1,241 results on '"Siliciano, Robert F."'
Search Results
2. A cell-free antigen processing system informs HIV-1 epitope selection and vaccine design
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Sengupta, Srona, Zhang, Josephine, Reed, Madison C, Yu, Jeanna, Kim, Aeryon, Boronina, Tatiana N, Board, Nathan L, Wrabl, James O, Shenderov, Kevin, Welsh, Robin A, Yang, Weiming, Timmons, Andrew E, Hoh, Rebecca, Cole, Robert N, Deeks, Steven G, Siliciano, Janet D, Siliciano, Robert F, and Sadegh-Nasseri, Scheherazade
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Medical Microbiology ,Biomedical and Clinical Sciences ,Immunology ,Infectious Diseases ,Clinical Research ,Prevention ,Immunization ,HIV/AIDS ,Aetiology ,2.1 Biological and endogenous factors ,Infection ,Good Health and Well Being ,Humans ,Antigen Presentation ,Chromatography ,Liquid ,Tandem Mass Spectrometry ,Epitopes ,T-Lymphocyte ,Antigens ,Viral ,Vaccines ,HIV Infections ,Medical and Health Sciences ,Biomedical and clinical sciences ,Health sciences - Abstract
Distinct CD4+ T cell epitopes have been associated with spontaneous control of HIV-1 replication, but analysis of antigen-dependent factors that influence epitope selection is lacking. To examine these factors, we used a cell-free antigen processing system that incorporates soluble HLA-DR (DR1), HLA-DM (DM), cathepsins, and full-length protein antigens for epitope identification by LC-MS/MS. HIV-1 Gag, Pol, Env, Vif, Tat, Rev, and Nef were examined using this system. We identified 35 novel epitopes, including glycopeptides. Epitopes from smaller HIV-1 proteins mapped to regions of low protein stability and higher solvent accessibility. HIV-1 antigens associated with limited CD4+ T cell responses were processed efficiently, while some protective epitopes were inefficiently processed. 55% of epitopes obtained from cell-free processing induced memory CD4+ T cell responses in HIV-1+ donors, including eight of 19 novel epitopes tested. Thus, an in vitro processing system utilizing the components of Class II processing reveals factors influencing epitope selection of HIV-1 and represents an approach to understanding epitope selection from non-HIV-1 antigens.
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- 2023
3. Assessing the impact of autologous virus neutralizing antibodies on viral rebound time in postnatally SHIV-infected ART-treated infant rhesus macaques
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Mainou, Ellie, Berendam, Stella J., Obregon-Perko, Veronica, Uffman, Emilie A., Phan, Caroline T., Shaw, George M., Bar, Katharine J., Kumar, Mithra R., Fray, Emily J., Siliciano, Janet M., Siliciano, Robert F., Silvestri, Guido, Permar, Sallie R., Fouda, Genevieve G., McCarthy, Janice, Chahroudi, Ann, Conway, Jessica M., and Chan, Cliburn
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- 2024
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4. Impact of anti-PD-1 and anti-CTLA-4 on the HIV reservoir in people living with HIV with cancer on antiretroviral therapy: The AIDS Malignancy Consortium-095 study
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Rasmussen, Thomas A, Rajdev, Lakshmi, Rhodes, Ajantha, Dantanarayana, Ashanti, Tennakoon, Surekha, Chea, Socheata, Spelman, Tim, Lensing, Shelly, Rutishauser, Rachel, Bakkour, Sonia, Busch, Michael, Siliciano, Janet D, Siliciano, Robert F, Einstein, Mark H, Dittmer, Dirk P, Chiao, Elizabeth, Deeks, Steven, Durand, Christine, and Lewin, Sharon R
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Genetics ,HIV/AIDS ,Infectious Diseases ,Clinical Research ,Cancer ,Infection ,Acquired Immunodeficiency Syndrome ,CTLA-4 Antigen ,HIV Infections ,HIV-1 ,Humans ,Neoplasms ,Programmed Cell Death 1 Receptor ,Virus Latency ,HIV ,HIV latency ,anti-PD-1 ,anti-CTLA-4 ,anti–CTLA-4 ,anti–PD-1 ,Biological Sciences ,Medical and Health Sciences ,Microbiology - Abstract
BackgroundAntibodies to programmed cell death 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) may perturb human immunodeficiency virus (HIV) persistence during antiretroviral therapy (ART) by reversing HIV latency and/or boosting HIV-specific immunity, leading to clearance of infected cells. We tested this hypothesis in a clinical trial of anti-PD-1 alone or in combination with anti-CTLA-4 in people living with HIV (PLWH) and cancer.MethodsThis was a substudy of the AIDS Malignancy Consortium 095 Study. ART-suppressed PLWH with advanced malignancies were assigned to nivolumab (anti-PD-1) with or without ipilimumab (anti-CTLA-4). In samples obtained preinfusion and 1 and 7 days after the first and fourth doses of immune checkpoint blockade (ICB), we quantified cell-associated unspliced (CA-US) HIV RNA and HIV DNA. Plasma HIV RNA was quantified during the first treatment cycle. Quantitative viral outgrowth assay (QVOA) to estimate the frequency of replication-competent HIV was performed before and after ICB for participants with samples available.ResultsOf 40 participants, 33 received nivolumab and 7 nivolumab plus ipilimumab. Whereas CA-US HIV RNA did not change with nivolumab monotherapy, we detected a median 1.44-fold increase (interquartile range, 1.16-1.89) after the first dose of nivolumab and ipilimumab combination therapy (P = .031). There was no decrease in the frequency of cells containing replication-competent HIV, but in the 2 individuals on combination ICB for whom we had longitudinal QVOA, we detected decreases of 97% and 64% compared to baseline.ConclusionsAnti-PD-1 alone showed no effect on HIV latency or the latent HIV reservoir, but the combination of anti-PD-1 and anti-CTL-4 induced a modest increase in CA-US HIV RNA and may potentially eliminate cells containing replication-competent HIV.Clinical trials registrationNCT02408861.
