841 results on '"Chomont, Nicolas"'
Search Results
2. Willingness of Older Canadians with HIV to Participate in HIV Cure Research Near and After the End of Life: A Mixed-Method Study
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Lessard, David, Dubé, Karine, Bilodeau, Martin, Keeler, Patrick, Margolese, Shari, Rosenes, Ron, Sinyavskaya, Liliya, Durand, Madeleine, Benko, Erika, Kovacs, Colin, Guerlotté, Charlotte, Tharao, Wangari, Arnold, Keresa, Masching, Renée, Taylor, Darien, Sousa, José, Ostrowski, Mario, Taylor, Jeff, Kaytes, Andy, Smith, Davey, Gianella, Sara, Chomont, Nicolas, Angel, Jonathan B, Routy, Jean-Pierre, Cohen, Éric A, Lebouché, Bertrand, and Costiniuk, Cecilia T
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Biomedical and Clinical Sciences ,Clinical Sciences ,Behavioral and Social Science ,Infectious Diseases ,HIV/AIDS ,Clinical Research ,Generic health relevance ,Infection ,Good Health and Well Being ,Aged ,Biological Specimen Banks ,Canada ,Death ,HIV Infections ,HIV-1 ,Humans ,Qualitative Research ,Virus Latency ,HIV ,HIV cure ,end-of-life research ,research autopsy ,mixed-methods research ,Virology ,Clinical sciences - Abstract
HIV cure research requires interrogating latent HIV reservoirs in deep tissues, which necessitates autopsies to avoid risks to participants. An HIV autopsy biobank would facilitate this research, but such research raises ethical issues and requires participant engagement. This study explores the willingness to participate in HIV cure research at the end of life. Participants include Canadians with HIV [people with HIV (PWHIV)] aged 55 years or older. Following a mixed-method study design, all participants completed a phone or online survey, and a subset of participants participated in in-depth phone or videoconference interviews. We produced descriptive statistics of quantitative data and a thematic analysis of qualitative data. Barriers and facilitators were categorized under domains of the Theoretical Domains Framework. From April 2020 to August 2021, 37 participants completed the survey (mean age = 69.9 years old; mean duration of HIV infection = 28.5 years), including 15 interviewed participants. About three quarters of participants indicated being willing to participate in hypothetical medical studies toward the end of life (n = 30; 81.1%), in HIV biobanking (n = 30; 81.1%), and in a research autopsy (n = 28; 75.7%) to advance HIV cure research, mainly for altruistic benefits. The main perceived risks had to do with physical pain and confidentiality. Barriers and facilitators were distributed across five domains: social/professional role and identity, environmental context and resources, social influences, beliefs about consequences, and capabilities. Participants wanted more information about study objectives and procedures, possible accommodations with their last will, and rationale for studies or financial interests funding studies. Our results indicate that older PWHIV would be willing to participate in HIV cure research toward the end of life, HIV biobanking, and research autopsy. However, a dialogue should be initiated to inform participants thoroughly about HIV cure studies, address concerns, and accommodate their needs and preferences. Additional work is required, likely through increased community engagement, to address educational needs.
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- 2022
3. Metformin facilitates viral reservoir reactivation and their recognition by anti-HIV-1 envelope antibodies
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Fert, Augustine, Richard, Jonathan, Raymond Marchand, Laurence, Planas, Delphine, Routy, Jean-Pierre, Chomont, Nicolas, Finzi, Andrés, and Ancuta, Petronela
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- 2024
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4. The HIV-1 proviral landscape reveals Nef contributes to HIV-1 persistence in effector memory CD4+ T-cells
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Duette, Gabriel, Hiener, Bonnie, Morgan, Hannah, Mazur, Fernando G, Mathivanan, Vennila, Horsburgh, Bethany A, Fisher, Katie, Tong, Orion, Lee, Eunok, Ahn, Haelee, Shaik, Ansari, Fromentin, Rémi, Hoh, Rebecca, Bacchus-Souffan, Charline, Nasr, Najla, Cunningham, Anthony, Hunt, Peter W, Chomont, Nicolas, Turville, Stuart G, Deeks, Steven G, Kelleher, Anthony D, Schlub, Timothy E, and Palmer, Sarah
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HIV/AIDS ,Infectious Diseases ,Clinical Research ,Aetiology ,2.1 Biological and endogenous factors ,Infection ,CD4-Positive T-Lymphocytes ,DNA ,Viral ,HIV Infections ,HIV-1 ,Humans ,Proviruses ,Viral Load ,nef Gene Products ,Human Immunodeficiency Virus ,AIDS/HIV ,Adaptive immunity ,Infectious disease ,Molecular genetics ,T cells ,Medical and Health Sciences ,Immunology - 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 naive 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 naive, 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.
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- 2022
5. Phenotypic characterization of single CD4+ T cells harboring genetically intact and inducible HIV genomes
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Dufour, Caroline, Richard, Corentin, Pardons, Marion, Massanella, Marta, Ackaoui, Antoine, Murrell, Ben, Routy, Bertrand, Thomas, Réjean, Routy, Jean-Pierre, Fromentin, Rémi, and Chomont, Nicolas
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- 2023
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6. Pembrolizumab induces HIV latency reversal in people living with HIV and cancer on antiretroviral therapy
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Uldrick, Thomas S, Adams, Scott V, Fromentin, Remi, Roche, Michael, Fling, Steven P, Gonçalves, Priscila H, Lurain, Kathryn, Ramaswami, Ramya, Wang, Chia-Ching Jackie, Gorelick, Robert J, Welker, Jorden L, O'Donoghue, Liz, Choudhary, Harleen, Lifson, Jeffrey D, Rasmussen, Thomas A, Rhodes, Ajantha, Tumpach, Carolin, Yarchoan, Robert, Maldarelli, Frank, Cheever, Martin A, Sékaly, Rafick, Chomont, Nicolas, Deeks, Steven G, and Lewin, Sharon R
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Medical Microbiology ,Biomedical and Clinical Sciences ,Immunology ,Infectious Diseases ,Genetics ,Cancer ,HIV/AIDS ,2.2 Factors relating to the physical environment ,Aetiology ,Infection ,Antibodies ,Monoclonal ,Humanized ,CD4-Positive T-Lymphocytes ,HIV Infections ,HIV-1 ,Humans ,Neoplasms ,Phylogeny ,Programmed Cell Death 1 Receptor ,RNA ,Virus Latency ,Biological Sciences ,Medical and Health Sciences ,Medical biotechnology ,Biomedical engineering - Abstract
In people living with HIV (PLWH) on antiretroviral therapy (ART), virus persists in a latent form where there is minimal transcription or protein expression. Latently infected cells are a major barrier to curing HIV. Increasing HIV transcription and viral production in latently infected cells could facilitate immune recognition and reduce the pool of infected cells that persist on ART. Given that programmed cell death protein 1 (PD-1) expressing CD4+ T cells are preferentially infected with HIV in PLWH on ART, we aimed to determine whether administration of antibodies targeting PD-1 would reverse HIV latency in vivo. We therefore evaluated the impact of intravenous administration of pembrolizumab every 3 weeks on HIV latency in 32 PLWH and cancer on ART. After the first infusion of anti-PD-1, we observed a median 1.32-fold increase in unspliced HIV RNA and 1.61-fold increase in unspliced RNA:DNA ratio in sorted blood CD4+ T cells compared to baseline. We also observed a 1.65-fold increase in plasma HIV RNA. The frequency of CD4+ T cells with inducible virus evaluated using the tat/rev limiting dilution assay was higher after 6 cycles compared to baseline. Phylogenetic analyses of HIV env sequences in a participant who developed low concentrations of HIV viremia after 6 cycles of pembrolizumab did not demonstrate clonal expansion of HIV-infected cells. These data are consistent with anti-PD-1 being able to reverse HIV latency in vivo and support the rationale for combining anti-PD-1 with other interventions to reduce the HIV reservoir.
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- 2022
7. First-in-human immunoPET imaging of HIV-1 infection using 89Zr-labeled VRC01 broadly neutralizing antibody
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Beckford-Vera, Denis R, Flavell, Robert R, Seo, Youngho, Martinez-Ortiz, Enrique, Aslam, Maya, Thanh, Cassandra, Fehrman, Emily, Pardons, Marion, Kumar, Shreya, Deitchman, Amelia N, Ravanfar, Vahid, Schulte, Brailee, Wu, I-Wei Katherine, Pan, Tony, Reeves, Jacqueline D, Nixon, Christopher C, Iyer, Nikita S, Torres, Leonel, Munter, Sadie E, Hyunh, Tony, Petropoulos, Christos J, Hoh, Rebecca, Franc, Benjamin L, Gama, Lucio, Koup, Richard A, Mascola, John R, Chomont, Nicolas, Deeks, Steven G, VanBrocklin, Henry F, and Henrich, Timothy J
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Medical Microbiology ,Biomedical and Clinical Sciences ,Immunology ,HIV/AIDS ,Infectious Diseases ,Biomedical Imaging ,Clinical Research ,2.1 Biological and endogenous factors ,Aetiology ,Infection ,Good Health and Well Being ,Antibodies ,Neutralizing ,Broadly Neutralizing Antibodies ,CD4-Positive T-Lymphocytes ,HIV Infections ,HIV-1 ,Humans ,Positron-Emission Tomography ,Viral Load ,Viremia - Abstract
A major obstacle to achieving long-term antiretroviral (ART) free remission or functional cure of HIV infection is the presence of persistently infected cells that establish a long-lived viral reservoir. HIV largely resides in anatomical regions that are inaccessible to routine sampling, however, and non-invasive methods to understand the longitudinal tissue-wide burden of HIV persistence are urgently needed. Positron emission tomography (PET) imaging is a promising strategy to identify and characterize the tissue-wide burden of HIV. Here, we assess the efficacy of using immunoPET imaging to characterize HIV reservoirs and identify anatomical foci of persistent viral transcriptional activity using a radiolabeled HIV Env-specific broadly neutralizing antibody, 89Zr-VRC01, in HIV-infected individuals with detectable viremia and on suppressive ART compared to uninfected controls (NCT03729752). We also assess the relationship between PET tracer uptake in tissues and timing of ART initiation and direct HIV protein expression in CD4 T cells obtained from lymph node biopsies. We observe significant increases in 89Zr-VRC01 uptake in various tissues (including lymph nodes and gut) in HIV-infected individuals with detectable viremia (N = 5) and on suppressive ART (N = 5) compared to uninfected controls (N = 5). Importantly, PET tracer uptake in inguinal lymph nodes in viremic and ART-suppressed participants significantly and positively correlates with HIV protein expression measured directly in tissue. Our strategy may allow non-invasive longitudinal characterization of residual HIV infection and lays the framework for the development of immunoPET imaging in a variety of other infectious diseases.
