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AIDS/HIVs

  • 129 Articles
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Comprehensive analysis of HIV reservoirs in elite controllers
Brooke D. Kennedy, … , Susan Moir, Tae-Wook Chun
Brooke D. Kennedy, … , Susan Moir, Tae-Wook Chun
Published February 1, 2023
Citation Information: J Clin Invest. 2023;133(3):e165446. https://doi.org/10.1172/JCI165446.
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Comprehensive analysis of HIV reservoirs in elite controllers

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Abstract

Authors

Brooke D. Kennedy, Jana Blazkova, Jesse S. Justement, Victoria Shi, M. Ali Rai, Maegan R. Manning, Lauren Praiss, Kathleen Gittens, Paul A. Wender, Sean Patro, Xiaolin Wu, Susan Moir, Tae-Wook Chun

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Clonally expanded HIV-1 proviruses with 5’-Leader defects can give rise to nonsuppressible residual viremia
Jennifer A. White, … , Janet D. Siliciano, Francesco R. Simonetti
Jennifer A. White, … , Janet D. Siliciano, Francesco R. Simonetti
Published January 5, 2023
Citation Information: J Clin Invest. 2023. https://doi.org/10.1172/JCI165245.
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Clonally expanded HIV-1 proviruses with 5’-Leader defects can give rise to nonsuppressible residual viremia

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Abstract

BACKGROUND. Antiretroviral therapy (ART) halts HIV-1 replication, decreasing viremia to below the detection limit of clinical assays. However, some individuals experience persistent nonsuppressible viremia (NSV) originating from CD4+ T cell clones carrying infectious proviruses. Defective proviruses represent over 90% of all proviruses persisting during ART and can express viral genes, but whether they can cause NSV and complicate ART management is unknown. METHODS. We carried an in-depth characterization of proviruses causing NSV in 4 study participants with optimal adherence and no drug resistance. We investigated the impact of the observed defects on 5’-Leader RNA properties, virus infectivity, and gene expression. Integration-site specific assays were used to track these proviruses over time and among cell subsets. RESULTS. Clones carrying proviruses with 5’-Leader defects can cause persistent NSV up to ~103 copies/mL. These proviruses had small, often identical deletions or point mutations involving the major splicing donor site (MSD) and showed partially reduced RNA dimerization and nucleocapsid binding. Nevertheless, they were inducible and produced non-infectious virions containing viral RNA but lacking Envelope. CONCLUSION. These findings show that proviruses with 5’-Leader defects in CD4+ T cell clones can give rise to NSV, affecting clinical care. Sequencing of the 5’-Leader can help understanding failure to completely suppress viremia. FUNDING. Office of the NIH Director and National Institute of Dental & Craniofacial Research, NIH; Howard Hughes Medical Institute; Johns Hopkins University Center for AIDS Research; National Institute for Allergy and Infectious Diseases, NIH, to the PAVE, BEAT-HIV and DARE Martin Delaney collaboratories.

Authors

Jennifer A. White, Fengting Wu, Saif Yasin, Milica Moskovljevic, Joseph Varriale, Filippo Dragoni, Angelica Camilo Contreras, Jiayi Duan, Mei Y. Zheng, Ndeh F. Tadzong, Heer B. Patel, Jeanelle Mae C. Quiambao, Kyle Rhodehouse, Hao Zhang, Jun Lai, Subul A. Beg, Michael Delannoy, Christin Kilcrease, Christopher J. Hoffmann, Sébastien Poulin, Frédéric Chano, Cecile Tremblay, Jerald Cherian, Patricia Barditch-Crovo, Natasha Chida, Richard D. Moore, Michael F. Summers, Robert F. Siliciano, Janet D. Siliciano, Francesco R. Simonetti

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Factors influencing maternal microchimerism throughout infancy and its impact on infant T cell immunity
Christina Balle, … , Heather B. Jaspan, Whitney E. Harrington
Christina Balle, … , Heather B. Jaspan, Whitney E. Harrington
Published May 12, 2022
Citation Information: J Clin Invest. 2022. https://doi.org/10.1172/JCI148826.
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Factors influencing maternal microchimerism throughout infancy and its impact on infant T cell immunity

