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#32272077   // To Up

The Biology of the HIV-1 Latent Reservoir and Implications for Cure Strategies.

Antiretroviral therapy (ART) inhibits HIV replication but is not curative. During ART, the integrated HIV genome persists indefinitely within CD4 T cells and perhaps other cells. Here, we describe the mechanisms thought to contribute to its persistence during treatment and highlight findings from numerous recent studies describing the importance of cell proliferation in that process. Continued progress elucidating the biology will enhance our ability to develop effective curative interventions.
Lillian B Cohn, Nicolas Chomont, Steven G Deeks

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#32272076   // To Up

Env Exceptionalism: Why Are HIV-1 Env Glycoproteins Atypical Immunogens?

Recombinant HIV-1 envelope (Env) glycoproteins of ever-increasing sophistication have been evaluated as vaccine candidates for over 30 years. Structurally defined mimics of native trimeric Env glycoproteins (e.g., SOSIP trimers) present multiple epitopes for broadly neutralizing antibodies (bNAbs) and their germline precursors, but elicitation of bNAbs remains elusive. Here, we argue that the interactions between Env and the immune system render it exceptional among viral vaccine antigens and hinder its immunogenicity in absolute and comparative terms. In other words, Env binds to CD4 on key immune cells and transduces signals that can compromise their function. Moreover, the extensive array of oligomannose glycans on Env shields peptidic B cell epitopes, impedes the presentation of T helper cell epitopes, and attracts mannose binding proteins, which could affect the antibody response. We suggest lines of research for assessing how to overcome obstacles that the exceptional features of Env impose on the creation of a successful HIV-1 vaccine.
P J Klasse, Gabriel Ozorowski, Rogier W Sanders, John P Moore

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#32272069   // To Up

HIV-1 Broadly Neutralizing Antibodies Take the Road Less Traveled, and That Makes All the Difference.

Broadly neutralizing antibodies (bnAbs) against HIV-1 provide critical insights into co-evolution between the virus and human B cell responses. In this issue of Cell Host & Microbe, Shen et al. (2020) describe a rare mutation in an antibody lineage targeting the fusion peptide of HIV-1 envelope creating a critical bifurcation, with only one path leading to bnAb development.
Krishnan Roskin, Paul Spearman

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#32271353   2020/04/09 To Up

Assessment of the Feasibility and Safety of Durvalumab for Treatment of Solid Tumors in Patients With HIV-1 Infection: The Phase 2 DURVAST Study.

Therapies targeting the programmed cell death 1 (PD-1) receptor or its ligand (PD-L1), such as the humanized monoclonal antibody durvalumab, have shown durable clinical responses in several tumor types. However, concerns about the safety and feasibility of PD-1/PD-L1 blockade in HIV-1-infected individuals have led to the exclusion of these patients from clinical trials on cancer immunotherapies.
Maria Gonzalez-Cao, Teresa Morán, Judith Dalmau, Javier Garcia-Corbacho, Jillian W P Bracht, Reyes Bernabe, Oscar Juan, Javier de Castro, Remei Blanco, Ana Drozdowskyj, Jordi Argilaguet, Andreas Meyerhans, Julia Blanco, Julia G Prado, Jorge Carrillo, Bonaventura Clotet, Bartomeu Massuti, Mariano Provencio, Miguel A Molina-Vila, Clara Mayo de Las Casa, Monica Garzon, Peng Cao, Chung-Ying Huang, Javier Martinez-Picado, Rafael Rosell

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#32270178   2020/04/09 To Up

Early virus clearance and delayed antibody response in a case of COVID-19 with a history of co-infection with HIV-1 and HCV.