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- 2022
8. Gag p24 Is a Marker of Human Immunodeficiency Virus Expression in Tissues and Correlates With Immune Response
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Wu, Guoxin, Zuck, Paul, Goh, Shih Lin, Milush, Jeffrey M, Vohra, Poonam, Wong, Joseph K, Somsouk, Ma, Yukl, Steven A, Shacklett, Barbara L, Chomont, Nicolas, Haase, Ashley T, Hatano, Hiroyu, Schacker, Timothy W, Deeks, Steven G, Hazuda, Daria J, Hunt, Peter W, and Howell, Bonnie J
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Medical Microbiology ,Biomedical and Clinical Sciences ,Immunology ,Sexually Transmitted Infections ,Infectious Diseases ,HIV/AIDS ,Infection ,Good Health and Well Being ,Biomarkers ,Biopsy ,CD4 Lymphocyte Count ,CD4-Positive T-Lymphocytes ,Female ,HIV Core Protein p24 ,HIV Infections ,HIV-1 ,Humans ,Lymphocyte Activation ,gag Gene Products ,Human Immunodeficiency Virus ,HIV ,gag p24 ,lymph nodes ,rectal biopsy ,fine needle aspirates ,biomarker ,HIV persistence ,Biological Sciences ,Medical and Health Sciences ,Microbiology ,Biological sciences ,Biomedical and clinical sciences ,Health sciences - Abstract
We demonstrate that human immunodeficiency virus (HIV) gag p24 protein is more readily detected in gut and lymph node tissues than in blood CD4+ T cells and correlates better with CD4 count during antiretroviral therapy (ART). Gut p24 levels also measurably decline with ART in natural controllers. During ART, gut p24 expression is more strongly associated both with HIV-specific CD8+ T-cell frequency and plasma soluble CD14 levels than gut HIV RNA expression. This study supports using gag p24 as a marker of HIV expression in HIV+ tissues to study effects of viral persistence and to monitor efficacy of treatment in HIV-based clearance studies.
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- 2021
9. Assessing the Suitability of Next-Generation Viral Outgrowth Assays to Measure Human Immunodeficiency Virus 1 Latent Reservoir Size.
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Mellors, John, Deeks, Steven, Lai, Jun, Beg, Subul, Siliciano, Janet, Pagliuzza, Amélie, Chomont, Nicolas, Lackman-Smith, Carol, Ptak, Roger, Busch, Michael, Stone, Mars, Rosenbloom, Daniel, Deng, Xutao, Dimapasoc, Melanie, Keating, Sheila, Bakkour, Sonia, Bacchetti, Peter, and Richman, Douglas
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HIV cure ,HIV reservoir ,IUPM ,Inducible HIV RNA ,assay comparison ,latency ,leukapheresis ,quantitative viral out growth assay (QVOA) ,Antiretroviral Therapy ,Highly Active ,CD4-Positive T-Lymphocytes ,Case-Control Studies ,HIV Infections ,HIV Reverse Transcriptase ,HIV-1 ,High-Throughput Nucleotide Sequencing ,Humans ,Leukapheresis ,Viral Load ,Virus Latency ,Virus Replication - Abstract
BACKGROUND: Evaluations of human immunodeficiency virus (HIV) curative interventions require reliable and efficient quantification of replication-competent latent reservoirs. The classic quantitative viral outgrowth assay (QVOA) has been regarded as the reference standard, although prohibitively resource and labor intensive. We compared 6 next-generation viral outgrowth assays, using polymerase chain reaction or ultrasensitive p24 to assess their suitability as scalable proxies for QVOA. METHODS: Next-generation QVOAs were compared with classic QVOA using single leukapheresis-derived samples from 5 antiretroviral therapy-suppressed HIV-infected participants and 1 HIV-uninfected control; each laboratory tested blinded batches of 3 frozen and 1 fresh sample. Markov chain Monte Carlo methods estimated extra-Poisson variation at aliquot, batch, and laboratory levels. Models also estimated the effect of testing frozen versus fresh samples. RESULTS: Next-generation QVOAs had similar estimates of variation to QVOA. Assays with ultrasensitive readout reported higher infectious units per million values than classic QVOA. Within-batch testing had 2.5-fold extra-Poisson variation (95% credible interval [CI], 2.1-3.5-fold) for next-generation assays. Between-laboratory variation increased extra-Poisson variation to 3.4-fold (95% CI, 2.6-5.4-fold). Frozen storage did not substantially alter infectious units per million values (-18%; 95% CI, -52% to 39%). CONCLUSIONS: The data offer cautious support for use of next-generation QVOAs as proxies for more laborious QVOA, while providing greater sensitivities and dynamic ranges. Measurement of latent reservoirs in eradication strategies would benefit from high throughput and scalable assays.
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- 2021
10. Assessing suitability of next-generation viral outgrowth assays as proxies for classic QVOA to measure HIV-1 latent reservoir size
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Stone, Mars, Rosenbloom, Daniel, Bacchetti, Peter, Deng, Xutao, Dimapasoc, Melanie, Keating, Sheila, Bakkour, Sonia, Richman, Douglas, Mellors, John, Deeks, Steven, Lai, Jun, Beg, Subul, Siliciano, Janet, Pagliuzza, Amélie, Chomont, Nicolas, Lackman-Smith, Carol, Ptak, Roger G, and Busch, Michael P
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Clinical Trials and Supportive Activities ,HIV/AIDS ,Clinical Research ,Infectious Diseases ,Infection ,Good Health and Well Being ,Antiretroviral Therapy ,Highly Active ,CD4-Positive T-Lymphocytes ,Case-Control Studies ,HIV Infections ,HIV Reverse Transcriptase ,HIV-1 ,High-Throughput Nucleotide Sequencing ,Humans ,Leukapheresis ,Viral Load ,Virus Latency ,Virus Replication ,HIV reservoir ,quantitative viral out growth assay ,assay comparison ,IUPM ,latency ,leukapheresis ,HIV cure ,Inducible HIV RNA ,Biological Sciences ,Medical and Health Sciences ,Microbiology - Abstract
BackgroundEvaluations of human immunodeficiency virus (HIV) curative interventions require reliable and efficient quantification of replication-competent latent reservoirs. The "classic" quantitative viral outgrowth assay (QVOA) has been regarded as the reference standard, although prohibitively resource and labor intensive. We compared 6 "next-generation" viral outgrowth assays, using polymerase chain reaction or ultrasensitive p24 to assess their suitability as scalable proxies for QVOA.MethodsNext-generation QVOAs were compared with classic QVOA using single leukapheresis-derived samples from 5 antiretroviral therapy-suppressed HIV-infected participants and 1 HIV-uninfected control; each laboratory tested blinded batches of 3 frozen and 1 fresh sample. Markov chain Monte Carlo methods estimated extra-Poisson variation at aliquot, batch, and laboratory levels. Models also estimated the effect of testing frozen versus fresh samples.ResultsNext-generation QVOAs had similar estimates of variation to QVOA. Assays with ultrasensitive readout reported higher infectious units per million values than classic QVOA. Within-batch testing had 2.5-fold extra-Poisson variation (95% credible interval [CI], 2.1-3.5-fold) for next-generation assays. Between-laboratory variation increased extra-Poisson variation to 3.4-fold (95% CI, 2.6-5.4-fold). Frozen storage did not substantially alter infectious units per million values (-18%; 95% CI, -52% to 39%).ConclusionsThe data offer cautious support for use of next-generation QVOAs as proxies for more laborious QVOA, while providing greater sensitivities and dynamic ranges. Measurement of latent reservoirs in eradication strategies would benefit from high throughput and scalable assays.
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- 2021
11. Assessing the Suitability of Next-Generation Viral Outgrowth Assays to Measure Human Immunodeficiency Virus 1 Latent Reservoir Size.
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Stone, Mars, Rosenbloom, Daniel IS, Bacchetti, Peter, Deng, Xutao, Dimapasoc, Melanie, Keating, Sheila, Bakkour, Sonia, Richman, Douglas D, Mellors, John W, Deeks, Steven G, Lai, Jun, Beg, Subul, Siliciano, Janet D, Pagliuzza, Amélie, Chomont, Nicolas, Lackman-Smith, Carol, Ptak, Roger G, and Busch, Michael P
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HIV cure ,HIV reservoir ,IUPM ,Inducible HIV RNA ,assay comparison ,latency ,leukapheresis ,quantitative viral out growth assay ,HIV/AIDS ,Clinical Research ,Clinical Trials and Supportive Activities ,Infectious Diseases ,Infection ,Microbiology ,Biological Sciences ,Medical and Health Sciences - Abstract
BackgroundEvaluations of human immunodeficiency virus (HIV) curative interventions require reliable and efficient quantification of replication-competent latent reservoirs. The "classic" quantitative viral outgrowth assay (QVOA) has been regarded as the reference standard, although prohibitively resource and labor intensive. We compared 6 "next-generation" viral outgrowth assays, using polymerase chain reaction or ultrasensitive p24 to assess their suitability as scalable proxies for QVOA.MethodsNext-generation QVOAs were compared with classic QVOA using single leukapheresis-derived samples from 5 antiretroviral therapy-suppressed HIV-infected participants and 1 HIV-uninfected control; each laboratory tested blinded batches of 3 frozen and 1 fresh sample. Markov chain Monte Carlo methods estimated extra-Poisson variation at aliquot, batch, and laboratory levels. Models also estimated the effect of testing frozen versus fresh samples.ResultsNext-generation QVOAs had similar estimates of variation to QVOA. Assays with ultrasensitive readout reported higher infectious units per million values than classic QVOA. Within-batch testing had 2.5-fold extra-Poisson variation (95% credible interval [CI], 2.1-3.5-fold) for next-generation assays. Between-laboratory variation increased extra-Poisson variation to 3.4-fold (95% CI, 2.6-5.4-fold). Frozen storage did not substantially alter infectious units per million values (-18%; 95% CI, -52% to 39%).ConclusionsThe data offer cautious support for use of next-generation QVOAs as proxies for more laborious QVOA, while providing greater sensitivities and dynamic ranges. Measurement of latent reservoirs in eradication strategies would benefit from high throughput and scalable assays.
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- 2021
12. CD8+ T-cell priming is quantitatively but not qualitatively impaired in people with HIV-1 on antiretroviral therapy
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Cabral-Piccin, Mariela P., Briceño, Olivia, Papagno, Laura, Liouville, Benjamin, White, Eoghann, Perdomo-Celis, Federico, Autaa, Gaëlle, Volant, Stevenn, Llewellyn-Lacey, Sian, Fromentin, Rémi, Chomont, Nicolas, Price, David A., Sáez-Cirión, Asier, Lambotte, Olivier, Katlama, Christine, and Appay, Victor
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- 2024
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13. Tracking coreceptor switch of the transmitted/founder HIV-1 identifies co-evolution of HIV-1 antigenicity, coreceptor usage and CD4 subset targeting: the RV217 acute infection cohort study
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Marichannegowda, Manukumar Honnayakanahalli, Zemil, Michelle, Wieczorek, Lindsay, Sanders-Buell, Eric, Bose, Meera, O'Sullivan, Anne Marie, King, David, Francisco, Leilani, Diaz-Mendez, Felisa, Setua, Saini, Chomont, Nicolas, Phanuphak, Nittaya, Ananworanich, Jintanat, Hsu, Denise, Vasan, Sandhya, Michael, Nelson L., Eller, Leigh Anne, Tovanabutra, Sodsai, Tagaya, Yutaka, Robb, Merlin L., Polonis, Victoria R., and Song, Hongshuo
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- 2023
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14. Intact Human Immunodeficiency Virus (HIV) Reservoir Estimated by the Intact Proviral DNA Assay Correlates With Levels of Total and Integrated DNA in the Blood During Suppressive Antiretroviral Therapy.