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Abstract

Determinants of the acquisition and maintenance of maternal microchimerism (MMc) during infancy and the impact of MMc on infant immune responses are unknown. We examined factors which influence MMc detection and level across infancy and the effect of MMc on T cell responses to BCG vaccination in a cohort of HIV exposed, uninfected and HIV unexposed infants in South Africa. MMc was measured in whole blood from 58 infants using a panel of quantitative PCR assays at day one and 7, 15, and 36 weeks of life. Infants received BCG at birth, and selected whole blood samples from infancy were stimulated in vitro with BCG and assessed for polyfunctional CD4+ T cell responses. MMc was present in most infants across infancy with levels ranging from 0-1,193/100,000 genomic equivalents and was positively impacted by absence of maternal HIV, maternal-infant HLA compatibility, infant female sex, and exclusive breastfeeding. Initiation of maternal antiretroviral therapy prior to pregnancy partially restored MMc levels in HIV exposed, uninfected infants. Birth MMc was associated with an improved polyfunctional CD4+ T cell response to BCG. These data emphasize that both maternal and infant factors influence MMc, which may subsequently impact infant T cell responses.

Authors

Christina Balle, Blair Armistead, Agano Kiravu, Xiaochang Song, Anna-Ursula Happel, Angela A. Hoffmann, Sami B. Kanaan, J. Lee Nelson, Clive M. Gray, Heather B. Jaspan, Whitney E. Harrington

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Combined noncanonical NF-κB agonism and targeted BET bromodomain inhibition reverse HIV latency ex vivo
Shane D. Falcinelli, … , Nancie M. Archin, David M. Margolis
Shane D. Falcinelli, … , Nancie M. Archin, David M. Margolis
Published April 15, 2022
Citation Information: J Clin Invest. 2022;132(8):e157281. https://doi.org/10.1172/JCI157281.
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Combined noncanonical NF-κB agonism and targeted BET bromodomain inhibition reverse HIV latency ex vivo

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Latency reversal strategies for HIV cure using inhibitor of apoptosis protein (IAP) antagonists (IAPi) induce unprecedented levels of latent reservoir expression without immunotoxicity during suppressive antiretroviral therapy (ART). However, full targeting of the reservoir may require combinatorial approaches. A Jurkat latency model screen for IAPi combination partners demonstrated synergistic latency reversal with bromodomain (BD) and extraterminal domain protein inhibitors (BETi). Mechanistic investigations using CRISPR-CAS9 and single-cell RNA-Seq informed comprehensive ex vivo evaluations of IAPi plus pan-BET, bD-selective BET, or selective BET isoform targeting in CD4+ T cells from ART-suppressed donors. IAPi+BETi treatment resulted in striking induction of cell-associated HIV gag RNA, but lesser induction of fully elongated and tat-rev RNA compared with T cell activation–positive controls. IAPi+BETi resulted in HIV protein induction in bulk cultures of CD4+ T cells using an ultrasensitive p24 assay, but did not result in enhanced viral outgrowth frequency using a standard quantitative viral outgrowth assay. This study defines HIV transcriptional elongation and splicing as important barriers to latent HIV protein expression following latency reversal, delineates the roles of BET proteins and their BDs in HIV latency, and provides a rationale for exploration of IAPi+BETi in animal models of HIV latency.

Authors

Shane D. Falcinelli, Jackson J. Peterson, Anne-Marie W. Turner, David Irlbeck, Jenna Read, Samuel L.M. Raines, Katherine S. James, Cameron Sutton, Anthony Sanchez, Ann Emery, Gavin Sampey, Robert Ferris, Brigitte Allard, Simon Ghofrani, Jennifer L. Kirchherr, Caroline Baker, JoAnn D. Kuruc, Cynthia L. Gay, Lindsey I. James, Guoxin Wu, Paul Zuck, Inmaculada Rioja, Rebecca C. Furze, Rab K. Prinjha, Bonnie J. Howell, Ronald Swanstrom, Edward P. Browne, Brian D. Strahl, Richard M. Dunham, Nancie M. Archin, David M. Margolis

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Reprogramming dysfunctional CD8+ T cells to promote properties associated with natural HIV control
Federico Perdomo-Celis, … , Olivier Lambotte, Asier Sáez-Cirión
Federico Perdomo-Celis, … , Olivier Lambotte, Asier Sáez-Cirión
Published April 5, 2022
Citation Information: J Clin Invest. 2022. https://doi.org/10.1172/JCI157549.
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Reprogramming dysfunctional CD8+ T cells to promote properties associated with natural HIV control