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- 2021
5. Antigen-driven clonal selection shapes the persistence of HIV-1 infected CD4+ T cells in vivo
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Simonetti, Francesco R, Zhang, Hao, Soroosh, Garshasb P, Duan, Jiayi, Rhodehouse, Kyle, Hill, Alison L, Beg, Subul A, McCormick, Kevin, Raymond, Hayley E, Nobles, Christopher L, Everett, John K, Kwon, Kyungyoon J, White, Jennifer A, Lai, Jun, Margolick, Joseph B, Hoh, Rebecca, Deeks, Steven G, Bushman, Frederic D, Siliciano, Janet D, and Siliciano, Robert F
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Medical Microbiology ,Biomedical and Clinical Sciences ,Immunology ,Infectious Diseases ,Sexually Transmitted Infections ,Clinical Research ,HIV/AIDS ,2.1 Biological and endogenous factors ,Aetiology ,Infection ,Adult ,CD4-Positive T-Lymphocytes ,Clonal Selection ,Antigen-Mediated ,Female ,HIV Infections ,HIV-1 ,Humans ,Male ,Virus Integration ,Virus Latency ,gag Gene Products ,Human Immunodeficiency Virus ,AIDS/HIV ,Adaptive immunity ,Clonal selection ,T cells ,Medical and Health Sciences ,Biological sciences ,Biomedical and clinical sciences ,Health sciences - Abstract
Clonal expansion of infected CD4+ T cells is a major mechanism of HIV-1 persistence and a barrier to achieving a cure. Potential causes are homeostatic proliferation, effects of HIV-1 integration, and interaction with antigens. Here, we show that it is possible to link antigen responsiveness, the full proviral sequence, the integration site, and the T cell receptor β-chain (TCRβ) sequence to examine the role of recurrent antigenic exposure in maintaining the HIV-1 reservoir. We isolated CMV- and Gag-responding CD4+ T cells from 10 treated individuals. Proviral populations in CMV-responding cells were dominated by large clones, including clones harboring replication-competent proviruses. TCRβ repertoires showed high clonality driven by converging adaptive responses. Although some proviruses were in genes linked to HIV-1 persistence (BACH2, STAT5B, MKL1), the proliferation of infected cells under antigenic stimulation occurred regardless of the site of integration. Paired TCRβ and integration site analysis showed that infection could occur early or late in the course of a clone's response to antigen and could generate infected cell populations too large to be explained solely by homeostatic proliferation. Together, these findings implicate antigen-driven clonal selection as a major factor in HIV-1 persistence, a finding that will be a difficult challenge to eradication efforts.
