and IRF3 , with concurrent loss of PMP70 immunoreactivity in glia. Our data indicate that human astrocytes and microglia are permissive to HPgV infection, resulting in peroxisome injury and suppressed antiviral signaling that is influenced by viral diversity. IMPORTANCE Human pegiviruses are detected in 1 to 5% of the general population, principally infecting leukocytes, although their effects on human health remain uncertain. Here, we show that human pegivirus infects specific neural cell types in culture and human brain and, like other neurotropic flaviviruses, causes suppression of peroxisome and antiviral signaling pathways, which could favor ongoing viral infection and perhaps confer susceptibility to the development of neurological disease.

Background: There are limited data regarding immunological correlates of protection for the modified vaccinia Ankara (MVA) smallpox vaccine., Methods: A total of 523 vaccinia-naive subjects were randomized to receive 2 vaccine doses, as lyophilized MVA given subcutaneously, liquid MVA given subcutaneously (liquid-SC group), or liquid MVA given intradermally (liquid-ID group) 28 days apart. For a subset of subjects, antibody-dependent cellular cytotoxicity (ADCC), interferon-γ release enzyme-linked immunospot (ELISPOT), and protein microarray antibody-binding assays were conducted. Protein microarray responses were assessed for correlations with plaque reduction neutralization titer (PRNT), enzyme-linked immunosorbent assay, ADCC, and ELISPOT results., Results: MVA elicited significant microarray antibody responses to 15 of 224 antigens, mostly virion membrane proteins, at day 28 or 42, particularly WR113/D8L and WR101H3L. In the liquid-SC group, responses to 9 antigens, including WR113/D8L and WR101/H3L, correlated with PRNT results. Three were correlated in the liquid-ID group. No significant correlations were observed with ELISPOT responses. In the liquid-ID group, WR052/F13L, a membrane glycoprotein, correlated with ADCC responses., Conclusions: MVA elicited antibodies to 15 vaccinia strain antigens representing virion membrane. Antibody responses to 2 proteins strongly increased and significantly correlated with increases in PRNT. Responses to these proteins are potential correlates of protection and may serve as immunogens for future vaccine development., Clinical Trials Registration: NCT00914732., (© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

The COVID-19 pandemic has caused a high demand for respiratory protection among health care workers in hospitals, especially surgical N95 filtering facepiece respirators (FFRs). To aid in alleviating that demand, a survey of commercially available filter media was conducted to determine whether any could serve as a substitute for an N95 FFR while held in a 3D-printed mask (Stopgap Surgical Face Mask from the NIH 3D Print Exchange). Fourteen filter media types and eight combinations were evaluated for filtration efficiency, breathing resistance (pressure drop), and liquid penetration. Additional testing was conducted to evaluate two filter media disinfection methods in the event that the filters were reused in a hospital setting. Efficiency testing was conducted in accordance with the procedures established for approving an N95 FFR. One apparatus used a filter-holding device and another apparatus employed a manikin head to which the 3D-printed mask could be sealed. The filter media and combinations exhibited collection efficiencies varied between 3.9% and 98.8% when tested with a face velocity comparable to that of a standard N95 FFR at the 85 L min -1 used in the approval procedure. Breathing resistance varied between 10.8 to >637 Pa (1.1 to > 65 mm H 2 O). When applied to the 3D-printed mask efficiency decreased by an average of 13% and breathing resistance increased 4-fold as a result of the smaller surface area of the filter media when held in that mask compared to that of an N95 FFR. Disinfection by dry heat, even after 25 cycles, did not significantly affect filter efficiency and reduced viral infectivity by > 99.9%. However, 10 cycles of 59% vaporized H 2 O 2 significantly (p < 0.001) reduced filter efficiency of the media tested. Several commercially available filter media were found to be potential replacements for the media used to construct the typical cup-like N95 FFR. However, their use in the 3D-printed mask demonstrated reduced efficiency and increased breathing resistance at 85 L min -1 .