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Virus-specific CD8+ T cells play a central role in HIV-1 natural controllers to maintain suppressed viremia in the absence of antiretroviral therapy. These cells display a memory program that confers them stemness properties, high survival, polyfunctionality, proliferative capacity, metabolic plasticity, and antiviral potential. The development and maintenance of such qualities by memory CD8+ T cells appear crucial to achieving natural HIV-1 control. Here we show that targeting the signaling pathways Wnt/TCF-1 and mTORC through GSK3 inhibition to reprogram HIV-specific CD8+ T cells from non-controllers promoted functional capacities associated with natural control of infection. Features of such reprogrammed cells included the enrichment in TCF-1+ less-differentiated subsets, superior response to antigen, enhanced survival, polyfunctionality, metabolic plasticity, less mTORC1-dependency, improved response to γ-chain cytokines and stronger HIV suppressive capacity. Thus, such CD8+ T cell reprogramming, combined with other available immunomodulators, might represent a promising strategy for adoptive cell therapy in the search for an HIV-1 cure.

Authors

Federico Perdomo-Celis, Caroline Passaes, Valérie Monceaux, Stevenn Volant, Faroudy Boufassa, Pierre de Truchis, Morgane Marcou, Katia Bourdic, Laurence Weiss, Corinne Jung, Christine Bourgeois, Cécile Goujard, Laurence Meyer, Michaela Müller-Trutwin, Olivier Lambotte, Asier Sáez-Cirión

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Gut-derived bacterial toxins impair memory CD4 T-cell mitochondrial function in HIV-1 infection
Brian Ferrari, … , Rafick-Pierre Sekaly, Souheil-Antoine Younes
Brian Ferrari, … , Rafick-Pierre Sekaly, Souheil-Antoine Younes
Published March 22, 2022
Citation Information: J Clin Invest. 2022. https://doi.org/10.1172/JCI149571.
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Gut-derived bacterial toxins impair memory CD4 T-cell mitochondrial function in HIV-1 infection

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Abstract

People living with HIV (PLWH) who are Immune Non-Responders (INR) persons are at greater risk of comorbidity and mortality than are Immune Responders (IR) who restore their CD4 T cells count (IR) after anti-retroviral therapy (ART). INR have low CD4-T cell counts (<350 c/ul), heightened systemic inflammation, and increased CD4-T cell cycling (Ki67+). Here we report the findings that memory CD4-T cells and plasma samples of INR from several cohorts are enriched in gut-derived bacterial solutes (GDBS) p-cresol-sulfate (PCS) and indoxyl sulfate (IS) that both negatively correlated with CD4-T cell counts. In vitro PCS or IS blocked CD4-T cell proliferation, induced apoptosis, and diminished the expression of mitochondrial proteins. Electron microscopy imaging (EMI) revealed perturbations of mitochondria networks similar to those found in INR following incubation of healthy memory CD4-T cells with PCS. Using the bacterial 16S rDNA, INR stool samples were found enriched with proteolytic bacterial genera that metabolize tyrosine and phenylalanine amino acids to produce PCS. We propose that toxic solutes from the gut bacterial flora may impair CD4-T cell recovery during ART and may contribute to CD4-T cell lymphopenia characteristic of INR.

Authors

Brian Ferrari, Amanda Cabral Da Silva, Ken H. Liu, Evgeniya V. Saidakova, Larisa B. Korolevskaya, Konstantin V. Shmagel, Carey Shive, Gabriela Pacheco Sanchez, Mauricio Retuerto, Ashish Arunkumar Sharma, Khader Ghneim, Laura Noel-Romas, Benigno Rodriguez, Mahmoud A. Ghannoum, Peter P. Hunt, Steven G. Deeks, Adam D. Burgener, Dean P. Jones, Mirela A. Dobre, Vincent C. Marconi, Rafick-Pierre Sekaly, Souheil-Antoine Younes

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Rapamycin limits CD4+ T cell proliferation in simian immunodeficiency virus-infected rhesus macaques on antiretroviral therapy
Benjamin D. Varco-Merth, … , Timothy J. Henrich, Afam A. Okoye
Benjamin D. Varco-Merth, … , Timothy J. Henrich, Afam A. Okoye
Published March 22, 2022
Citation Information: J Clin Invest. 2022. https://doi.org/10.1172/JCI156063.
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Rapamycin limits CD4+ T cell proliferation in simian immunodeficiency virus-infected rhesus macaques on antiretroviral therapy