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- 2021
6. Shared Mechanisms Govern HIV Transcriptional Suppression in Circulating CD103+ and Gut CD4+ T Cells
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Yukl, Steven A, Khan, Shahzada, Chen, Tsui-Hua, Trapecar, Martin, Wu, Frank, Xie, Guorui, Telwatte, Sushama, Fulop, Daniel, Pico, Alexander R, Laird, Gregory M, Ritter, Kristen D, Jones, Norman G, Lu, Chuanyi M, Siliciano, Robert F, Roan, Nadia R, Milush, Jeffrey M, Somsouk, Ma, Deeks, Steven G, Hunt, Peter W, and Sanjabi, Shomyseh
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Medical Microbiology ,Biomedical and Clinical Sciences ,Immunology ,Genetics ,HIV/AIDS ,Infectious Diseases ,Sexually Transmitted Infections ,2.1 Biological and endogenous factors ,1.1 Normal biological development and functioning ,Infection ,Good Health and Well Being ,Antigens ,CD ,Antiviral Agents ,CD4-Positive T-Lymphocytes ,DNA ,Viral ,Gastrointestinal Tract ,Gene Expression Regulation ,HIV Infections ,HIV-1 ,Humans ,Integrin alpha Chains ,Intraepithelial Lymphocytes ,Proviruses ,RNA ,Viral ,Ribosomal Proteins ,T-Lymphocyte Subsets ,Transcription ,Genetic ,Virus Latency ,CD103 ,CD4 T cell ,PD-1 ,gamma delta T cell ,human immunodeficiency virus ,intestines ,latency ,tissue-resident memory cell ,transforming growth factor receptors ,Biological Sciences ,Agricultural and Veterinary Sciences ,Medical and Health Sciences ,Virology ,Agricultural ,veterinary and food sciences ,Biological sciences ,Biomedical and clinical sciences - Abstract
Latent HIV infection is the main barrier to cure, and most HIV-infected cells reside in the gut, where distinct but unknown mechanisms may promote viral latency. Transforming growth factor β (TGF-β), which induces the expression of CD103 on tissue-resident memory T cells, has been implicated in HIV latency. Using CD103 as a surrogate marker to identify cells that have undergone TGF-β signaling, we compared the HIV RNA/DNA contents and cellular transcriptomes of CD103+ and CD103- CD4 T cells from the blood and rectum of HIV-negative (HIV-) and antiretroviral therapy (ART)-suppressed HIV-positive (HIV+) individuals. Like gut CD4+ T cells, circulating CD103+ cells harbored more HIV DNA than did CD103- cells but transcribed less HIV RNA per provirus. Circulating CD103+ cells also shared a gene expression profile that is closer to that of gut CD4 T cells than to that of circulating CD103- cells, with significantly lower expression levels of ribosomal proteins and transcriptional and translational pathways associated with HIV expression but higher expression levels of a subset of genes implicated in suppressing HIV transcription. These findings suggest that blood CD103+ CD4 T cells can serve as a model to study the molecular mechanisms of HIV latency in the gut and reveal new cellular factors that may contribute to HIV latency.IMPORTANCE The ability of HIV to establish a reversibly silent, "latent" infection is widely regarded as the main barrier to curing HIV. Most HIV-infected cells reside in tissues such as the gut, but it is unclear what mechanisms maintain HIV latency in the blood or gut. We found that circulating CD103+ CD4+ T cells are enriched for HIV-infected cells in a latent-like state. Using RNA sequencing (RNA-seq), we found that CD103+ T cells share a cellular transcriptome that more closely resembles that of CD4+ T cells from the gut, suggesting that they are homing to or from the gut. We also identified the cellular genes whose expression distinguishes gut CD4+ or circulating CD103+ T cells from circulating CD103- T cells, including some genes that have been implicated in HIV expression. These genes may contribute to latent HIV infection in the gut and may serve as new targets for therapies aimed at curing HIV.
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- 2020
7. Allogeneic immunity clears latent virus following allogeneic stem cell transplantation in SIV-infected ART-suppressed macaques
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Wu, Helen L., Busman-Sahay, Kathleen, Weber, Whitney C., Waytashek, Courtney M., Boyle, Carla D., Bateman, Katherine B., Reed, Jason S., Hwang, Joseph M., Shriver-Munsch, Christine, Swanson, Tonya, Northrup, Mina, Armantrout, Kimberly, Price, Heidi, Robertson-LeVay, Mitch, Uttke, Samantha, Kumar, Mithra R., Fray, Emily J., Taylor-Brill, Sol, Bondoc, Stephen, Agnor, Rebecca, Junell, Stephanie L., Legasse, Alfred W., Moats, Cassandra, Bochart, Rachele M., Sciurba, Joseph, Bimber, Benjamin N., Sullivan, Michelle N., Dozier, Brandy, MacAllister, Rhonda P., Hobbs, Theodore R., Martin, Lauren D., Panoskaltsis-Mortari, Angela, Colgin, Lois M.A., Siliciano, Robert F., Siliciano, Janet D., Estes, Jacob D., Smedley, Jeremy V., Axthelm, Michael K., Meyers, Gabrielle, Maziarz, Richard T., Burwitz, Benjamin J., Stanton, Jeffrey J., and Sacha, Jonah B.