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Papasavvas, Emmanouil, Azzoni, Livio, Ross, Brian N, Fair, Matthew, Yuan, Zhe, Gyampoh, Kwasi, Mackiewicz, Agnieszka, Sciorillo, Amanda C, Pagliuzza, Amelie, Lada, Steven M, Wu, Guoxin, Goh, Shih Lin, Bahnck-Teets, Carolyn, Holder, Daniel J, Zuck, Paul D, Damra, Mohammad, Lynn, Kenneth M, Tebas, Pablo, Mounzer, Karam, Kostman, Jay R, Abdel-Mohsen, Mohamed, Richman, Douglas, Chomont, Nicolas, Howell, Bonnie J, and Montaner, Luis J
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Infectious Diseases ,HIV/AIDS ,Genetics ,Clinical Research ,Infection ,Good Health and Well Being ,CD4-Positive T-Lymphocytes ,DNA ,Viral ,HIV Infections ,HIV-1 ,Humans ,Proviruses ,Virus Latency ,HIV latency ,IPDA ,TILDA ,p24 ,integrated HIV ,Integrated HIV ,Biological Sciences ,Medical and Health Sciences ,Microbiology - Abstract
Accurate characterization of the HIV reservoir is imperative to develop an effective cure. HIV was measured in antiretroviral therapy-suppressed individuals using the intact proviral DNA assay (IPDA), along with assays for total or integrated HIV DNA, and inducible HIV RNA or p24. Intact provirus correlated with total and integrated HIV.
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- 2021
15. Near full-length HIV sequencing in multiple tissues collected postmortem reveals shared clonal expansions across distinct reservoirs during ART
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Dufour, Caroline, Ruiz, Maria Julia, Pagliuzza, Amélie, Richard, Corentin, Shahid, Aniqa, Fromentin, Rémi, Ponte, Rosalie, Cattin, Amélie, Wiche Salinas, Tomas Raul, Salahuddin, Syim, Sandstrom, Teslin, Schinkel, Stephanie Burke, Costiniuk, Cecilia T., Jenabian, Mohammad-Ali, Ancuta, Petronela, Routy, Jean-Pierre, Cohen, Éric A., Brumme, Zabrina L., Power, Christopher, Angel, Jonathan B., and Chomont, Nicolas
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- 2023
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16. Spontaneous HIV expression during suppressive ART is associated with the magnitude and function of HIV-specific CD4+ and CD8+ T cells
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Dubé, Mathieu, Tastet, Olivier, Dufour, Caroline, Sannier, Gérémy, Brassard, Nathalie, Delgado, Gloria-Gabrielle, Pagliuzza, Amélie, Richard, Corentin, Nayrac, Manon, Routy, Jean-Pierre, Prat, Alexandre, Estes, Jacob D., Fromentin, Rémi, Chomont, Nicolas, and Kaufmann, Daniel E.
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- 2023
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17. An active HIV reservoir during ART is associated with maintenance of HIV-specific CD8+ T cell magnitude and short-lived differentiation status
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Takata, Hiroshi, Mitchell, Julie L., Pacheco, Julian, Pagliuzza, Amélie, Pinyakorn, Suteeraporn, Buranapraditkun, Supranee, Sacdalan, Carlo, Leyre, Louise, Nathanson, Sam, Kakazu, Juyeon C., Intasan, Jintana, Prueksakaew, Peeriya, Chomchey, Nitiya, Phanuphak, Nittaya, de Souza, Mark, Haddad, Elias K., Rolland, Morgane, Tovanabutra, Sodsai, Vasan, Sandhya, Hsu, Denise C., Chomont, Nicolas, and Trautmann, Lydie
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- 2023
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18. Primary role of type I interferons for the induction of functionally optimal antigen-specific CD8+ T cells in HIV infection
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Cabral-Piccin, Mariela P., Papagno, Laura, Lahaye, Xavier, Perdomo-Celis, Federico, Volant, Stevenn, White, Eoghann, Monceaux, Valérie, Llewellyn-Lacey, Sian, Fromentin, Rémi, Price, David A., Chomont, Nicolas, Manel, Nicolas, Saez-Cirion, Asier, and Appay, Victor
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- 2023
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19. Recommendations for measuring HIV reservoir size in cure-directed clinical trials.
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Abdel-Mohsen, Mohamed, Richman, Douglas, Siliciano, Robert F, Nussenzweig, Michel C, Howell, Bonnie J, Martinez-Picado, Javier, Chomont, Nicolas, Bar, Katharine J, Yu, Xu G, Lichterfeld, Mathias, Alcami, Jose, Hazuda, Daria, Bushman, Frederic, Siliciano, Janet D, Betts, Michael R, Spivak, Adam M, Planelles, Vicente, Hahn, Beatrice H, Smith, Davey M, Ho, Ya-Chi, Buzon, Maria J, Gaebler, Christian, Paiardini, Mirko, Li, Qingsheng, Estes, Jacob D, Hope, Thomas J, Kostman, Jay, Mounzer, Karam, Caskey, Marina, Fox, Lawrence, Frank, Ian, Riley, James L, Tebas, Pablo, Montaner, Luis J, and BEAT-HIV Delaney Collaboratory to Cure HIV-1 infection
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BEAT-HIV Delaney Collaboratory to Cure HIV-1 infection ,Medical and Health Sciences ,Immunology - Abstract
Therapeutic strategies are being clinically tested either to eradicate latent HIV reservoirs or to achieve virologic control in the absence of antiretroviral therapy. Attaining this goal will require a consensus on how best to measure the numbers of persistently infected cells with the potential to cause viral rebound after antiretroviral-therapy cessation in assessing the results of cure-directed strategies in vivo. Current measurements assess various aspects of the HIV provirus and its functionality and produce divergent results. Here, we provide recommendations from the BEAT-HIV Martin Delaney Collaboratory on which viral measurements should be prioritized in HIV-cure-directed clinical trials.
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- 2020
20. Intact HIV reservoir estimated by the intact proviral DNA assay correlates with levels of total and integrated DNA in the blood during suppressive antiretroviral therapy.
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Papasavvas, Emmanouil, Azzoni, Livio, Ross, Brian N, Fair, Matthew, Yuan, Zhe, Gyampoh, Kwasi, Mackiewicz, Agnieszka, Sciorillo, Amanda C, Paggliuzza, Amelie, Lada, Steven M, Wu, Guoxin, Goh, Shih Lin, Bahnck-Teets, Carolyn, Holder, Daniel J, Zuck, Paul D, Damra, Mohammad, Lynn, Kenneth M, Tebas, Pablo, Mounzer, Karam, Kostman, Jay R, Abdel-Mohsen, Mohamed, Richman, Douglas, Chomont, Nicolas, Howell, Bonnie J, and Montaner, Luis J
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HIV latency ,IPDA ,Integrated HIV ,TILDA ,p24 ,Microbiology ,Biological Sciences ,Medical and Health Sciences - Abstract
Accurate characterization of the HIV reservoir is imperative to develop an effective cure. HIV was measured in antiretroviral therapy-suppressed individuals using the intact proviral DNA assay (IPDA), along with assays for total or integrated HIV DNA, and inducible HIV RNA or p24. Intact provirus correlated with total and integrated HIV.
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- 2020
21. High levels of genetically intact HIV in HLA-DR+ memory T cells indicates their value for reservoir studies.
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Horsburgh, Bethany A, Lee, Eunok, Hiener, Bonnie, Eden, John-Sebastian, Schlub, Timothy E, von Stockenstrom, Susanne, Odevall, Lina, Milush, Jeffrey M, Liegler, Teri, Sinclair, Elizabeth, Hoh, Rebecca, Boritz, Eli A, Douek, Daniel C, Fromentin, Remi, Chomont, Nicolas, Deeks, Steven G, Hecht, Frederick M, and Palmer, Sarah
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Medical Microbiology ,Biomedical and Clinical Sciences ,Immunology ,Genetics ,Human Genome ,Sexually Transmitted Infections ,Infectious Diseases ,HIV/AIDS ,Immunization ,Generic health relevance ,Infection ,Adult ,Anti-HIV Agents ,CD4-Positive T-Lymphocytes ,DNA ,Viral ,Female ,HIV Infections ,HIV-1 ,HLA-DR Antigens ,Humans ,Immunologic Memory ,Male ,Sequence Analysis ,DNA ,Sequence Analysis ,RNA ,full-length sequencing ,genetically intact HIV ,HIV reservoir ,HLA-DR plus memory cells ,Biological Sciences ,Medical and Health Sciences ,Psychology and Cognitive Sciences ,Virology ,Biomedical and clinical sciences ,Health sciences - Abstract
ObjectiveThe contribution of HLA-DR+ memory CD4 T cells to the HIV reservoir during prolonged antiretroviral therapy is unclear as these cells are commonly excluded when assessing for replication-competent HIV. To address this issue, we examined the distribution of genetically intact HIV DNA within HLA-DR- and HLA-DR+ memory CD4 T cells and the RNA transcriptional profile of these cells during antiretroviral therapy.Design/methodsFull-length DNA sequencing was used to examine the HIV DNA landscape within HLA-DR+ and HLA-DR- memory CD4 T cells. RNA quantification and sequencing was used to interrogate the relationship between HLA-DR status and HIV RNA transcription.ResultsHLA-DR+ CD4 T cells contained a high frequency of genetically intact HIV genomes, contributing over half of the genetically intact viral sequences to the reservoir. Expansions of genetically identical sequences were identified in all T-cell subsets, indicating that cellular proliferation maintains genetically intact and defective viral DNA during therapy. Intracellular HIV RNA levels in HLA-DR+ and HLA-DR- T cells were not statistically different by either long terminal repeat quantitative PCR quantification or single-genome RNA sequencing of the p6-RT region.ConclusionThe high proportion of intact viral DNA sequences in the proliferative HLA-DR+ subset suggests they are critical in maintaining HIV infection during effective therapy. As such, these cells should be included in any immune intervention targeting HIV during effective therapy.
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- 2020
22. The Biology of the HIV-1 Latent Reservoir and Implications for Cure Strategies
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Cohn, Lillian B, Chomont, Nicolas, and Deeks, Steven G
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Medical Microbiology ,Biomedical and Clinical Sciences ,Immunology ,HIV/AIDS ,Sexually Transmitted Infections ,Infectious Diseases ,Infection ,Acquired Immunodeficiency Syndrome ,Age Factors ,Animals ,Anti-Retroviral Agents ,Antiretroviral Therapy ,Highly Active ,B-Lymphocytes ,Biomarkers ,CD4-Positive T-Lymphocytes ,Coinfection ,HIV Infections ,HIV-1 ,Host Microbial Interactions ,Humans ,Sex Factors ,Viral Load ,Virus Latency ,Virus Replication ,Microbiology ,Biochemistry and cell biology ,Medical microbiology - Abstract
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.