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Proliferation of latently-infected CD4+ T cells with replication-competent proviruses is an important mechanism contributing to HIV persistence during antiretroviral therapy (ART). One approach to target this latent cell expansion is to inhibit the mechanistic target of rapamycin (mTOR), a regulatory kinase involved with cell growth, metabolism and proliferation. Here we determined the effects of chronic mTOR inhibition with rapamycin +/- T cell activation in SIV-infected rhesus macaques (RM) on ART. Rapamycin perturbed the expression of multiple genes and signaling pathways important for cellular proliferation and substantially decreased the frequencies of proliferating CD4+ memory T cells (TM) in blood and tissues. However, levels of cell-associated SIV DNA and SIV RNA were not markedly different between rapamycin-treated RM relative to controls during ART. T cell activation with an anti-CD3LALA antibody induced increases in SIV RNA in plasma of RM on rapamycin, consistent with SIV production. However, upon ART cessation, both rapamycin + CD3LALA-treated and control-treated RM rebounded in less than 12 days, with no difference in the time to viral rebound or post-ART viral load set points. These results indicate that while rapamycin can decrease the proliferation of CD4+ TM, chronic mTOR inhibition alone or in combination with T cell activation, was not sufficient to disrupt the stability of the SIV reservoir.

Authors

Benjamin D. Varco-Merth, William Brantley, Alejandra Marenco, Derick D. Duell, Devin N. Fachko, Brian Richardson, Kathleen Busman-Sahay, Danica Shao, Walter Flores, Kathleen Engelman, Yoshinori Fukazawa, Scott W. Wong, Rebecca L. Skalsky, Jeremy Smedley, Michael K Axthelm, Jeffrey D. Lifson, Jacob D. Estes, Paul T. Edlefsen, Louis Picker, Cheryl M.A. Cameron, Timothy J. Henrich, Afam A. Okoye

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Interleukin-10 contributes to reservoir establishment and persistence in SIV-infected macaques treated with antiretroviral therapy
Justin Harper, … , Rafick-Pierre Sekaly, Mirko Paiardini
Justin Harper, … , Rafick-Pierre Sekaly, Mirko Paiardini
Published March 1, 2022
Citation Information: J Clin Invest. 2022. https://doi.org/10.1172/JCI155251.
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Interleukin-10 contributes to reservoir establishment and persistence in SIV-infected macaques treated with antiretroviral therapy

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Abstract

Interleukin (IL)-10 is an immunosuppressive cytokine that signals through STAT3 to regulate T follicular helper cell (TFH) differentiation and germinal center formation. In SIV-infected macaques, levels of IL-10 in plasma and lymph node (LN) were induced by infection and not normalized with ART. During chronic infection, plasma IL-10 and transcriptomic signatures of IL-10 signaling were correlated with the cell-associated SIV-DNA content within LN CD4+ memory subsets, including TFH, and predicted the frequency of CD4+ TFH and their cell-associated SIV-DNA content during ART, respectively. In ART-treated RMs, cells harboring SIV-DNA by DNAscope were preferentially found in the LN B-cell follicle in proximity to IL-10. Finally, we demonstrated that the in vivo neutralization of soluble IL-10 in ART-treated, SIV-infected macaques reduced B cell follicle maintenance and by extension LN memory CD4+ T-cells, including TFH and those expressing PD-1 and CTLA-4. Thus, these data support a role for IL-10 in maintaining a pool of target cells in lymphoid tissue that serve as a niche for viral persistence. Targeting IL-10 signaling to impair CD4+ T-cell survival and improve antiviral immune responses may represent a novel approach to limit viral persistence in ART-suppressed people living with HIV.

Authors

Justin Harper, Susan P. Ribeiro, Chi Ngai Chan, Malika Aid, Claire Deleage, Luca Micci, Maria Pino, Barbara Cervasi, Gopalan Raghunathan, Eric Rimmer, Gulesi Ayanoglu, Guoxin Wu, Neeta Shenvi, Richard J.O. Barnard, Gregory Q. Del Prete, Kathleen Busman-Sahay, Guido Silvestri, Deanna A. Kulpa, Steven E. Bosinger, Kirk Easley, Bonnie J. Howell, Dan Gorman, Daria J. Hazuda, Jacob D. Estes, Rafick-Pierre Sekaly, Mirko Paiardini

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The HIV-1 proviral landscape reveals Nef contributes to HIV-1 persistence in effector memory CD4+ T-cells
Gabriel Duette, … , Timothy E. Schlub, Sarah Palmer
Gabriel Duette, … , Timothy E. Schlub, Sarah Palmer
Published February 8, 2022
Citation Information: J Clin Invest. 2022. https://doi.org/10.1172/JCI154422.
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The HIV-1 proviral landscape reveals Nef contributes to HIV-1 persistence in effector memory CD4+ T-cells