Background: The increasing global prevalence of pulmonary nontuberculous mycobacteria (NTM) disease has called attention to challenges in NTM diagnosis and management. This study was conducted to understand management and outcomes of patients with pulmonary NTM disease at diverse centers across the United States., Methods: We conducted a 10-year (2005-2015) retrospective study at 7 Vaccine and Treatment Evaluation Units to evaluate pulmonary NTM treatment outcomes in human immunodeficiency virus-negative adults. Demographic and clinical information was abstracted through medical record review. Microbiologic and clinical cure were evaluated using previously defined criteria., Results: Of 297 patients diagnosed with pulmonary NTM, the most frequent NTM species were Mycobacterium avium-intracellulare complex (83.2%), M. kansasii (7.7%), and M. abscessus (3.4%). Two hundred forty-five (82.5%) patients received treatment, while 45 (15.2%) were followed without treatment. Eighty-six patients had available drug susceptibility results; of these, >40% exhibited resistance to rifampin, ethambutol, or amikacin. Of the 138 patients with adequate outcome data, 78 (56.5%) experienced clinical and/or microbiologic cure. Adherence to the American Thoracic Society/Infectious Diseases Society of America (ATS/IDSA) treatment guidelines was significantly more common in patients who were cured (odds ratio, 4.5, 95% confidence interval, 2.0-10.4; P < .001). Overall mortality was 15.7%., Conclusions: Despite ATS/IDSA Guidelines, management of pulmonary NTM disease was heterogeneous and cure rates were relatively low. Further work is required to understand which patients are suitable for monitoring without treatment and the impact of antimicrobial therapy on pulmonary NTM morbidity and mortality., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: Personal protective equipment (PPE) is a critical need during the coronavirus disease 2019 (COVID-19) pandemic. Alternative sources of surgical masks, including 3-dimensionally (3D) printed approaches that may be reused, are urgently needed to prevent PPE shortages. Few data exist identifying decontamination strategies to inactivate viral pathogens and retain 3D-printing material integrity., Objective: To test viral disinfection methods on 3D-printing materials., Methods: The viricidal activity of common disinfectants (10% bleach, quaternary ammonium sanitizer, 3% hydrogen peroxide, or 70% isopropanol and exposure to heat (50°C, and 70°C) were tested on four 3D-printed materials used in the healthcare setting, including a surgical mask design developed by the Veterans' Health Administration. Inactivation was assessed for several clinically relevant RNA and DNA pathogenic viruses, including severe acute respiratory coronavirus virus 2 (SARS-CoV-2) and human immunodeficiency virus 1 (HIV-1)., Results: SARS-CoV-2 and all viruses tested were completely inactivated by a single application of bleach, ammonium quaternary compounds, or hydrogen peroxide. Similarly, exposure to dry heat (70°C) for 30 minutes completely inactivated all viruses tested. In contrast, 70% isopropanol reduced viral titers significantly less well following a single application. Inactivation did not interfere with material integrity of the 3D-printed materials., Conclusions: Several standard decontamination approaches effectively disinfected 3D-printed materials. These approaches were effective in the inactivation SARS-CoV-2, its surrogates, and other clinically relevant viral pathogens. The decontamination of 3D-printed surgical mask materials may be useful during crisis situations in which surgical mask supplies are limited.

Background: Diverse vaccination outcomes and protection levels among different populations pose a serious challenge to the development of an effective malaria vaccine. Co-infections are among many factors associated with immune dysfunction and sub-optimal vaccination outcomes. Chronic, asymptomatic viral infections can contribute to the modulation of vaccine efficacy through various mechanisms. Human Pegivirus-1 (HPgV-1) persists in immune cells thereby potentially modulating immune responses. We investigated whether Pegivirus infection influences vaccine-induced responses and protection in African volunteers undergoing whole P. falciparum sporozoites-based malaria vaccination and controlled human malaria infections (CHMI)., Methods: HPgV-1 prevalence was quantified by RT-qPCR in plasma samples of 96 individuals before, post vaccination with PfSPZ Vaccine and after CHMI in cohorts from Tanzania and Equatorial Guinea. The impact of HPgV-1 infection was evaluated on (1) systemic cytokine and chemokine levels measured by Luminex, (2) PfCSP-specific antibody titers quantified by ELISA, (3) asexual blood-stage parasitemia pre-patent periods and parasite multiplication rates, (4) HPgV-1 RNA levels upon asexual blood-stage parasitemia induced by CHMI., Results: The prevalence of HPgV-1 was 29.2% (28/96) and sequence analysis of the 5' UTR and E2 regions revealed the predominance of genotypes 1, 2 and 5. HPgV-1 infection was associated with elevated systemic levels of IL-2 and IL-17A. Comparable vaccine-induced anti-PfCSP antibody titers, asexual blood-stage multiplication rates and pre-patent periods were observed in HPgV-1 positive and negative individuals. However, a tendency for higher protection levels was detected in the HPgV-1 positive group (62.5%) compared to the negative one (51.6%) following CHMI. HPgV-1 viremia levels were not significantly altered after CHMI., Conclusions: HPgV-1 infection did not alter PfSPZ Vaccine elicited levels of PfCSP-specific antibody responses and parasite multiplication rates. Ongoing HPgV-1 infection appears to improve to some degree protection against CHMI in PfSPZ-vaccinated individuals. This is likely through modulation of immune system activation and systemic cytokines as higher levels of IL-2 and IL17A were observed in HPgV-1 infected individuals. CHMI is safe and well tolerated in HPgV-1 infected individuals. Identification of cell types and mechanisms of both silent and productive infection in individuals will help to unravel the biology of this widely present but largely under-researched virus.