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- 2020
23. Human Immunodeficiency Virus (HIV)–Infected CCR6+ Rectal CD4+ T Cells and HIV Persistence On Antiretroviral Therapy
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Anderson, Jenny L, Khoury, Gabriela, Fromentin, Rémi, Solomon, Ajantha, Chomont, Nicolas, Sinclair, Elizabeth, Milush, Jeffrey M, Hartogensis, Wendy, Bacchetti, Peter, Roche, Michael, Tumpach, Carolin, Gartner, Matthew, Pitman, Matthew C, Epling, Christine Lorrie, Hoh, Rebecca, Hecht, Frederick M, Somsouk, Ma, Cameron, Paul U, Deeks, Steven G, and Lewin, Sharon R
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Medical Microbiology ,Biomedical and Clinical Sciences ,Immunology ,Sexually Transmitted Infections ,HIV/AIDS ,Infectious Diseases ,Clinical Research ,Aetiology ,2.1 Biological and endogenous factors ,Infection ,Anti-Retroviral Agents ,CD4-Positive T-Lymphocytes ,Chemokines ,DNA ,Viral ,Female ,HIV ,HIV Infections ,Humans ,Lymph Nodes ,Male ,Middle Aged ,Polymerase Chain Reaction ,RNA ,Viral ,Receptors ,CCR6 ,Rectum ,HIV reservoir ,latency ,persistence ,chemokine receptor ,CCR6 ,CXCR3 ,chemokines ,rectal tissue ,lymph node ,Biological Sciences ,Medical and Health Sciences ,Microbiology ,Biological sciences ,Biomedical and clinical sciences ,Health sciences - Abstract
BackgroundIdentifying where human immunodeficiency virus (HIV) persists in people living with HIV and receiving antiretroviral therapy is critical to develop cure strategies. We assessed the relationship of HIV persistence to expression of chemokine receptors and their chemokines in blood (n = 48) and in rectal (n = 20) and lymph node (LN; n = 8) tissue collected from people living with HIV who were receiving suppressive antiretroviral therapy.MethodsCell-associated integrated HIV DNA, unspliced HIV RNA, and chemokine messenger RNA were quantified by quantitative polymerase chain reaction. Chemokine receptor expression on CD4+ T cells was determined using flow cytometry.ResultsIntegrated HIV DNA levels in CD4+ T cells, CCR6+CXCR3+ memory CD4+ T-cell frequency, and CCL20 expression (ligand for CCR6) were highest in rectal tissue, where HIV-infected CCR6+ T cells accounted for nearly all infected cells (median, 89.7%). Conversely in LN tissue, CCR6+ T cells were infrequent, and there was a statistically significant association of cell-associated HIV DNA and RNA with CCL19, CCL21, and CXCL13 chemokines.ConclusionsHIV-infected CCR6+ CD4+ T cells accounted for the majority of infected cells in rectal tissue. The different relationships between HIV persistence and T-cell subsets and chemokines in rectal and LN tissue suggest that different tissue-specific strategies may be required to eliminate HIV persistence and that assessment of biomarkers for HIV persistence may not be generalizable between blood and other tissues.
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- 2020
24. Impact of Antiretroviral Therapy Duration on HIV-1 Infection of T Cells within Anatomic Sites
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Lee, Eunok, von Stockenstrom, Susanne, Morcilla, Vincent, Odevall, Lina, Hiener, Bonnie, Shao, Wei, Hartogensis, Wendy, Bacchetti, Peter, Milush, Jeffrey, Liegler, Teri, Sinclair, Elizabeth, Hatano, Hiroyu, Hoh, Rebecca, Somsouk, Ma, Hunt, Peter, Boritz, Eli, Douek, Daniel, Fromentin, Remi, Chomont, Nicolas, Deeks, Steven G, Hecht, Frederick M, and Palmer, Sarah
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Medical Microbiology ,Biomedical and Clinical Sciences ,Immunology ,HIV/AIDS ,Clinical Research ,Infectious Diseases ,Genetics ,Sexually Transmitted Infections ,2.2 Factors relating to the physical environment ,Infection ,Good Health and Well Being ,Adolescent ,Anti-Retroviral Agents ,CD4-Positive T-Lymphocytes ,Child ,Child ,Preschool ,Cross-Sectional Studies ,DNA ,Viral ,Duration of Therapy ,HIV Infections ,HIV-1 ,Humans ,Lymph Nodes ,Proviruses ,T-Lymphocyte Subsets ,Viral Load ,Viremia ,Virus Replication ,acute/early infection ,anatomic sites ,CD4(+) T cell subsets ,cellular proliferation ,chronic infection ,HIV-1 persistence ,long-term antiretroviral therapy ,single-genome sequencing ,single-proviral sequencing ,CD4+ T cell subsets ,Biological Sciences ,Agricultural and Veterinary Sciences ,Medical and Health Sciences ,Virology ,Agricultural ,veterinary and food sciences ,Biological sciences ,Biomedical and clinical sciences - Abstract
Understanding the impact of antiretroviral therapy (ART) duration on HIV-infected cells is critical for developing successful curative strategies. To address this issue, we conducted a cross-sectional/inter-participant genetic characterization of HIV-1 RNA from pre- and on-therapy plasmas and HIV-1 DNA from CD4+ T cell subsets derived from peripheral blood (PB), lymph node (LN), and gut tissues of 26 participants after 3 to 17.8 years of ART. Our studies revealed in four acute/early participants who had paired PB and LN samples a substantial reduction in the proportion of HIV-infected cells per year on therapy within the LN. Extrapolation to all 12 acute/early participants estimated a much smaller reduction in the proportion of HIV-1-infected cells within LNs per year on therapy that was similar to that in the participants treated during chronic infection. LN-derived effector memory T (TEM) cells contained HIV-1 DNA that was genetically identical to viral sequences derived from pre- and on-therapy plasma samples. The proportion of identical HIV-1 DNA sequences increased within PB-derived TEM cells. However, the infection frequency of TEM cells in PB was stable, indicating that cellular proliferation that compensates for T cell loss over time contributes to HIV-1 persistence. This study suggests that ART reduces HIV-infected T cells and that clonal expansion of HIV-infected cells maintains viral persistence. Importantly, LN-derived TEM cells are a probable source of HIV-1 genomes capable of producing infectious HIV-1 and should be targeted by future curative strategies.IMPORTANCE HIV-1 persists as an integrated genome in CD4+ memory T cells during effective therapy, and cessation of current treatments results in resumption of viral replication. To date, the impact of antiretroviral therapy duration on HIV-infected CD4+ T cells and the mechanisms of viral persistence in different anatomic sites is not clearly elucidated. In the current study, we found that treatment duration was associated with a reduction in HIV-infected T cells. Our genetic analyses revealed that CD4+ effector memory T (TEM) cells derived from the lymph node appeared to contain provirus that was genetically identical to plasma-derived virions. Moreover, we found that cellular proliferation counterbalanced the decay of HIV-infected cells throughout therapy. The contribution of cellular proliferation to viral persistence is particularly significant in TEM cells. Our study emphasizes the importance of HIV-1 intervention and provides new insights into the location of memory T cells infected with HIV-1 DNA, which is capable of contributing to viremia.
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- 2020
25. Differentiation into an Effector Memory Phenotype Potentiates HIV-1 Latency Reversal in CD4+ T Cells
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Kulpa, Deanna A, Talla, Aarthi, Brehm, Jessica H, Ribeiro, Susan Pereira, Yuan, Sally, Bebin-Blackwell, Anne-Gaelle, Miller, Michael, Barnard, Richard, Deeks, Steven G, Hazuda, Daria, Chomont, Nicolas, and Sékaly, Rafick-Pierre
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Medical Microbiology ,Biomedical and Clinical Sciences ,Immunology ,Sexually Transmitted Infections ,Infectious Diseases ,HIV/AIDS ,Genetics ,Clinical Research ,2.1 Biological and endogenous factors ,Infection ,Good Health and Well Being ,CD4-Positive T-Lymphocytes ,Cell Differentiation ,DNA ,Viral ,Gene Expression ,HIV Infections ,HIV-1 ,Humans ,Immunologic Memory ,Phenotype ,T-Lymphocyte Subsets ,Virus Latency ,CD4 T cells ,HIV latency ,HIV persistence ,Biological Sciences ,Agricultural and Veterinary Sciences ,Medical and Health Sciences ,Virology ,Agricultural ,veterinary and food sciences ,Biological sciences ,Biomedical and clinical sciences - Abstract
During antiretroviral therapy (ART), human immunodeficiency virus type 1 (HIV-1) persists as a latent reservoir in CD4+ T cell subsets in central memory (TCM), transitional memory (TTM), and effector memory (TEM) CD4+ T cells. We have identified differences in mechanisms underlying latency and responses to latency-reversing agents (LRAs) in ex vivo CD4+ memory T cells from virally suppressed HIV-infected individuals and in an in vitro primary cell model of HIV-1 latency. Our ex vivo and in vitro results demonstrate the association of transcriptional pathways of T cell differentiation, acquisition of effector function, and cell cycle entry in response to LRAs. Analyses of memory cell subsets showed that effector memory pathways and cell surface markers of activation and proliferation in the TEM subset are predictive of higher frequencies of cells carrying an inducible reservoir. Transcriptional profiling also demonstrated that the epigenetic machinery (known to control latency and reactivation) in the TEM subset is associated with frequencies of cells with HIV-integrated DNA and inducible HIV multispliced RNA. TCM cells were triggered to differentiate into TEM cells when they were exposed to LRAs, and this increase of TEM subset frequencies upon LRA stimulation was positively associated with higher numbers of p24+ cells. Together, these data highlight differences in underlying biological latency control in different memory CD4+ T cell subsets which harbor latent HIV in vivo and support a role for differentiation into a TEM phenotype in facilitating latency reversal.IMPORTANCE By performing phenotypic analysis of latency reversal in CD4+ T cells from virally suppressed individuals, we identify the TEM subset as the largest contributor to the inducible HIV reservoir. Differential responses of memory CD4+ T cell subsets to latency-reversing agents (LRAs) demonstrate that HIV gene expression is associated with heightened expression of transcriptional pathways associated with differentiation, acquisition of effector function, and cell cycle entry. In vitro modeling of the latent HIV reservoir in memory CD4+ T cell subsets identify LRAs that reverse latency with ranges of efficiency and specificity. We found that therapeutic induction of latency reversal is associated with upregulation of identical sets of TEM-associated genes and cell surface markers shown to be associated with latency reversal in our ex vivo and in vitro models. Together, these data support the idea that the effector memory phenotype supports HIV latency reversal in CD4+ T cells.