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- 2023
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8. Distinct viral reservoirs in individuals with spontaneous control of HIV-1
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Jiang, Chenyang, Lian, Xiaodong, Gao, Ce, Sun, Xiaoming, Einkauf, Kevin B, Chevalier, Joshua M, Chen, Samantha MY, Hua, Stephane, Rhee, Ben, Chang, Kaylee, Blackmer, Jane E, Osborn, Matthew, Peluso, Michael J, Hoh, Rebecca, Somsouk, Ma, Milush, Jeffrey, Bertagnolli, Lynn N, Sweet, Sarah E, Varriale, Joseph A, Burbelo, Peter D, Chun, Tae-Wook, Laird, Gregory M, Serrao, Erik, Engelman, Alan N, Carrington, Mary, Siliciano, Robert F, Siliciano, Janet M, Deeks, Steven G, Walker, Bruce D, Lichterfeld, Mathias, and Yu, Xu G
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Medical Microbiology ,Biomedical and Clinical Sciences ,Immunology ,Biotechnology ,Infectious Diseases ,Minority Health ,Sexually Transmitted Infections ,Health Disparities ,Clinical Research ,HIV/AIDS ,Genetics ,Infection ,Adult ,Aged ,Centromere ,Chromosomes ,Human ,Pair 19 ,DNA ,Satellite ,Female ,Gene Silencing ,Genome ,Viral ,HIV Infections ,HIV-1 ,Heterochromatin ,Humans ,Male ,Middle Aged ,Proviruses ,Repressor Proteins ,Transcription Initiation Site ,Virus Integration ,Virus Latency ,General Science & Technology - Abstract
Sustained, drug-free control of HIV-1 replication is naturally achieved in less than 0.5% of infected individuals (here termed 'elite controllers'), despite the presence of a replication-competent viral reservoir1. Inducing such an ability to spontaneously maintain undetectable plasma viraemia is a major objective of HIV-1 cure research, but the characteristics of proviral reservoirs in elite controllers remain to be determined. Here, using next-generation sequencing of near-full-length single HIV-1 genomes and corresponding chromosomal integration sites, we show that the proviral reservoirs of elite controllers frequently consist of oligoclonal to near-monoclonal clusters of intact proviral sequences. In contrast to individuals treated with long-term antiretroviral therapy, intact proviral sequences from elite controllers were integrated at highly distinct sites in the human genome and were preferentially located in centromeric satellite DNA or in Krüppel-associated box domain-containing zinc finger genes on chromosome 19, both of which are associated with heterochromatin features. Moreover, the integration sites of intact proviral sequences from elite controllers showed an increased distance to transcriptional start sites and accessible chromatin of the host genome and were enriched in repressive chromatin marks. These data suggest that a distinct configuration of the proviral reservoir represents a structural correlate of natural viral control, and that the quality, rather than the quantity, of viral reservoirs can be an important distinguishing feature for a functional cure of HIV-1 infection. Moreover, in one elite controller, we were unable to detect intact proviral sequences despite analysing more than 1.5 billion peripheral blood mononuclear cells, which raises the possibility that a sterilizing cure of HIV-1 infection, which has previously been observed only following allogeneic haematopoietic stem cell transplantation2,3, may be feasible in rare instances.
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- 2020
9. 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
10. HSF1 inhibition attenuates HIV-1 latency reversal mediated by several candidate LRAs In Vitro and Ex Vivo
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Timmons, Andrew, Fray, Emily, Kumar, Mithra, Wu, Fengting, Dai, Weiwei, Bullen, Cynthia Korin, Kim, Peggy, Hetzel, Carrie, Yang, Chao, Beg, Subul, Lai, Jun, Pomerantz, Joel L, Yukl, Steven A, Siliciano, Janet D, and Siliciano, Robert F
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HIV/AIDS ,Aetiology ,2.1 Biological and endogenous factors ,Anti-HIV Agents ,Apoptosis Regulatory Proteins ,Cyclin T ,HIV Infections ,HIV-1 ,Heat Shock Transcription Factors ,Histone Deacetylase Inhibitors ,Humans ,Mitochondrial Proteins ,Positive Transcriptional Elongation Factor B ,Protein Kinase C ,RNA ,Viral ,Small Molecule Libraries ,Terminal Repeat Sequences ,Virus Activation ,Virus Latency ,HIV ,latency ,reservoir ,LRA ,HSF1 - Abstract
HIV-1 latency is a major barrier to cure. Identification of small molecules that destabilize latency and allow immune clearance of infected cells could lead to treatment-free remission. In vitro models of HIV-1 latency involving cell lines or primary cells have been developed for characterization of HIV-1 latency and high-throughput screening for latency-reversing agents (LRAs). We have shown that the majority of LRAs identified to date are relatively ineffective in cells from infected individuals despite activity in model systems. We show here that, for diverse LRAs, latency reversal observed in model systems involves a heat shock factor 1 (HSF1)-mediated stress pathway. Small-molecule inhibition of HSF1 attenuated HIV-1 latency reversal by histone deactylase inhibitors, protein kinase C agonists, and proteasome inhibitors without interfering with the known mechanism of action of these LRAs. However, latency reversal by second mitochondria-derived activator of caspase (SMAC) mimetics was not affected by inhibition of HSF1. In cells from infected individuals, inhibition of HSF1 attenuated latency reversal by phorbol ester+ionomycin but not by anti-CD3+anti-CD28. HSF1 promotes elongation of HIV-1 RNA by recruiting P-TEFb to the HIV-1 long terminal repeat (LTR), and we show that inhibition of HSF1 attenuates the formation of elongated HIV-1 transcripts. We demonstrate that in vitro models of latency have higher levels of the P-TEFb subunit cyclin T1 than primary cells, which may explain why many LRAs are functional in model systems but relatively ineffective in primary cells. Together, these studies provide insights into why particular LRA combinations are effective in reversing latency in cells from infected individuals.