Objectives: Francisella tularensis , the causative agent of tularaemia, is an exceptionally infectious bacterium, potentially fatal for humans if left untreated and with the potential to be developed as a bioweapon. Both natural infection and live-attenuated vaccine strain (LVS) confer good protection against tularaemia. LVS vaccination is traditionally administered by scarification, and the formation of a cutaneous reaction or take at the vaccination site is recognised as a clinical correlate of protection. Although previous studies have suggested that high antibody titres following vaccination might serve as a useful surrogate marker, the immunological correlates of protection remain unknown., Methods: We investigated the host T-cell-mediated immune (T-CMI) responses elicited following immunisation with LVS vaccine formulated by the DynPort Vaccine Company (DVC-LVS) or the United States Army Medical Research Institute of Infectious Diseases (USAMRIID-LVS). We compared T-CMI responses prompted by these vaccines and correlated them with take size., Results: We found that both LVS vaccines elicited similar T-CMI responses. Interestingly, take size associated with the T cells' ability to proliferate, secrete IFN-γ and mobilise degranulation, suggesting that these responses play an essential role in tularaemia protection., Conclusions: These results renew the appreciation for vaccination through the scarification as a prime route of inoculation to target pathogens driving specific T-CMI responses and provide further evidence that T-CMI plays a role in protection from tularaemia., Competing Interests: The authors declare no conflict of interest., (© 2021 The Authors. Clinical & Translational Immunology published by John Wiley & Sons Australia, Ltd on behalf of Australian and New Zealand Society for Immunology, Inc.)

Although extracellular vesicle (EV) surface electrostatic properties (measured as zeta potential, ζ-potential) have been reported by many investigators, the biophysical implications of charge and EV origin remains uncertain. Here, we compared the ζ-potential of human blood EVs (BEVs) and semen EVs (SEVs) from 26 donors that were HIV-infected (HIV+, n = 13) or HIV uninfected (HIV-, n = 13). We found that, compared to BEVs that bear neutral surface charge, SEVs were significantly more negatively charged, even when BEVs and SEVs were from the same individual. Comparison of BEVs and SEVs from HIV- and HIV+ groups revealed subtle HIV-induced alteration in the ζ-potential of EVs, with the effect being more significant in SEVs (∆ζ-potential = -8.82 mV, p -value = 0.0062) than BEVs (∆ζ-potential = -1.4 mV, p -value = 0.0462). These observations were validated by differences in the isoelectric point (IEP) of EVs, which was in the order of HIV + SEV ≤ HIV-SEV ≪ HIV + BEV ≤ HIV-BEV. Functionally, the rate and efficiency of SEV internalization by the human cervical epithelial cell line, primary peripheral blood lymphocytes, and primary blood-derived monocytes were significantly higher than those of BEVs. Mechanistically, removal of sialic acids from the surface of EVs using neuraminidase treatment significantly decreased SEV's surface charge, concomitant with a substantial reduction in SEV's internalization. The neuraminidase effect was independent of HIV infection and insignificant for BEVs. Finally, these results were corroborated by enrichment of glycoproteins in SEVs versus BEVs. Taken together, these findings uncover fundamental tissue-specific differences in surface electrostatic properties of EVs and highlight the critical role of surface charge in EV/target cell interactions.