The effect of host immune status on SARS-CoV-2 infection remains unknown. Here, we report the first case of COVID-19 with HIV-1 and HCV co-infection, who showed a persistently negative SARS-CoV-2 RNA test, but delayed antibody response in the plasma. This case highlights the influence of HIV-1-induced immune dysfunction on the early SARS-CoV-2 clearance.
Juanjuan Zhao, Xuejiao Liao, Haiyan Wang, Lanlan Wei, Mingzhao Xing, Lei Liu, Zheng Zhang

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#32269232   2020/04/08 To Up

Polyfunctional HIV-1 specific response by CD8+ T lymphocytes expressing high levels of CD300a.

CD300a receptor is found on different CD8+ T cell subsets and its expression has been associated to a more cytotoxic molecular signature. CD300a has an important role in some viral infections and its expression levels are known to be modulated by human immunodeficiency virus (HIV)-1 infection on several cell types. The main objective of this work was to investigate CD300a expression and its regulation during HIV-1 specific CD8+ T cell responses. CD300a receptor expression was analysed by multiparametric flow cytometry on CD8+ T lymphocytes from HIV negative donors, naive HIV-1+ individuals and HIV-1+ subjects under suppressive combined antiretroviral therapy (cART). HIV-1 specific CD8+ T cell response was studied by stimulating cells with HIV-1 derived peptides or with a Gag HIV-1 peptide. Our results showed that HIV-1 specific CD8+ T cells expressing higher levels of CD300a were more polyfunctional showing an increased degranulation and cytokine production. Moreover, we observed an up-regulation of CD300a expression after Gag HIV-1 peptide stimulation. Finally, our results demonstrated an inverse correlation between CD300a expression on CD8+ T lymphocytes and HIV disease progression markers. In conclusion, CD300a expression is associated to a better and more polyfunctional HIV-1 specific CD8+ T cell response.
Joana Vitallé, Iñigo Terrén, Leire Gamboa-Urquijo, Ane Orrantia, Laura Tarancón-Díez, Miguel Genebat, Manuel Leal, Ezequiel Ruiz-Mateos, Francisco Borrego, Olatz Zenarruzabeitia

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#32269129   2020/04/08 To Up

Deep Sequencing Reveals Compartmentalized HIV-1 in the Semen of Men With and Without STI-Associated Urethritis.

Concurrent sexually transmitted infections (STI) can increase the probability of HIV-1 transmission primarily by increasing the viral load present in semen. In this study, we explored the relationship of HIV-1 in blood and seminal plasma in the presence and absence of urethritis and after treatment of the concurrent STI. Primer ID deep sequencing of the V1/V3 region of the HIV-1 gene was done for paired blood and semen samples from ART-naïve men living in Malawi with (n = 19) and without (n = 5) STI-associated urethritis; for a subset of samples full length genes were generated for sequence analysis and to test entry phenotype. Cytokine concentrations in the blood and semen were also measured, and a reduction in the levels of pro-inflammatory cytokines was observed following STI treatment. We observed no difference in the prevalence of diverse compartmentalized semen-derived lineages in men with or without STI-associated urethritis, and these viral populations were largely stable during STI treatment. Clonal amplification of one or a few viral sequences accounted for nearly 50% of the viral population indicating a recent bottleneck followed by limited viral replication. We conclude that the male genital tract is a site where virus can be brought in from the blood, where localized sustained replication can occur, and where specific genotypes can be amplified perhaps initially by cellular proliferation but further by limited viral replication. HIV-1 is a sexually transmitted infection that co-exists with other STIs. Here we examine the impact of a concurrent STI resulting in urethritis on the HIV-1 population within the male genital tract. We found that viral populations remain largely stable even with treatment of the STI. These results show that viral populations within the male genital tract are defined by factors beyond transient inflammation associated with a concurrent STI.
Olivia D Council, Shuntai Zhou, Chase D McCann, Irving Hoffman, Gerald Tegha, Deborah Kamwendo, Mitch Matoga, Sergei L Kosakovsky Pond, Myron S Cohen, Ronald Swanstrom

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#32269124   2020/04/08 To Up

Compartmentalization and clonal amplification of HIV-1 in the male genital tract characterized using next generation sequencing.