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- 2020
11. Longitudinal study reveals HIV-1-infected CD4+ T cell dynamics during long-term antiretroviral therapy
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Antar, Annukka AR, Jenike, Katharine M, Jang, Sunyoung, Rigau, Danielle N, Reeves, Daniel B, Hoh, Rebecca, Krone, Melissa R, Keruly, Jeanne C, Moore, Richard D, Schiffer, Joshua T, Nonyane, Bareng AS, Hecht, Frederick M, Deeks, Steven G, Siliciano, Janet D, Ho, Ya-Chi, and Siliciano, Robert F
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Medical Microbiology ,Biomedical and Clinical Sciences ,Immunology ,Sexually Transmitted Infections ,Clinical Research ,Infectious Diseases ,HIV/AIDS ,Women's Health ,Infection ,Adult ,Anti-Retroviral Agents ,CD4-Positive T-Lymphocytes ,Female ,HIV Infections ,HIV-1 ,Humans ,Immunity ,Cellular ,Longitudinal Studies ,Male ,Middle Aged ,Proviruses ,AIDS/HIV ,Adaptive immunity ,Antigen presentation ,T cells ,Medical and Health Sciences ,Biological sciences ,Biomedical and clinical sciences ,Health sciences - Abstract
Proliferation of CD4+ T cells harboring HIV-1 proviruses is a major contributor to viral persistence in people on antiretroviral therapy (ART). To determine whether differential rates of clonal proliferation or HIV-1-specific cytotoxic T lymphocyte (CTL) pressure shape the provirus landscape, we performed an intact proviral DNA assay (IPDA) and obtained 661 near-full-length provirus sequences from 8 individuals with suppressed viral loads on ART at time points 7 years apart. We observed slow decay of intact proviruses but no changes in the proportions of various types of defective proviruses. The proportion of intact proviruses in expanded clones was similar to that of defective proviruses in clones. Intact proviruses observed in clones did not have more escaped CTL epitopes than intact proviruses observed as singlets. Concordantly, total proviruses at later time points or observed in clones were not enriched in escaped or unrecognized epitopes. Three individuals with natural control of HIV-1 infection (controllers) on ART, included because controllers have strong HIV-1-specific CTL responses, had a smaller proportion of intact proviruses but a distribution of defective provirus types and escaped or unrecognized epitopes similar to that of the other individuals. This work suggests that CTL selection does not significantly check clonal proliferation of infected cells or greatly alter the provirus landscape in people on ART.
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- 2020
12. Differential decay of intact and defective proviral DNA in HIV-1-infected individuals on suppressive antiretroviral therapy
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Peluso, Michael J, Bacchetti, Peter, Ritter, Kristen D, Beg, Subul A, Lai, Jun, Martin, Jeffrey N, Hunt, Peter W, Henrich, Timothy J, Siliciano, Janet D, Siliciano, Robert F, Laird, Gregory M, and Deeks, Steven G
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Medical Microbiology ,Biomedical and Clinical Sciences ,HIV/AIDS ,Infectious Diseases ,Substance Misuse ,Sexually Transmitted Infections ,Drug Abuse (NIDA only) ,Cancer ,Infection ,Adult ,Anti-HIV Agents ,CD4 Lymphocyte Count ,CD4-CD8 Ratio ,CD4-Positive T-Lymphocytes ,Cohort Studies ,DNA ,Viral ,Disease Reservoirs ,Female ,HIV Infections ,HIV-1 ,Humans ,Male ,Middle Aged ,Polymerase Chain Reaction ,Proviruses ,Virus Latency ,AIDS/HIV ,Molecular biology ,Biomedical and clinical sciences ,Health sciences - Abstract
BACKGROUNDThe relative stabilities of the intact and defective HIV genomes over time during effective antiretroviral therapy (ART) have not been fully characterized.METHODSWe used the intact proviral DNA assay (IPDA) to estimate the rate of change of intact and defective proviruses in HIV-infected adults on ART. We used linear spline models with a knot at seven years and a random intercept and slope up to the knot. We estimated the influence of covariates on rates of change.RESULTSWe studied 81 individuals for a median of 7.3 (IQR 5.9-9.6) years. Intact genomes declined more rapidly from initial suppression through seven years (15.7% per year decline; 95% CI -22.8%, -8.0%) and more slowly after seven years (3.6% per year; 95% CI -8.1%, +1.1%). The estimated half-life of the reservoir was 4.0 years (95% CI 2.7-8.3) until year seven and 18.7 years (95% CI 8.2-infinite) thereafter. There was substantial variability between individuals in the rate of decline until year seven. Intact provirus declined more rapidly than defective provirus (P < 0.001) and showed a faster decline in individuals with higher CD4+ T cell nadirs.CONCLUSIONThe biology of the replication-competent (intact) reservoir differs from that of the replication-incompetent (non-intact) pool of proviruses. The IPDA will likely be informative when investigating the impact of interventions targeting the reservoir.FUNDINGDelaney AIDS Research Enterprise, UCSF/Gladstone Institute of Virology & Immunology CFAR, CFAR Network of Integrated Systems, amfAR Institute for HIV Cure Research, I4C and Beat-HIV Collaboratories, Howard Hughes Medical Institute, Gilead Sciences, Bill and Melinda Gates Foundation.