- Published
- 2019
26. Preferential and persistent impact of acute HIV-1 infection on CD4⁺ iNKT cells in colonic mucosa
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RV217, RV254/SEARCH010, RV304/SEARCH013 StudyGroup, Paquin-Proulx, Dominic, Lal, Kerri G., Phuang-Ngern, Yuwadee, Creegan, Matthew, Tokarev, Andrey, Suhkumvittay, Suchada, Alrubayyi, Aljawharah, Kroon, Eugène, Pinyakorn, Suteeraporn, Slike, Bonnie M., Bolton, Diane L., Krebs, Shelly J., Eller, Leigh Anne, Sajjaweerawan, Chayada, Pagliuzza, Amélie, Chomont, Nicolas, Rerknimitr, Rungsun, Chomchey, Nitiya, Phanuphak, Nittaya, de Souza, Mark S., Michael, Nelson L., Robb, Merlin L., Ananworanich, Jintanat, Sandberg, Johan K., Eller, Michael A., and Schuetz, Alexandra
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- 2021
27. HIV rapidly targets a diverse pool of CD4+ T cells to establish productive and latent infections
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Gantner, Pierre, Buranapraditkun, Supranee, Pagliuzza, Amélie, Dufour, Caroline, Pardons, Marion, Mitchell, Julie L., Kroon, Eugène, Sacdalan, Carlo, Tulmethakaan, Nicha, Pinyakorn, Suteeraporn, Robb, Merlin L., Phanuphak, Nittaya, Ananworanich, Jintanat, Hsu, Denise, Vasan, Sandhya, Trautmann, Lydie, Fromentin, Rémi, and Chomont, Nicolas
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- 2023
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28. Memory CD4+ T cells that co-express PD1 and CTLA4 have reduced response to activating stimuli facilitating HIV latency
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Rasmussen, Thomas A., Zerbato, Jennifer M., Rhodes, Ajantha, Tumpach, Carolin, Dantanarayana, Ashanti, McMahon, James H., Lau, Jillian S.Y., Chang, J. Judy, Gubser, Celine, Brown, Wendy, Hoh, Rebecca, Krone, Melissa, Pascoe, Rachel, Chiu, Chris Y., Bramhall, Michael, Lee, Hyun Jae, Haque, Ashraful, Fromentin, Rèmi, Chomont, Nicolas, Milush, Jeffrey, Van der Sluis, Renee M., Palmer, Sarah, Deeks, Steven G., Cameron, Paul U., Evans, Vanessa, and Lewin, Sharon R.
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- 2022
- Full Text
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29. Sex-Based Differences in Human Immunodeficiency Virus Type 1 Reservoir Activity and Residual Immune Activation
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Scully, Eileen P, Gandhi, Monica, Johnston, Rowena, Hoh, Rebecca, Lockhart, Ainsley, Dobrowolski, Curtis, Pagliuzza, Amélie, Milush, Jeffrey M, Baker, Christopher A, Girling, Valerie, Ellefson, Arlvin, Gorelick, Robert, Lifson, Jeffrey, Altfeld, Marcus, Alter, Galit, Cedars, Marcelle, Solomon, Ajantha, Lewin, Sharon R, Karn, Jonathan, Chomont, Nicolas, Bacchetti, Peter, and Deeks, Steven G
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Medical Microbiology ,Biomedical and Clinical Sciences ,Immunology ,Health Disparities ,Clinical Research ,Minority Health ,HIV/AIDS ,Women's Health ,Sexually Transmitted Infections ,Infectious Diseases ,Genetics ,2.2 Factors relating to the physical environment ,Aetiology ,Infection ,Good Health and Well Being ,Adult ,Anti-HIV Agents ,CD4-Positive T-Lymphocytes ,CD8-Positive T-Lymphocytes ,DNA ,Viral ,Female ,HIV Infections ,HIV-1 ,Humans ,Lymphocyte Activation ,Male ,Middle Aged ,Programmed Cell Death 1 Receptor ,Prospective Studies ,RNA ,Viral ,Receptors ,CCR5 ,Sex Factors ,Viral Load ,sex differences ,cure ,reservoir ,immune activation ,Biological Sciences ,Medical and Health Sciences ,Microbiology ,Biological sciences ,Biomedical and clinical sciences ,Health sciences - Abstract
Plasma human immunodeficiency virus type 1 (HIV-1) RNA levels in women are lower early in untreated HIV-1 infection compared with those in men, but women have higher T-cell activation and faster disease progression when adjusted for viral load. It is not known whether these sex differences persist during effective antiretroviral therapy (ART), or whether they would be relevant for the evaluation and implementation of HIV-1 cure strategies. We prospectively enrolled a cohort of reproductive-aged women and matched men on suppressive ART and measured markers of HIV-1 persistence, residual virus activity, and immune activation. The frequency of CD4+ T cells harboring HIV-1 DNA was comparable between the sexes, but there was higher cell-associated HIV-1 RNA, higher plasma HIV-1 (single copy assay), and higher T-cell activation and PD-1 expression in men compared with women. These sex-related differences in immune phenotype and HIV-1 persistence on ART have significant implications for the design and measurement of curative interventions.
- Published
- 2019
30. PD-1 blockade potentiates HIV latency reversal ex vivo in CD4+ T cells from ART-suppressed individuals.
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Fromentin, Rémi, DaFonseca, Sandrina, Costiniuk, Cecilia T, El-Far, Mohamed, Procopio, Francesco Andrea, Hecht, Frederick M, Hoh, Rebecca, Deeks, Steven G, Hazuda, Daria J, Lewin, Sharon R, Routy, Jean-Pierre, Sékaly, Rafick-Pierre, and Chomont, Nicolas
- Subjects
CD4-Positive T-Lymphocytes ,Humans ,HIV-1 ,Antiretroviral Therapy ,Highly Active ,Lymphocyte Activation ,Virus Latency ,Bryostatins ,Antibodies ,Monoclonal ,Humanized ,Programmed Cell Death 1 Receptor ,B7-H1 Antigen ,Antiretroviral Therapy ,Highly Active ,Antibodies ,Monoclonal ,Humanized - Abstract
HIV persists in latently infected CD4+ T cells during antiretroviral therapy (ART). Immune checkpoint molecules, including PD-1, are preferentially expressed at the surface of persistently infected cells. However, whether PD-1 plays a functional role in HIV latency and reservoir persistence remains unknown. Using CD4+ T cells from HIV-infected individuals, we show that the engagement of PD-1 inhibits viral production at the transcriptional level and abrogates T-cell receptor (TCR)-induced HIV reactivation in latently infected cells. Conversely, PD-1 blockade with the monoclonal antibody pembrolizumab enhances HIV production in combination with the latency reversing agent bryostatin without increasing T cell activation. Our results suggest that the administration of immune checkpoint blockers to HIV-infected individuals on ART may facilitate latency disruption.
- Published
- 2019
31. Memory CD4 + T-Cells Expressing HLA-DR Contribute to HIV Persistence During Prolonged Antiretroviral Therapy
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Lee, Eunok, Bacchetti, Peter, Milush, Jeffery, Shao, Wei, Boritz, Eli, Douek, Daniel, Fromentin, Remi, Liegler, Teri, Hoh, Rebecca, Deeks, Steve G, Hecht, Frederick M, Chomont, Nicolas, and Palmer, Sarah
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Medical Microbiology ,Biomedical and Clinical Sciences ,Immunology ,Sexually Transmitted Infections ,Clinical Research ,HIV/AIDS ,Infectious Diseases ,2.1 Biological and endogenous factors ,Infection ,Good Health and Well Being ,HLA-DR ,CD4+T-cells ,prolonged ART ,HIV persistence ,cell activation/exhaustion markers ,cellular proliferation ,single-proviral sequencing ,CD4+ T-cells ,Environmental Science and Management ,Soil Sciences ,Microbiology ,Medical microbiology - Abstract
To date, most assays for measuring the human immunodeficiency virus (HIV-1) reservoir do not include memory CD4+ T-cells expressing the activation marker, human leukocyte antigen-antigen D related (HLA-DR). However, little is known concerning the role these cells play in maintaining persistent HIV-1 during effective antiretroviral therapy (ART). To address this issue, we examined, cellular activation/exhaustion markers (Ki67, CCR5, PD-1, Lag-3 and Tim-3) and viral gag-pol DNA sequences within HLA-DR- and HLA-DR+ memory CD4+ T-cell subsets longitudinally from the peripheral blood of six participants over 3 to ≥15 years of effective therapy. HLA-DR expression was readily detected during the study period in all participants. The average expression levels of CCR5, PD-1 and Tim-3 were higher on the HLA-DR+ T-cell subset whereas the average of LAG-3 expression was higher on their HLA-DR- counterpart. The proportion of HIV-infected cells increased within the HLA-DR+ subset by an average of 18% per year of ART whereas the frequency of infected HLA-DR- T-cells slightly decreased over time (5% per year). We observed that 20-33% of HIV-DNA sequences from the early time points were genetically identical to viral sequences from the last time point within the same cell subset during ART. This indicates that a fraction of proviruses persists within HLA-DR+ and HLA-DR- T-cell subsets during prolonged ART. Our HIV-DNA sequence analyses also revealed that cells transitioned between the HLA-DR+ and HLA-DR- phenotypes. The Ki67 expression, a marker for cellular proliferation, and the combined markers of Ki67/PD-1 averaged 19-fold and 22-fold higher on the HLA-DR+ T-cell subset compared to their HLA-DR- counterpart. Moreover, cellular proliferation, as reflected by the proportion of genetically identical HIV-DNA sequences, increased within both T-cell subsets over the study period; however, this increase was greater within the HLA-DR+ T-cells. Our research revealed that cellular transition and proliferation contribute to the persistence of HIV in HLA-DR+ and HLA-DR- T-cell subsets during prolonged therapy. As such, the HIV reservoir expands during effective ART when both the HLA-DR+ and HLA-DR- cell subsets are included, and therapeutic interventions aimed at reducing the HIV-1 reservoir should target HLA-DR+ and HLA-DR- T-cells.