Background: Human pegivirus (HPgV) is a single-strand RNA virus belonging to the Flaviviridae. Although no definitive association between HPgV infection and disease has been identified, previous studies have suggested an association of HPgV viremia with risk of lymphomas., Methods: We conducted a systematic review and meta-analysis, including 1 cohort study and 14 case-control studies, assessing the association of HPgV viremia with adult lymphomas. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using a random-effects model, overall and by geographic region and lymphoma subtype., Results: The overall OR for lymphoma was 2.85 (95% CI, 1.98-4.11), with statistically significantly elevated ORs observed in 8 of 15 studies. There was a small amount of heterogeneity among studies (I2 = 28.9%; Q = 18.27, P = .16), and the funnel plot provided no evidence for publication bias. The strongest association with lymphoma risk was observed for studies from Southern Europe (OR, 5.68 [95% CI, 1.98-16.3]), whereas weaker ORs (with 95% CIs) were observed for studies from North America (2.24 [1.76-2.85]), Northern Europe (2.90 [.45-18.7), and the Middle East (2.51 [.87-7.27]), but all of similar magnitude. Participants with HPgV viremia had statistically significantly increased risks (OR [95% CI]) for developing diffuse large B-cell (3.29 [1.63-6.62]), follicular (3.01 [1.95-4.63]), marginal zone (1.90 [1.13-3.18]), and T-cell (2.11 [1.17-3.89]) lymphomas, while the risk for Hodgkin lymphoma (3.53 [.48-25.9]) and chronic lymphocytic leukemia (1.45 [.45-4.66]) were increased but did not achieve statistical significance., Conclusions: This meta-analysis supports a positive association of HPgV viremia with lymphoma risk, overall and for the major lymphoma subtypes., (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Introduction: Subjects with rheumatoid arthritis (RA) receiving tumor necrosis factor-inhibiting (TNFi) therapies are at risk for severe influenza, and may respond less well to influenza vaccine. We examined the safety and immunogenicity of high dose influenza vaccine (HD) compared to standard dose vaccine (SD) in participants with RA receiving stable TNFi., Methods: A randomized, double-blinded, Phase II study was conducted in adults with RA receiving TNFi, and healthy, gender and age-matched control subjects. Participants were immunized with HD (Sanofi Pasteur Fluzone High Dose [60 mcg × 3 strains]) or SD (Sanofi Pasteur Fluzone® [15 mcg × 3 strains]) intramuscularly (IM). A self-administered memory aid recorded temperature and systemic and local adverse events (AEs) for 8 days, and safety was evaluated and serum obtained to measure HAI activity on days 7, 21 and 180 days following vaccination., Results: A greater proportion of RA subjects who received HD seroconverted at day 21 compared to SD, although this was not statistically significant. GMT antibody responses in RA subjects who received HD compared to SD were greater for all strains on day 21, and this was significant for H1N1. Seroconversion rates and GMT values were not different between RA subjects and control subjects. There were no safety concerns for HD or SD in RA subjects, and RA-related symptoms did not differ between SD and HD recipients by a RA-symptom questionnaire (RAPID 3)., Conclusions: TNF-inhibitor therapy in people with RA did not appear to influence the immunogenicity of either SD or HD. Influenza seroconversion and GMT values were higher among RA subjects receiving HD compared to SD; however, differences were small and a larger study is needed to validate these findings. Given the apparent risk of increased influenza-related morbidity and mortality among immune compromised subjects, the higher GMT values generated by HD may be beneficial., 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 Ltd.)

The vaginal microbiota influences sexual transmission of human immunodeficiency virus type 1 (HIV-1). Colonization of the vaginal tract is normally dominated by Lactobacillus species. Both Lactobacillus and Enterococcus faecalis may secrete reutericyclin, which inhibits the growth of a variety of pathogenic bacteria. Increasing evidence suggests a potential therapeutic role for an analogue of reutericyclin, glycerol monolaurate (GML), against microbial pathogens. Previous studies using a macaque vaginal simian immunodeficiency virus (SIV) transmission model demonstrated that GML reduces transmission and alters immune responses to infection in vitro Previous studies showed that structural analogues of GML negatively impact other enveloped viruses. We sought to expand understanding of how GML inhibits HIV-1 and other enveloped viruses and show that GML restricts HIV-1 entry post-CD4 engagement at the step of coreceptor binding. Further, HIV-1 and yellow fever virus (YFV) particles were more sensitive to GML interference than particles "matured" by proteolytic processing. We show that high-pressure-liquid-chromatography (HPLC)-purified reutericyclin and reutericyclin secreted by Lactobacillus inhibit HIV-1. These data emphasize the importance and protective nature of the normal vaginal flora during viral infections and provide insights into the antiviral mechanism of GML during HIV-1 infection and, more broadly, to other enveloped viruses. IMPORTANCE A total of 340 million sexually transmitted infections (STIs) are acquired each year. Antimicrobial agents that target multiple infectious pathogens are ideal candidates to reduce the number of newly acquired STIs. The antimicrobial and immunoregulatory properties of GML make it an excellent candidate to fit this critical need. Previous studies established the safety profile and antibacterial activity of GML against both Gram-positive and Gram-negative bacteria. GML protected against high-dose SIV infection and reduced inflammation, which can exacerbate disease, during infection. We found that GML inhibits HIV-1 and other human-pathogenic viruses (yellow fever virus, mumps virus, and Zika virus), broadening its antimicrobial range. Because GML targets diverse infectious pathogens, GML may be an effective agent against the broad range of sexually transmitted pathogens. Further, our data show that reutericyclin, a GML analog expressed by some lactobacillus species, also inhibits HIV-1 replication and thus may contribute to the protective effect of Lactobacillus in HIV-1 transmission., (Copyright © 2020 Welch et al.)