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- 2020
13. Different human resting memory CD4+ T cell subsets show similar low inducibility of latent HIV-1 proviruses
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Kwon, Kyungyoon J, Timmons, Andrew E, Sengupta, Srona, Simonetti, Francesco R, Zhang, Hao, Hoh, Rebecca, Deeks, Steven G, Siliciano, Janet D, and Siliciano, Robert F
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Medical Microbiology ,Biomedical and Clinical Sciences ,Immunology ,Infectious Diseases ,HIV/AIDS ,Clinical Research ,Sexually Transmitted Infections ,2.1 Biological and endogenous factors ,2.2 Factors relating to the physical environment ,Aetiology ,Infection ,Good Health and Well Being ,Adult ,CD4-Positive T-Lymphocytes ,Cell Differentiation ,Cell Proliferation ,DNA ,Viral ,Gene Expression Regulation ,Viral ,HIV-1 ,Humans ,Immunologic Memory ,Lymphocyte Activation ,Lymphocyte Count ,Phenotype ,Phylogeny ,Proviruses ,T-Lymphocyte Subsets ,Transcription ,Genetic ,Virus Replication ,Biological Sciences ,Medical and Health Sciences ,Medical biotechnology ,Biomedical engineering - Abstract
The latent reservoir of HIV-1 in resting CD4+ T cells is a major barrier to cure. It is unclear whether the latent reservoir resides principally in particular subsets of CD4+ T cells, a finding that would have implications for understanding its stability and developing curative therapies. Recent work has shown that proliferation of HIV-1-infected CD4+ T cells is a major factor in the generation and persistence of the latent reservoir and that latently infected T cells that have clonally expanded in vivo can proliferate in vitro without producing virions. In certain CD4+ memory T cell subsets, the provirus may be in a deeper state of latency, allowing the cell to proliferate without producing viral proteins, thus permitting escape from immune clearance. To evaluate this possibility, we used a multiple stimulation viral outgrowth assay to culture resting naïve, central memory (TCM), transitional memory (TTM), and effector memory (TEM) CD4+ T cells from 10 HIV-1-infected individuals on antiretroviral therapy. On average, only 1.7% of intact proviruses across all T cell subsets were induced to transcribe viral genes and release replication-competent virus after stimulation of the cells. We found no consistent enrichment of intact or inducible proviruses in any T cell subset. Furthermore, we observed notable plasticity among the canonical memory T cell subsets after activation in vitro and saw substantial person-to-person variability in the inducibility of infectious virus release. This finding complicates the vision for a targeted approach for HIV-1 cure based on T cell memory subsets.
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- 2020
14. Analyzing the unperturbed HIV-1 T cell reservoir
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Lopez, Brianna and Siliciano, Robert F.
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- 2023
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15. Engaging innate immunity in HIV-1 cure strategies
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Board, Nathan L., Moskovljevic, Milica, Wu, Fengting, Siliciano, Robert F., and Siliciano, Janet D.
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- 2022
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16. The latent reservoir of inducible, infectious HIV-1 does not decrease despite decades of antiretroviral therapy
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McMyn, Natalie F., Varriale, Joseph, Fray, Emily J., Zitzmann, Carolin, MacLeod, Hannah, Lai, Jun, Singhal, Anushka, Moskovljevic, Milica, Garcia, Mauro A., Lopez, Brianna M., Hariharan, Vivek, Rhodehouse, Kyle, Lynn, Kenneth, Tebas, Pablo, Mounzer, Karam, Montaner, Luis J., Benko, Erika, Kovacs, Colin, Hoh, Rebecca, Simonetti, Francesco R., Laird, Gregory M., Deeks, Steven G., Ribeiro, Ruy M., Perelson, Alan S., Siliciano, Robert F., and Siliciano, Janet M.
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HIV (Viruses) -- Analysis ,T cells -- Analysis ,Antiviral agents -- Analysis ,Highly active antiretroviral therapy -- Analysis ,Health care industry - Abstract
HIV-1 persists in a latent reservoir in resting [CD4.sup.+] T cells despite antiretroviral therapy (ART). The reservoir decays slowly over the first 7 years of ART ([t.sub.1/2] = 44 months). However, whether decay continues with long-term ART is unclear. Recent integration site studies indicate gradual selection against inducible, intact proviruses, raising speculation that decades of ART might allow treatment interruption without viral rebound. Therefore, we measured the reservoir in 42 people on long-term ART (mean 22 years) using a quantitative viral outgrowth assay. After 7 years of ART, there was no long-term decrease in the frequency of inducible, replication-competent provi ruses but rather an increase with an estimated doubling time of 23 years. Another reservoir assay, the intact proviral DNA assay, confirmed that reservoir decay with [t.sub.1/2] of 44 months did not continue with long-term ART. The lack of decay reflected proliferation of infected cells. Most inducible, replication-competent viruses (79.8%) had env sequences identical to those of other isolates from the same sample. Thus, although integration site analysis indicates changes in reservoir composition, the proliferation of CD4* T cells counteracts decay, maintaining the frequency of inducible, replication-competent proviruses at roughly constant levels over the long term. These results reinforce the need for lifelong ART., Introduction Antiretroviral therapy (ART) blocks HIV-1 replication, reducing plasma virus levels to below the detection limit of clinical assays (1-3). ART prevents disease progression but does not eliminate the latent [...]