- Published
- 2019
32. Limited impact of fingolimod treatment during the initial weeks of ART in SIV-infected rhesus macaques
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Pino, Maria, Pagliuzza, Amélie, Pampena, M. Betina, Deleage, Claire, Viox, Elise G., Nguyen, Kevin, Shim, Inbo, Zhang, Adam, Harper, Justin L., Samer, Sadia, King, Colin T., Cervasi, Barbara, Gill, Kiran P., Ehnert, Stephanie, Jean, Sherrie M., Freeman, Michael L., Lifson, Jeffrey D., Kulpa, Deanna, Betts, Michael R., Chomont, Nicolas, Lederman, Michael M., and Paiardini, Mirko
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- 2022
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33. Silence, escape and survival drive the persistence of HIV
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Chomont, Nicolas
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- 2023
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34. Estrogen receptor-1 is a key regulator of HIV-1 latency that imparts gender-specific restrictions on the latent reservoir
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Das, Biswajit, Dobrowolski, Curtis, Luttge, Benjamin, Valadkhan, Saba, Chomont, Nicolas, Johnston, Rowena, Bacchetti, Peter, Hoh, Rebecca, Gandhi, Monica, Deeks, Steven G, Scully, Eileen, and Karn, Jonathan
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Medical Microbiology ,Biomedical and Clinical Sciences ,Immunology ,Women's Health ,Genetics ,Estrogen ,Infectious Diseases ,Sexually Transmitted Infections ,HIV/AIDS ,Adult ,Estrogen Receptor Modulators ,Estrogen Receptor alpha ,Female ,HIV-1 ,Humans ,Jurkat Cells ,Male ,Receptors ,Antigen ,T-Cell ,Sex Characteristics ,T-Lymphocytes ,Transcription ,Genetic ,Virus Latency ,HIV-1 latency ,HIV-1 reservoir ,estrogen receptor ,latency-reversing agents ,selective estrogen receptor modulators - Abstract
Unbiased shRNA library screens revealed that the estrogen receptor-1 (ESR-1) is a key factor regulating HIV-1 latency. In both Jurkat T cells and a Th17 primary cell model for HIV-1 latency, selective estrogen receptor modulators (SERMs, i.e., fulvestrant, raloxifene, and tamoxifen) are weak proviral activators and sensitize cells to latency-reversing agents (LRAs) including low doses of TNF-α (an NF-κB inducer), the histone deacetylase inhibitor vorinostat (soruberoylanilide hydroxamic acid, SAHA), and IL-15. To probe the physiologic relevance of these observations, leukapheresis samples from a cohort of 12 well-matched reproductive-age women and men on fully suppressive antiretroviral therapy were evaluated by an assay measuring the production of spliced envelope (env) mRNA (the EDITS assay) by next-generation sequencing. The cells were activated by T cell receptor (TCR) stimulation, IL-15, or SAHA in the presence of either β-estradiol or an SERM. β-Estradiol potently inhibited TCR activation of HIV-1 transcription, while SERMs enhanced the activity of most LRAs. Although both sexes responded to SERMs and β-estradiol, females showed much higher levels of inhibition in response to the hormone and higher reactivity in response to ESR-1 modulators than males. Importantly, the total inducible RNA reservoir, as measured by the EDITS assay, was significantly smaller in the women than in the men. We conclude that concurrent exposure to estrogen is likely to limit the efficacy of viral emergence from latency and that ESR-1 is a pharmacologically attractive target that can be exploited in the design of therapeutic strategies for latency reversal.
- Published
- 2018
35. Pegylated IFN-alpha-2b decreases latent HIV measures in ART-suppressed subjects
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Azzoni, Livio, Papasavvas, Emmanouil, Chomont, Nicolas, Li, Qingsheng, Howel, Bonnie J, Richman, Douglas D, Tebas, Pablo, Mounzer, Karam, Kostman, Jay, and Montaner, Luis J
- Subjects
Immunology ,Biochemistry and Cell Biology ,Genetics - Published
- 2017
36. Extensive virologic and immunologic characterization in an HIV-infected individual following allogeneic stem cell transplant and analytic cessation of antiretroviral therapy: A case study.
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Cummins, Nathan W, Rizza, Stacey, Litzow, Mark R, Hua, Stephane, Lee, Guinevere Q, Einkauf, Kevin, Chun, Tae-Wook, Rhame, Frank, Baker, Jason V, Busch, Michael P, Chomont, Nicolas, Dean, Patrick G, Fromentin, Rémi, Haase, Ashley T, Hampton, Dylan, Keating, Sheila M, Lada, Steven M, Lee, Tzong-Hae, Natesampillai, Sekar, Richman, Douglas D, Schacker, Timothy W, Wietgrefe, Stephen, Yu, Xu G, Yao, Joseph D, Zeuli, John, Lichterfeld, Mathias, and Badley, Andrew D
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Leukocytes ,Mononuclear ,Humans ,HIV ,HIV-1 ,HIV Infections ,Anti-Retroviral Agents ,Stem Cell Transplantation ,Viral Load ,Phylogeny ,Middle Aged ,Male ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,General & Internal Medicine ,Medical and Health Sciences - Abstract
BackgroundNotwithstanding 1 documented case of HIV-1 cure following allogeneic stem cell transplantation (allo-SCT), several subsequent cases of allo-SCT in HIV-1 positive individuals have failed to cure HIV-1 infection. The aim of our study was to describe changes in the HIV reservoir in a single chronically HIV-infected patient on suppressive antiretroviral therapy who underwent allo-SCT for treatment of acute lymphoblastic leukemia.Methods and findingsWe prospectively collected peripheral blood mononuclear cells (PBMCs) by leukapheresis from a 55-year-old man with chronic HIV infection before and after allo-SCT to measure the size of the HIV-1 reservoir and characterize viral phylogeny and phenotypic changes in immune cells. At day 784 post-transplant, when HIV-1 was undetectable by multiple measures-including PCR measurements of both total and integrated HIV-1 DNA, replication-competent virus measurement by large cell input quantitative viral outgrowth assay, and in situ hybridization of colon tissue-the patient consented to an analytic treatment interruption (ATI) with frequent clinical monitoring. He remained aviremic off antiretroviral therapy until ATI day 288, when a low-level virus rebound of 60 HIV-1 copies/ml occurred, which increased to 1,640 HIV-1 copies/ml 5 days later, prompting reinitiation of ART. Rebounding plasma HIV-1 sequences were phylogenetically distinct from proviral HIV-1 DNA detected in circulating PBMCs before transplantation. The main limitations of this study are the insensitivity of reservoir measurements, and the fact that it describes a single case.Conclusionsallo-SCT led to a significant reduction in the size of the HIV-1 reservoir and a >9-month-long ART-free remission from HIV-1 replication. Phylogenetic analyses suggest that the origin of rebound virus was distinct from the viruses identified pre-transplant in the PBMCs.
- Published
- 2017
37. HIV-1 persistence following extremely early initiation of antiretroviral therapy (ART) during acute HIV-1 infection: An observational study.
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Henrich, Timothy J, Hatano, Hiroyu, Bacon, Oliver, Hogan, Louise E, Rutishauser, Rachel, Hill, Alison, Kearney, Mary F, Anderson, Elizabeth M, Buchbinder, Susan P, Cohen, Stephanie E, Abdel-Mohsen, Mohamed, Pohlmeyer, Christopher W, Fromentin, Remi, Hoh, Rebecca, Liu, Albert Y, McCune, Joseph M, Spindler, Jonathan, Metcalf-Pate, Kelly, Hobbs, Kristen S, Thanh, Cassandra, Gibson, Erica A, Kuritzkes, Daniel R, Siliciano, Robert F, Price, Richard W, Richman, Douglas D, Chomont, Nicolas, Siliciano, Janet D, Mellors, John W, Yukl, Steven A, Blankson, Joel N, Liegler, Teri, and Deeks, Steven G
- Subjects
Humans ,HIV-1 ,HIV Infections ,Recurrence ,Anti-Retroviral Agents ,Treatment Outcome ,Flow Cytometry ,Prospective Studies ,Phenotype ,Adult ,Middle Aged ,Male ,Secondary Prevention ,Biomarkers ,HIV/AIDS ,Genetics ,Infectious Diseases ,Clinical Research ,2.1 Biological and endogenous factors ,Infection ,General & Internal Medicine ,Medical and Health Sciences - Abstract
BackgroundIt is unknown if extremely early initiation of antiretroviral therapy (ART) may lead to long-term ART-free HIV remission or cure. As a result, we studied 2 individuals recruited from a pre-exposure prophylaxis (PrEP) program who started prophylactic ART an estimated 10 days (Participant A; 54-year-old male) and 12 days (Participant B; 31-year-old male) after infection with peak plasma HIV RNA of 220 copies/mL and 3,343 copies/mL, respectively. Extensive testing of blood and tissue for HIV persistence was performed, and PrEP Participant A underwent analytical treatment interruption (ATI) following 32 weeks of continuous ART.Methods and findingsColorectal and lymph node tissues, bone marrow, cerebral spinal fluid (CSF), plasma, and very large numbers of peripheral blood mononuclear cells (PBMCs) were obtained longitudinally from both participants and were studied for HIV persistence in several laboratories using molecular and culture-based detection methods, including a murine viral outgrowth assay (mVOA). Both participants initiated PrEP with tenofovir/emtricitabine during very early Fiebig stage I (detectable plasma HIV-1 RNA, antibody negative) followed by 4-drug ART intensification. Following peak viral loads, both participants experienced full suppression of HIV-1 plasma viremia. Over the following 2 years, no further HIV could be detected in blood or tissue from PrEP Participant A despite extensive sampling from ileum, rectum, lymph nodes, bone marrow, CSF, circulating CD4+ T cell subsets, and plasma. No HIV was detected from tissues obtained from PrEP Participant B, but low-level HIV RNA or DNA was intermittently detected from various CD4+ T cell subsets. Over 500 million CD4+ T cells were assayed from both participants in a humanized mouse outgrowth assay. Three of 8 mice infused with CD4+ T cells from PrEP Participant B developed viremia (50 million input cells/surviving mouse), but only 1 of 10 mice infused with CD4+ T cells from PrEP Participant A (53 million input cells/mouse) experienced very low level viremia (201 copies/mL); sequence confirmation was unsuccessful. PrEP Participant A stopped ART and remained aviremic for 7.4 months, rebounding with HIV RNA of 36 copies/mL that rose to 59,805 copies/mL 6 days later. ART was restarted promptly. Rebound plasma HIV sequences were identical to those obtained during acute infection by single-genome sequencing. Mathematical modeling predicted that the latent reservoir size was approximately 200 cells prior to ATI and that only around 1% of individuals with a similar HIV burden may achieve lifelong ART-free remission. Furthermore, we observed that lymphocytes expressing the tumor marker CD30 increased in frequency weeks to months prior to detectable HIV-1 RNA in plasma. This study was limited by the small sample size, which was a result of the rarity of individuals presenting during hyperacute infection.ConclusionsWe report HIV relapse despite initiation of ART at one of the earliest stages of acute HIV infection possible. Near complete or complete loss of detectable HIV in blood and tissues did not lead to indefinite ART-free HIV remission. However, the small numbers of latently infected cells in individuals treated during hyperacute infection may be associated with prolonged ART-free remission.