Compartmentalization of HIV-1 between the systemic circulation and the male genital tract may have a substantial impact on which viruses are available for sexual transmission to new hosts. We studied compartmentalization and clonal amplification of HIV-1 populations between blood and the genital tract from ten antiretroviral-naive men using Illumina MiSeq with a PrimerID approach. We found evidence of some degree of compartmentalization in every study participant, unlike previous reports, which collectively show that only ∼50% of analyzed individuals exhibit compartmentalization of HIV-1 lineages between the male genital tract and blood. Using down-sampling simulations, we determined that this disparity can be explained by differences in sampling depth in that, had we sequenced to a lower depth, we would also have found compartmentalization in only ∼50% of the study participants. For most study participants, phylogenetic trees were rooted in blood, suggesting that the male genital tract reservoir is seeded by incoming variants from the blood. Clonal amplification was observed in all study participants and was a characteristic of both blood and semen viral populations. We also show evidence for independent viral replication in the genital tract in the individual with the most severely compartmentalized HIV-1 populations. The degree of clonal amplification was not obviously associated with the extent of compartmentalization. We were also unable to detect any association between history of sexually transmitted infections and level of HIV-1 compartmentalization. Overall, our findings contribute to a better understanding of the dynamics that affect the composition of virus populations that are available for transmission. Within an individual living with HIV-1, factors that restrict the movement of HIV-1 between different compartments - such as between the blood and the male genital tract - could strongly influence which viruses reach sites in the body from which they can be transmitted. Using deep sequencing, we found strong evidence of restricted HIV-1 movements between the blood and genital tract of all ten men that we studied. We additionally found that neither the degree to which particular genetic variants of HIV-1 proliferate (in blood or genital tract), nor an individual's history of sexually transmitted infections, detectably influenced the degree to which virus movements were restricted between the blood and genital tract. Last, we show evidence that viral replication gave rise to a large clonal amplification in semen in a donor with highly compartmentalized HIV-1 populations, raising the possibility that differential selection of HIV-1 variants in the genital tract may occur.
Samuel Mundia Kariuki, Philippe Selhorst, Colin Anthony, David Matten, Melissa-Rose Abrahams, Darren P Martin, Kevin K Ariën, Kevin Rebe, Carolyn Williamson, Jeffrey R Dorfman

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#32263469   2016/08/01 To Up

Zinc-stabilized colloidal polyelectrolyte complexes of chitosan/hyaluronan: a tool for the inhibition of HIV-1 infection.

Zinc(ii) stabilized polyelectrolyte nano-complexes (PECs) of chitosan and hyaluronan (HYA) were designed as safe and efficient drug delivery systems. HIV-1 reverse transcriptase inhibitor tenofovir (TF) was quantitatively encapsulated and the particle interface could be functionalized in PBS with targeting proteins such as anti-α4β7 immunoglobulin A. Chitosan-HYA nanoPECs were non-cytotoxic on human peripheral blood mononuclear cells (PBMCs), within the investigated nanoparticle concentrations. A dose-dependent reduction of the HIV-1 infection of PBMCs co-cultured with the nanocarriers was observed. Even more interestingly, a synergistic effect was evidenced with the nanocarriers by comparing the IC (50% inhibitory concentration) value of the aqueous TF solution (4.35 μmol L) with that of TF loaded nanoPECs (1.71 μmol L) and anti-α4β7 IgA functionalized TF/nanoPECs (1.01 μmol L). This effect could be attributed to the presence of zinc(ii) in the formulation of the colloids. All these data establish that the zinc(ii) stabilized chitosan-HYA nanoPECs can be potentially efficient and safe colloidal delivery system candidates for enhancing antiviral activities in the treatment of HIV infection and AIDS.
Danjun Wu, Agathe Ensinas, Bernard Verrier, Charlotte Primard, Armelle Cuvillier, Gaël Champier, Stephane Paul, Thierry Delair

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