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- 2023
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17. Comparative Analysis of Within-Host Dynamics of Acute Infection and Viral Rebound Dynamics in Postnatally SHIV-Infected ART-Treated Infant Rhesus Macaques
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Mainou, Ellie, primary, Berendam, Stella J, additional, Obregon-Perko, Veronica, additional, Uffman, Emilie A, additional, Phan, Caroline T, additional, Shaw, George M, additional, Bar, Katharine J, additional, Kumar, Mithra R, additional, Fray, Emily J, additional, Siliciano, Janet M, additional, Siliciano, Robert F, additional, Silvestri, Guido, additional, Permar, Sallie R, additional, Fouda, Genevieve G, additional, McCarthy, Janice, additional, Chahroudi, Ann, additional, Chan, Cliburn, additional, and Conway, Jessica M, additional
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- 2024
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18. A quantitative approach for measuring the reservoir of latent HIV-1 proviruses
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Bruner, Katherine M, Wang, Zheng, Simonetti, Francesco R, Bender, Alexandra M, Kwon, Kyungyoon J, Sengupta, Srona, Fray, Emily J, Beg, Subul A, Antar, Annukka AR, Jenike, Katharine M, Bertagnolli, Lynn N, Capoferri, Adam A, Kufera, Joshua T, Timmons, Andrew, Nobles, Christopher, Gregg, John, Wada, Nikolas, Ho, Ya-Chi, Zhang, Hao, Margolick, Joseph B, Blankson, Joel N, Deeks, Steven G, Bushman, Frederic D, Siliciano, Janet D, Laird, Gregory M, and Siliciano, Robert F
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Medical Microbiology ,Biomedical and Clinical Sciences ,Immunology ,Genetics ,HIV/AIDS ,Sexually Transmitted Infections ,Infectious Diseases ,Clinical Research ,Infection ,Good Health and Well Being ,CD4-Positive T-Lymphocytes ,Carrier State ,Cell Line ,DNA ,Viral ,Defective Viruses ,HIV Infections ,HIV-1 ,Humans ,Lymphocyte Activation ,Polymerase Chain Reaction ,Proviruses ,Virus Latency ,General Science & Technology - Abstract
A stable latent reservoir for HIV-1 in resting CD4+ T cells is the principal barrier to a cure1-3. Curative strategies that target the reservoir are being tested4,5 and require accurate, scalable reservoir assays. The reservoir was defined with quantitative viral outgrowth assays for cells that release infectious virus after one round of T cell activation1. However, these quantitative outgrowth assays and newer assays for cells that produce viral RNA after activation6 may underestimate the reservoir size because one round of activation does not induce all proviruses7. Many studies rely on simple assays based on polymerase chain reaction to detect proviral DNA regardless of transcriptional status, but the clinical relevance of these assays is unclear, as the vast majority of proviruses are defective7-9. Here we describe a more accurate method of measuring the HIV-1 reservoir that separately quantifies intact and defective proviruses. We show that the dynamics of cells that carry intact and defective proviruses are different in vitro and in vivo. These findings have implications for targeting the intact proviruses that are a barrier to curing HIV infection.
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- 2019
19. Therapeutic efficacy of an Ad26/MVA vaccine with SIV gp140 protein and vesatolimod in ART-suppressed rhesus macaques
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Ventura, John D., Nkolola, Joseph P., Chandrashekar, Abishek, Borducchi, Erica N., Liu, Jinyan, Mercado, Noe B., Hope, David L., Giffin, Victoria M., McMahan, Katherine, Geleziunas, Romas, Murry, Jeffrey P., Yang, Yunling, Lewis, Mark G., Pau, Maria G., Wegmann, Frank, Schuitemaker, Hanneke, Fray, Emily J., Kumar, Mithra R., Siliciano, Janet D., Siliciano, Robert F., Robb, Merlin L., Michael, Nelson L., and Barouch, Dan H.
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- 2022
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20. Therapeutic efficacy of combined active and passive immunization in ART-suppressed, SHIV-infected rhesus macaques
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Walker-Sperling, Victoria E. K., Mercado, Noe B., Chandrashekar, Abishek, Borducchi, Erica N., Liu, Jinyan, Nkolola, Joseph P., Lewis, Mark, Murry, Jeffrey P., Yang, Yunling, Geleziunas, Romas, Robb, Merlin L., Michael, Nelson L., Pau, Maria G., Wegmann, Frank, Schuitemaker, Hanneke, Fray, Emily J., Kumar, Mithra R., Siliciano, Janet D., Siliciano, Robert F., and Barouch, Dan H.