- Published
- 2017
38. Identification of Genetically Intact HIV-1 Proviruses in Specific CD4+ T Cells from Effectively Treated Participants
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Hiener, Bonnie, Horsburgh, Bethany A, Eden, John-Sebastian, Barton, Kirston, Schlub, Timothy E, Lee, Eunok, von Stockenstrom, Susanne, Odevall, Lina, Milush, Jeffrey M, Liegler, Teri, Sinclair, Elizabeth, Hoh, Rebecca, Boritz, Eli A, Douek, Daniel, Fromentin, Rémi, Chomont, Nicolas, Deeks, Steven G, Hecht, Frederick M, and Palmer, Sarah
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Biological Sciences ,Women's Health ,HIV/AIDS ,Infectious Diseases ,Clinical Research ,Genetics ,Sexually Transmitted Infections ,Infection ,Adult ,Aged ,Antiretroviral Therapy ,Highly Active ,Base Sequence ,CD4-Positive T-Lymphocytes ,Disease Reservoirs ,HIV Infections ,HIV-1 ,Humans ,Lymphocyte Count ,Lymphocyte Subsets ,Male ,Middle Aged ,Phylogeny ,Proviruses ,Sequence Analysis ,DNA ,HIV ,antiretroviral therapy ,cellular proliferation ,clonal expansion ,full-length HIV sequencing ,latency ,replication competency ,single proviral sequencing ,Biochemistry and Cell Biology ,Medical Physiology ,Biological sciences - Abstract
Latent replication-competent HIV-1 persists in individuals on long-term antiretroviral therapy (ART). We developed the Full-Length Individual Proviral Sequencing (FLIPS) assay to determine the distribution of latent replication-competent HIV-1 within memory CD4+ T cell subsets in six individuals on long-term ART. FLIPS is an efficient, high-throughput assay that amplifies and sequences near full-length (∼9 kb) HIV-1 proviral genomes and determines potential replication competency through genetic characterization. FLIPS provides a genome-scale perspective that addresses the limitations of other methods that also genetically characterize the latent reservoir. Using FLIPS, we identified 5% of proviruses as intact and potentially replication competent. Intact proviruses were unequally distributed between T cell subsets, with effector memory cells containing the largest proportion of genetically intact HIV-1 proviruses. We identified multiple identical intact proviruses, suggesting a role for cellular proliferation in the maintenance of the latent HIV-1 reservoir.
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- 2017
39. IL-17A reprograms intestinal epithelial cells to facilitate HIV-1 replication and outgrowth in CD4+ T cells
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Wiche Salinas, Tomas Raul, Gosselin, Annie, Raymond Marchand, Laurence, Moreira Gabriel, Etiene, Tastet, Olivier, Goulet, Jean-Philippe, Zhang, Yuwei, Vlad, Dragos, Touil, Hanane, Routy, Jean-Pierre, Bego, Mariana G., El-Far, Mohamed, Chomont, Nicolas, Landay, Alan L., Cohen, Éric A., Tremblay, Cécile, and Ancuta, Petronela
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- 2021
- Full Text
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40. Intra-Host Evolution Analyses in an Immunosuppressed Patient Supports SARS-CoV-2 Viral Reservoir Hypothesis
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Fournelle, Dominique, primary, Mostefai, Fatima, additional, Brunet-Ratnasingham, Elsa, additional, Poujol, Raphaël, additional, Grenier, Jean-Christophe, additional, Gálvez, José Héctor, additional, Pagliuzza, Amélie, additional, Levade, Inès, additional, Moreira, Sandrine, additional, Benlarbi, Mehdi, additional, Beaudoin-Bussières, Guillaume, additional, Gendron-Lepage, Gabrielle, additional, Bourassa, Catherine, additional, Tauzin, Alexandra, additional, Grandjean Lapierre, Simon, additional, Chomont, Nicolas, additional, Finzi, Andrés, additional, Kaufmann, Daniel E., additional, Craig, Morgan, additional, and Hussin, Julie G., additional
- Published
- 2024
- Full Text
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41. Metformin Enhances Antibody-Mediated Recognition of HIV-Infected CD4+ T-Cells by Decreasing Viral Release
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Fert, Augustine, primary, Richard, Jonathan, additional, Raymond Marchand, Laurence, additional, Planas, Delphine, additional, Routy, Jean-Pierre, additional, Chomont, Nicolas, additional, Finzi, Andres, additional, and Ancuta, Petronela, additional
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- 2024
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42. Combined single-cell transcriptional, translational, and genomic profiling reveals HIV-1 reservoir diversity
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Sannier, Gérémy, Dubé, Mathieu, Dufour, Caroline, Richard, Corentin, Brassard, Nathalie, Delgado, Gloria-Gabrielle, Pagliuzza, Amélie, Baxter, Amy E., Niessl, Julia, Brunet-Ratnasingham, Elsa, Charlebois, Roxanne, Routy, Bertrand, Routy, Jean-Pierre, Fromentin, Rémi, Chomont, Nicolas, and Kaufmann, Daniel E.
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- 2021
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43. Human Immunodeficiency Virus Persistence and T-Cell Activation in Blood, Rectal, and Lymph Node Tissue in Human Immunodeficiency Virus–Infected Individuals Receiving Suppressive Antiretroviral Therapy
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Khoury, Gabriela, Fromentin, Rémi, Solomon, Ajantha, Hartogensis, Wendy, Killian, Marisela, Hoh, Rebecca, Somsouk, Ma, Hunt, Peter W, Girling, Valerie, Sinclair, Elizabeth, Bacchetti, Peter, Anderson, Jenny L, Hecht, Frederick M, Deeks, Steven G, Cameron, Paul U, Chomont, Nicolas, and Lewin, Sharon R
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Medical Microbiology ,Biomedical and Clinical Sciences ,Immunology ,HIV/AIDS ,Clinical Research ,Infectious Diseases ,Sexually Transmitted Infections ,Aetiology ,2.1 Biological and endogenous factors ,Infection ,Antiretroviral Therapy ,Highly Active ,Australia ,Biomarkers ,CD4 Lymphocyte Count ,CD4-Positive T-Lymphocytes ,CD8-Positive T-Lymphocytes ,Cross-Sectional Studies ,DNA ,Viral ,Female ,HIV Infections ,HIV-1 ,HLA-DR Antigens ,Humans ,Lymph Nodes ,Lymphocyte Activation ,Male ,Middle Aged ,Programmed Cell Death 1 Receptor ,Rectum ,Regression Analysis ,Sex Factors ,United States ,Viral Load ,HIV ,HIV persistence ,Antiretroviral therapy ,T-cell activation ,lymph node ,rectum ,reservoir ,PD-1 ,Biological Sciences ,Medical and Health Sciences ,Microbiology ,Biological sciences ,Biomedical and clinical sciences ,Health sciences - Abstract
Background. Immune activation and inflammation remain elevated in human immunodeficiency virus (HIV)-infected individuals receiving antiretroviral therapy (ART) and may contribute to HIV persistence. Methods. Using flow cytometry expression of CD38, HLA-DR and PD-1 were measured in blood (n = 48), lymph node (LN; n = 9), and rectal tissue (n = 17) from virally suppressed individuals. Total and integrated HIV DNA, 2-LTR circles, and cell-associated unspliced HIV RNA were quantified. Results. CD4+ T cells from rectal tissue had a higher frequency of integrated HIV DNA compared with blood (4.26 fold-change in DNA; 95% confidence interval [CI] = 2.61-7.00; P
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- 2017
44. Association of Arterial and Lymph Node Inflammation With Distinct Inflammatory Pathways in Human Immunodeficiency Virus Infection
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Tawakol, Ahmed, Ishai, Amorina, Li, Danny, Takx, Richard AP, Hur, Sophia, Kaiser, Yannick, Pampaloni, Miguel, Rupert, Adam, Hsu, Denise, Sereti, Irini, Fromentin, Rémi, Chomont, Nicolas, Ganz, Peter, Deeks, Steven G, and Hsue, Priscilla Y
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Medical Microbiology ,Biomedical and Clinical Sciences ,Immunology ,Sexually Transmitted Infections ,Infectious Diseases ,Clinical Research ,HIV/AIDS ,2.1 Biological and endogenous factors ,Aetiology ,Inflammatory and immune system ,Infection ,Good Health and Well Being ,Arteritis ,CD4 Lymphocyte Count ,California ,Case-Control Studies ,DNA ,Viral ,HIV ,HIV Infections ,Humans ,Incidence ,Lymph Nodes ,Lymphadenitis ,Male ,Middle Aged ,Positron-Emission Tomography ,Viral Load ,Cardiovascular medicine and haematology - Abstract
ImportanceHuman immunodeficiency virus (HIV) infection is associated with a high risk of cardiovascular disease and increased arterial inflammation. In HIV, inflammation is also increased within lymph nodes (LNs), tissues known to harbor the virus even among treated and suppressed individuals.ObjectiveTo test the hypothesis that arterial inflammation is linked to HIV disease activity and to inflammation within HIV-infected tissues (LNs).Design, setting, and participantsFor this case-control study, participants were recruited from the SCOPE (Observational Study of the Consequences of the Protease Inhibitor Era) cohort, a clinic-based cohort of individuals receiving care at San Francisco General Hospital and the San Francisco Veteran's Affairs Medical Center. Arterial and LN inflammation were measured using 18F-fluorodeoxyglucose positron emission tomography. Detailed immunophenotyping was performed, along with measurement of viral activity/persistence and of circulating inflammatory biomarkers.Main outcomes and measuresArterial and LN inflammation.ResultsA total of 74 men were studied (45 HIV-infected men with a median age of 53 years [interquartile range, 49-59 years] and 29 uninfected male controls with a median age of 52 years [interquartile range, 46-56 years]). Lymph node inflammation was higher in HIV-infected individuals and correlated with markers of viral disease activity (viral load, CD8+ T cells, and CD4/CD8 ratio) and CD4+ T-cell activation. Uninfected controls had the lowest LN activity (mean [SD] maximum axillary LN standardized uptake value, 1.53 [0.56]), the elite controller and ART-suppressed groups had intermediate levels of LN (mean [SD] maximum axillary LN standardized uptake value, 2.12 [0.87] and 2.32 [1.79], respectively), and the noncontrollers had the highest activity (mean [SD] maximum axillary LN standardized uptake value, 8.82 [3.08]). Arterial inflammation was modestly increased in HIV-infected individuals and was positively correlated with circulating inflammatory biomarkers (high-sensitivity C-reactive protein and IL-6) and activated monocytes (CD14dimCD16+; nonclassical) but not with markers of HIV. While LN and arterial inflammation were increased in HIV, inflammatory activity in these tissues was not related (r = 0.09, P = .56).Conclusions and relevanceWhile LNs and, to a lesser degree, the arterial wall are inflamed in HIV, inflammation in these tissues is not closely linked. Namely, measures of HIV disease activity are strongly associated with LN inflammation but not with arterial inflammation. These data suggest that LN and arterial inflammation do not share underlying pathways of immune activation and also that therapeutic interventions that reduce viral disease activity may not predictably reduce arterial inflammation in HIV or its downstream consequence (ie, cardiovascular disease).