Traditional replicating smallpox vaccines are associated with serious safety concerns in the general population and are contraindicated in immunocompromised individuals. However, this very population remains at greatest risk for severe complications following viral infections, making vaccine prevention particularly relevant. MVA-BN was developed as a non-replicating smallpox vaccine that is potentially safer for people who are immunocompromised. In this phase II trial, 3 MVA-BN dosing regimens were evaluated for safety, tolerability, and immunogenicity in persons with HIV (PWH) who had a history of AIDS. Following randomization, 87 participants who were predominately male and African American received either 2 standard doses on weeks 0 and 4 in the standard dose (SD) group (N = 27), 2 double-standard doses on the same schedule in the double dose (DD) group (N = 29), or 3 standard doses on weeks 0, 4 and 12 in the booster dose (BD) group (N = 31). No safety concerns were identified, and injection site pain was the most commonly reported solicited adverse event (AE) in all groups (66.7%), with no meaningful differences between groups. The incidence of severe (Grade 3) AEs was low across groups and no serious AEs or AEs of special interest considered related to study vaccine were reported. Doubling the standard MVA-BN dose had no significant effect on induction of neutralizing antibodies, with 100% seroconversion and comparable GMTs at week 6 in the SD and DD groups (78.9 and 100.3, respectively). A booster dose significantly increased peak neutralizing titers in the BD group (GMT: 281.1), which remained elevated at 12 months (GMT: 45.3) compared to the SD (GMT: 6.2) and DD (GMT: 10.6) groups. However, based on the immune response previously reported for healthy participants, a third dose (booster) does not appear necessary, even for immunocompromised participants. Clinical Trial Registry Number: NCT02038881., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: The authors Heinz Weidenthaler, Darja Schmidt, Brigitte Koenen, Günter Silbernagl, and Katrin Nopora are employees and stakeholders of Bavarian Nordic GmbH; Paul Chaplin is the company CEO. Drs. Edgar Turner Overton, Steven J. Lawrence, and Jack T. Stapleton were investigators for this study, which was funded by Bavarian Nordic. All authors attest they meet the ICMJE criteria for authorship., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Semen exosomes (SE) inhibit HIV infection. However, the effect of SE on cell activation and inflammation remains unknown. We characterized the response of peripheral blood mononuclear cells (PBMCs) from HIV-uninfected and antiretroviral therapy-suppressed HIV-infected (HIV+) subjects to SE. Quiescent PBMCs or T-cell receptor (TCR)-activated PBMCs from HIV- and HIV+ donors were stimulated with SE in the presence/absence of ex vivo HIV infection. In HIV-infected PBMCs, SE did not reactivate HIV, did not induce lymphoblast development, nor increase CD69+/CD25+ numbers. Furthermore, SE inhibited de novo HIV infection without altering cell activation. SE also asynchronously downregulated HIV-inducible IL1β, IL8, and TNFα and upregulated CXCL10. These data suggest that SE inhibits HIV infection and production of HIV-induced proinflammatory cytokines while preserving lymphocyte activation., (© 2019 Federation of European Biochemical Societies.)