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Abstract

Despite long-term antiretroviral therapy (ART), HIV-1 persists within a reservoir of CD4+ T-cells that contribute to viral rebound if treatment is interrupted. Identifying the cellular populations that contribute to the HIV-1 reservoir and understanding the mechanisms of viral persistence are necessary to achieve an effective cure. In this regard, through Full-Length Individual Proviral Sequencing, we observed that the HIV-1 proviral landscape was different and changed with time on ART across naïve and memory CD4+ T-cell subsets isolated from 24 participants. We found that the proportion of genetically-intact HIV-1 proviruses was higher and persisted over time in effector memory CD4+ T-cells when compared with naïve, central, and transitional memory CD4+ T-cells. Interestingly, we found that escape mutations remained stable over time within effector memory T-cells during therapy. Finally, we provided evidence that Nef plays a role in the persistence of genetically-intact HIV-1. These findings posit effector memory T-cells as a key component of the HIV-1 reservoir and suggest Nef as an attractive therapeutic target.

Authors

Gabriel Duette, Bonnie Hiener, Hannah Morgan, Fernando G. Mazur, Vennila Mathivanan, Bethany A. Horsburgh, Katie Fisher, Orion Tong, Eunok Lee, Haelee Ahn, Ansari Shaik, Rémi Fromentin, Rebecca Hoh, Charline Bacchus-Souffan, Najla Nasr, Anthony Cunningham, Peter W. Hunt, Nicolas Chomont, Stuart G. Turville, Steven G. Deeks, Anthony D. Kelleher, Timothy E. Schlub, Sarah Palmer

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Antiretroviral therapy timing impacts latent tuberculosis infection reactivation in a tuberculosis/simian immunodeficiency virus coinfection model
Riti Sharan, … , Jyothi Rengarajan, Deepak Kaushal
Riti Sharan, … , Jyothi Rengarajan, Deepak Kaushal
Published December 2, 2021
Citation Information: J Clin Invest. 2021. https://doi.org/10.1172/JCI153090.
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Antiretroviral therapy timing impacts latent tuberculosis infection reactivation in a tuberculosis/simian immunodeficiency virus coinfection model

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Abstract

Studies using the nonhuman primate model of M. tuberculosis /Simian Immunodeficiency Virus co-infection have revealed protective CD4+ T cell-independent immune responses that suppress LTBI reactivation. In particular, chronic immune activation rather than the mere depletion of CD4+ T cells correlates with reactivation due to SIV co-infection. Here, we administered cART at 2 weeks post-SIV co-infection to study if restoration of CD4+ T cell immunity occurred more broadly, and if this prevented reactivation of LTBI compared to cART initiated at 4 weeks post-SIV. Earlier initiation of cART enhanced survival, led to better control of viral replication and reduced immune activation in the periphery and lung vasculature thereby reducing the rate of SIV-induced reactivation. We observed robust CD8+ T effector memory responses and significantly reduced macrophage turnover in the lung tissue. However, skewed CD4+ T effector memory responses persisted and new TB lesions formed post SIV co-infection. Thus, reactivation of LTBI is governed by very early events of SIV infection. Timing of cART is critical in mitigating chronic immune activation. The novelty of these findings mainly relates to the development of a robust animal model of human Mtb/HIV co-infection that allows the testing of underlying mechanisms.

Authors

Riti Sharan, Shashank R. Ganatra, Allison N. Bucsan, Journey Cole, Dhiraj K. Singh, Xavier Alvarez, Maya Gough, Cynthia Alvarez, Alyssa Blakley, Justin Ferdin, Rajesh Thippeshappa, Bindu Singh, Ruby Escobedo, Vinay Shivanna, Edward J. Dick, Jr., Shannan Hall-Ursone, Shabaana A. Khader, Smriti Mehra, Jyothi Rengarajan, Deepak Kaushal

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Insight into CD8+ T cell expansion during HIV-1 infection
Souheil-Antoine Younes and colleagues provide evidence that IL-15 is involved in the expansion of CD8+ T cells in chronic HIV infection...
Published June 20, 2016
Scientific Show StopperAIDS/HIV

Designer proteins to hunt and kill latent HIV-1
Julia Sung, Joy Pickeral, Liquin Liu and colleagues developed designer proteins that detect and destroy rare populations of HIV-infected cells…
Published September 28, 2015
Scientific Show StopperAIDS/HIV
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