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- 2017
45. HIV persists in CCR6+CD4+ T cells from colon and blood during antiretroviral therapy
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Gosselin, Annie, Salinas, Tomas Raul Wiche, Planas, Delphine, Wacleche, Vanessa S, Zhang, Yuwei, Fromentin, Rémi, Chomont, Nicolas, Cohen, Éric A, Shacklett, Barbara, Mehraj, Vikram, Ghali, Maged P, Routy, Jean-Pierre, and Ancuta, Petronela
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Medical Microbiology ,Biomedical and Clinical Sciences ,Immunology ,HIV/AIDS ,Infectious Diseases ,Infection ,Adult ,Aged ,Anti-Retroviral Agents ,Blood ,CD4-Positive T-Lymphocytes ,Colon ,DNA ,Viral ,Female ,Flow Cytometry ,HIV Infections ,Humans ,Male ,Middle Aged ,Polymerase Chain Reaction ,Real-Time Polymerase Chain Reaction ,Receptors ,CCR6 ,T-Lymphocyte Subsets ,Virus Activation ,Young Adult ,antiretroviral therapy ,CCR6 ,central memory CD4(+) T cells ,HIV reservoirs ,retinoic acid ,Th17 ,viral outgrowth assay ,Biological Sciences ,Medical and Health Sciences ,Psychology and Cognitive Sciences ,Virology ,Biomedical and clinical sciences ,Health sciences - Abstract
ObjectivesThe objective of this article is to investigate the contribution of colon and blood CD4 T-cell subsets expressing the chemokine receptor CCR6 to HIV persistence during antiretroviral therapy.DesignMatched sigmoid biopsies and blood samples (n = 13) as well as leukapheresis (n = 20) were collected from chronically HIV-infected individuals receiving antiretroviral therapy. Subsets of CD4 T cells with distinct differentiation/polarization profiles were identified using surface markers as follows: memory (TM, CD45RA), central memory (TCM; CD45RACCR7), effector (TEM/TM; CD45RACCR7), Th17 (CCR6CCR4), Th1Th17 (CCR6CXCR3), Th1 (CCR6CXCR3), and Th2 (CCR6CCR4).MethodsWe used polychromatic flow cytometry for cell sorting, nested real-time PCR for HIV DNA quantification, ELISA and flow cytometry for HIV p24 quantification. HIV reactivation was induced by TCR triggering in the presence/absence of all-trans retinoic acid.ResultsCompared with blood, the frequency of CCR6 TM was higher in the colon. In both colon and blood compartments, CCR6 TM were significantly enriched in HIV DNA when compared with their CCR6 counterparts (n = 13). In blood, integrated HIV DNA levels were significantly enriched in CCR6 versus CCR6 TCM of four of five individuals and CCR6 versus CCR6 TEM of three of five individuals. Among blood TCM, Th17 and Th1Th17 contributed the most to the pool of cells harboring integrated HIV DNA despite their reduced frequency compared with Th2, which were infected the least. HIV reactivation was induced by TCR triggering and/or retinoic acid exposure at higher levels in CCR6 versus CCR6 TM, TCM, and TEM.ConclusionCCR6 is a marker for colon and blood CD4 T cells enriched for replication-competent HIV DNA. Novel eradication strategies should target HIV persistence in CCR6CD4 T cells from various anatomic sites.
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- 2017
46. New insights into the heterogeneity of Th17 subsets contributing to HIV-1 persistence during antiretroviral therapy
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Wacleche, Vanessa Sue, Goulet, Jean-Philippe, Gosselin, Annie, Monteiro, Patricia, Soudeyns, Hugo, Fromentin, Rémi, Jenabian, Mohammad-Ali, Vartanian, Shant, Deeks, Steven G, Chomont, Nicolas, Routy, Jean-Pierre, and Ancuta, Petronela
- Subjects
Microbiology ,Biological Sciences ,Infectious Diseases ,Sexually Transmitted Infections ,HIV/AIDS ,Aetiology ,2.1 Biological and endogenous factors ,Infection ,Antiretroviral Therapy ,Highly Active ,Cross-Sectional Studies ,HIV Infections ,HIV-1 ,Humans ,Immunologic Memory ,Longitudinal Studies ,Receptors ,CCR4 ,Receptors ,CCR6 ,Receptors ,CXCR3 ,Th17 Cells ,Virus Replication ,Human ,Th17 ,CCR6 ,CCR4 ,CXCR3 ,HIV reservoirs ,ART ,Clinical Sciences ,Virology - Abstract
BackgroundTh17 cells are permissive to HIV-1 infection and their depletion from the gut of infected individuals leads to microbial translocation, a major cause for non-AIDS co-morbidities. Most recent evidence supports the contribution of long-lived Th17 cells to HIV persistence during antiretroviral therapy (ART). However, the identity of long-lived Th17 cells remains unknown.ResultsHere, we performed an in-depth transcriptional and functional characterization of four distinct Th17 subsets and investigated their contribution to HIV reservoir persistence during ART. In addition to the previously characterized CCR6(+)CCR4(+) (Th17) and CCR6(+)CXCR3(+) (Th1Th17) subsets, we reveal the existence of two novel CCR6(+) subsets, lacking (double negative, CCR6(+)DN) or co-expressing CXCR3 and CCR4 (double positive, CCR6(+)DP). The four subsets shared multiple Th17-polarization markers, a fraction of cells proliferated in response to C. albicans, and exhibited lineage commitment and plasticity when cultured under Th17 and Th1 conditions, respectively. Of note, fractions of CCR6(+)DN and Th17 demonstrated stable Th17-lineage commitment under Th1-polarization conditions. Among the four subsets, CCR6(+)DN expressed a unique transcriptional signature indicative of early Th17 development (IL-17F, STAT3), lymph-node homing (CCR7, CD62L), follicular help (CXCR5, BCL6, ASCL2), and self-renewal (LEFI, MYC, TERC). Cross sectional and longitudinal studies demonstrated that CCR6(+)DN cells were the most predominant CCR6(+) subset in the blood before and after ART initiation; high frequencies of these cells were similarly observed in inguinal lymph nodes of individuals receiving long-term ART. Importantly, replication competent HIV was isolated from CCR6(+)DN of ART-treated individuals.ConclusionsTogether, these results provide new insights into the functional heterogeneity of Th17-polarized CCR6(+)CD4(+) T-cells and support the major contribution of CCR6(+)DN cells to HIV persistence during ART.
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- 2016
47. IL-32 Drives the Differentiation of Cardiotropic CD4+ T Cells Carrying HIV DNA in People With HIV.
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Ramani, Hardik, Gosselin, Annie, Bunet, Rémi, Jenabian, Mohammad-Ali, Sylla, Mohamed, Pagliuzza, Amélie, Chartrand-Lefebvre, Carl, Routy, Jean-Pierre, Goulet, Jean-Philippe, Thomas, Réjean, Trottier, Benoit, Martel-Laferrière, Valérie, Fortin, Claude, Chomont, Nicolas, Fromentin, Rémi, Landay, Alan L, Durand, Madeleine, Ancuta, Petronela, El-Far, Mohamed, and Tremblay, Cecile
- Subjects
T cells ,HIV-positive persons ,INTERLEUKIN-32 ,PROTEIN-tyrosine kinases ,IMMUNOLOGIC memory ,VIRAL tropism - Abstract
Interleukin 32 (IL-32) is a potent multi-isoform proinflammatory cytokine, which is upregulated in people with HIV (PWH) and is associated with cardiovascular disease (CVD) risk. However, the impact of IL-32 isoforms on CD4 T-cell cardiotropism, a mechanism potentially contributing to heart inflammation, remains unknown. Here we show that IL-32 isoforms β and γ induce the generation of CCR4
+ CXCR3+ double positive (DP) memory CD4 T-cell subpopulation expressing the tyrosine kinase receptor c-Met, a phenotype associated with heart-homing of T cells. Our ex vivo studies on PWH show that the frequency of DP CD4 T cells is significantly higher in individuals with, compared to individuals without, subclinical atherosclerosis and that DP cells from antiretroviral-naive and treated individuals are highly enriched with HIV DNA. Together, these data demonstrate that IL-32 isoforms have the potential to induce heart-homing of HIV-infected CD4 T cells, which may further aggravate heart inflammation and CVD in PWH. [ABSTRACT FROM AUTHOR]- Published
- 2024
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48. ‘Rinse and Replace’: Boosting T Cell Turnover To Reduce HIV-1 Reservoirs
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Kawabe, Takeshi, Bocharov, Gennady, Meier-Schellersheim, Martin, Alon, Hagit, Chomont, Nicolas, Grossman, Zehava, Sousa, Ana E, Margolis, Leonid, Maldarelli, Frank, Grossman, Zvi, Singh, Nevil J., Simonetti, Francesco R., Lederman, Michael M., Douek, Daniel C., and Deeks, Steven G.
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- 2020
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49. Persistent HIV transcription and variable antiretroviral drug penetration in lymph nodes during plasma viral suppression
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Fletcher, Courtney V., Kroon, Eugène, Schacker, Timothy, Pinyakorn, Suteeraporn, Chomont, Nicolas, Chottanapund, Suthat, Prueksakaew, Peeriya, Benjapornpong, Khunthalee, Buranapraditkun, Supranee, Phanuphak, Nittaya, Ananworanich, Jintanat, Vasan, Sandhya, and Hsu, Denise
- Published
- 2022
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50. International AIDS Society global scientific strategy: towards an HIV cure 2016
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Deeks, Steven G, Lewin, Sharon R, Ross, Anna Laura, Ananworanich, Jintanat, Benkirane, Monsef, Cannon, Paula, Chomont, Nicolas, Douek, Daniel, Lifson, Jeffrey D, Lo, Ying-Ru, Kuritzkes, Daniel, Margolis, David, Mellors, John, Persaud, Deborah, Tucker, Joseph D, Barre-Sinoussi, Françoise, Alter, Galit, Auerbach, Judith, Autran, Brigitte, Barouch, Dan H, Behrens, Georg, Cavazzana, Marina, Chen, Zhiwei, Cohen, Éric A, Corbelli, Giulio Maria, Eholié, Serge, Eyal, Nir, Fidler, Sarah, Garcia, Laurindo, Grossman, Cynthia, Henderson, Gail, Henrich, Timothy J, Jefferys, Richard, Kiem, Hans-Peter, McCune, Joseph, Moodley, Keymanthri, Newman, Peter A, Nijhuis, Monique, Nsubuga, Moses Supercharger, Ott, Melanie, Palmer, Sarah, Richman, Douglas, Saez-Cirion, Asier, Sharp, Matthew, Siliciano, Janet, Silvestri, Guido, Singh, Jerome, Spire, Bruno, Taylor, Jeffrey, Tolstrup, Martin, Valente, Susana, van Lunzen, Jan, Walensky, Rochelle, Wilson, Ira, and Zack, Jerome
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Medical Microbiology ,Biomedical and Clinical Sciences ,Immunology ,Good Health and Well Being ,Acquired Immunodeficiency Syndrome ,Goals ,HIV Infections ,Humans ,International Cooperation ,Organizational Objectives ,Research ,Societies ,Medical ,International AIDS Society Towards a Cure Working Group ,Medical and Health Sciences ,Biomedical and clinical sciences ,Health sciences - Abstract
Antiretroviral therapy is not curative. Given the challenges in providing lifelong therapy to a global population of more than 35 million people living with HIV, there is intense interest in developing a cure for HIV infection. The International AIDS Society convened a group of international experts to develop a scientific strategy for research towards an HIV cure. This Perspective summarizes the group's strategy.
- Published
- 2016
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