Blood and semen are important body-fluids that carry exosomes for bioinformation transmission. Therefore, characterization of their proteomes is necessary for understanding body-fluid-specific physiologic and pathophysiologic functions. Using systematic multifactorial proteomic profiling, we characterized the proteomes of exosomes and exosome-free fractions from autologous blood and semen from three HIV-uninfected and three HIV-infected participants (total of 24 samples). We identified exosome-based protein signatures specific to blood and semen along with HIV-induced tissue-dependent proteomic perturbations. We validated our findings with samples from 16 additional donors and showed that unlike blood exosomes (BE), semen exosomes (SE) are enriched in clusterin. SE but not BE promote Protein·Nucleic acid binding and increase cell adhesion irrespective of HIV infection. This is the first comparative study of the proteome of autologous BE and SE. The proteins identified may be developed as biomarkers applicable to different fields of medicine, including reproduction and infectious diseases., (© 2020 Kaddour et al.)

Background: Extracellular vesicles (EVs) are cell-derived vesicles with diverse functions in intercellular communication including disease and infection, and EVs seem to influence HIV-1 pathogenesis. EVs isolated from HIV-1-uninfected semen (SE), but not blood (BE), contain factors that interfere with HIV-1 infection and replication in target cells. The reason for this dichotomy is unknown. Furthermore, the effect of HIV-1 infection and antiretroviral (ARV) drugs on the anti-HIV-1 effects of SE and BE is unknown. Here, we characterize EVs and EV-free plasma isolated from HIV-infected donor semen and blood and their effects on HIV infection., Methods: EVs and EV-free plasma were purified from autologous blood and semen of HIV-negative, HIV-infected antiretroviral therapy (ART)-naïve, and HIV-infected ART-treated participants. HIV infection was assessed in a TZM-bl cell reporter system. ARV concentrations were analyzed using liquid chromatography-mass spectrometry., Results: SE isolated from both HIV-negative and HIV-infected, ART-naïve donors inhibited HIV-1 infection, but BE and semen and blood EV-free plasma did not. By contrast, BE, SE, and EV-free plasma from HIV-infected, ART-treated donors inhibited HIV-1. Importantly, exosomes isolated from ART-treated donors contained concentrations of ARV drugs (ART-EVs) at biologically relevant inhibitory levels., Conclusions: The HIV-1-inhibitory phenotype of SE is independent of donor HIV-1 or ART status, and ARV drugs and their metabolites are SE- and BE-associated in vivo.

Semen exosomes (SE) from HIV-uninfected (HIV-) individuals potently inhibit HIV infection in vitro. However, morphological changes in target cells in response to SE have not been characterized or have the effect of HIV infection or the use of illicit substances, specifically psychostimulants, on the function of SE been elucidated. The objective of this study was to evaluate the effect of HIV infection, psychostimulant use, and both together on SE-mediated regulation of monocyte function. SE were isolated from semen of HIV- and HIV-infected (HIV+) antiretroviral therapy (ART)-naive participants who reported either using or not using psychostimulants. The SE samples were thus designated as HIV-Drug-, HIV-Drug+, HIV+Drug-, and HIV+Drug+. U937 monocytes were treated with different SEs and analyzed for changes in transcriptome, morphometrics, actin reorganization, adhesion, and chemotaxis. HIV infection and/or use of psychostimulants had minimal effects on the physical characteristics of SE. However, different SEs had diverse effects on the messenger RNA signature of monocytes and rapidly induced monocyte adhesion and spreading. SE from HIV infected or psychostimulants users but not HIV-Drug- SE, stimulated actin reorganization, leading to the formation of filopodia-like structures and membrane ruffles containing F-actin and vinculin that in some cases were colocalized. All SE stimulated monocyte chemotaxis to HIV secretome and activated the secretion of matrix metalloproteinases, a phenotype exacerbated by HIV infection and psychostimulant use. SE-directed regulation of cellular morphometrics and chemotaxis depended on the donor clinical status because HIV infection and psychostimulant use altered SE function. Although our inclusion criteria specified the use of cocaine, humans are poly-drug and alcohol users and our study participants used psychostimulants, marijuana, opiates, and alcohol. Thus, it is possible that the effects observed in this study may be due to one of these other substances or due to an interaction between different substances., Competing Interests: The authors have no competing interests.

Many microbes, toxins, autoimmune diseases, and neoplastic diseases may cause liver inflammation; however, 5 viruses whose main pathogenesis is liver disease are referred to as hepatitis A, B, C, D, and E viruses. These viruses cause a significant burden of global illness. With the exception of hepatitis A virus, all may cause chronic infection potentially leading to cirrhosis and hepatocellular carcinoma. Excellent serologic and nucleic acid detection methods are available for determining the precise cause and, in some cases, the duration of infection. Diagnostics are critical for identifying individuals needing treatment and for monitoring the treatment success., (Published by Elsevier Inc.)