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- 2022
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21. Autologous IgG antibodies block outgrowth of a substantial but variable fraction of viruses in the latent reservoir for HIV-1
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Bertagnolli, Lynn N., Varriale, Joseph, Sweet, Sarah, Brockhurst, Jacqueline, Simonetti, Francesco R., White, Jennifer, Beg, Subul, Lynn, Kenneth, Mounzer, Karam, Frank, Ian, Tebas, Pablo, Bar, Katharine J., Montaner, Luis J., Siliciano, Robert F., and Siliciano, Janet D.
- Published
- 2020
22. The role of CD32 during HIV-1 infection
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Bertagnolli, Lynn N, White, Jennifer A, Simonetti, Francesco R, Beg, Subul A, Lai, Jun, Tomescu, Costin, Murray, Alexandra J, Antar, Annukka AR, Zhang, Hao, Margolick, Joseph B, Hoh, Rebecca, Deeks, Stephen G, Tebas, Pablo, Montaner, Luis J, Siliciano, Robert F, Laird, Gregory M, and Siliciano, Janet D
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General Science & Technology - Abstract
Persistence of latent HIV-1 in long-lived resting memory CD4+ T cells is a major barrier to curing HIV-1 infection, and thus a biomarker for latently infected cells would be of great scientific and clinical importance.,,,, Through an elegant discovery-based approach, Descours et al. reported that CD32a, an Fcγ receptor not normally expressed on T cells, is a potential biomarker for latently infected cells. Using the quantitative viral outgrowth assay, we show that CD32+ CD4+ T cells do not harbor the majority of intact proviruses in the latent reservoir and that the enrichment found by Descours et al. may in part reflect the use of an ultrasensitive ELISA for HIV-1 p24 antigen that does not predict exponential viral outgrowth. Our studies show that CD32 is not a biomarker for the major population of latently infected CD4+ T cells.
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- 2018
23. 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
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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.
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- 2017
24. Cognate Antigen Engagement Induces HIV-1 Expression In CD4+T Cells From People On Long-Term ART
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Moskovljevic, Milica, primary, Dragoni, Filippo, additional, Board, Nathan L., additional, Wu, Fengting, additional, Lai, Jun, additional, Zhang, Hao, additional, White, James R., additional, Hoh, Rebecca, additional, Lynn, Kenneth, additional, Tebas, Pablo, additional, Mounzer, Karam, additional, Deeks, Steven G., additional, Montaner, Luis J., additional, Siliciano, Janet D., additional, Simonetti, Francesco R., additional, and Siliciano, Robert F., additional
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- 2024
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25. HIV cure: The daunting scale of the problem
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Siliciano, Janet D., primary and Siliciano, Robert F., additional
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- 2024
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26. Mild HIV-specific selective forces overlaying natural CD4+ T cell dynamics explain the clonality and decay dynamics of HIV reservoir cells
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Reeves, Daniel B., primary, Rigau, Danielle N., additional, Romero, Arianna, additional, Zhang, Hao, additional, Simonetti, Francesco R., additional, Varriale, Joseph, additional, Hoh, Rebecca, additional, Zhang, Li, additional, Smith, Kellie N., additional, Montaner, Luis J., additional, Rubin, Leah H., additional, Gange, Stephen J., additional, Roan, Nadia R., additional, Tien, Phyllis C., additional, Margolick, Joseph B., additional, Peluso, Michael J., additional, Deeks, Steven G., additional, Schiffer, Joshua T., additional, Siliciano, Janet D., additional, Siliciano, Robert F., additional, and Antar, Annukka A. R., additional
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- 2024
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27. Intact proviral DNA assay analysis of large cohorts of people with HIV provides a benchmark for the frequency and composition of persistent proviral DNA
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Simonetti, Francesco R., White, Jennifer A., Tumiotto, Camille, Ritter, Kristen D., Cai, Mian, Gandhi, Rajesh T., Deeks, Steven G., Howell, Bonnie J., Montaner, Luis J., Blankson, Joel N., Martin, Albine, Laird, Gregory M., Siliciano, Robert F., Mellors, John W., and Siliciano, Janet D.
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- 2020
28. Clonally expanded HIV-1 proviruses with 5'-leader defects can give rise to nonsuppressible residual viremia
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White, Jennifer A., Wu, Fengting, Yasin, Saif, Moskovljevic, Milica, Varriale, Joseph, Dragoni, Filippo, Camilo-Contreras, Angelica, Duan, Jiayi, Zheng, Mei Y., Tadzong, Ndeh F., Patel, Heer B., Quiambao, Jeanelle Mae C., Rhodehouse, Kyle, Zhang, Hao, Lai, Jun, Beg, Subul A., Delannoy, Michael, Kilcrease, Christin, Hoffmann, Christopher J., Poulin, Sebastien, Chano, Frederic, Tremblay, Cecile, Cherian, Jerald, Barditch-Crovo, Patricia, Chida, Natasha, Moore, Richard D., Summers, Michael F., Siliciano, Robert F., Siliciano, Janet D., and Simonetti, Francesco R.
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T cells -- Health aspects ,Antiviral agents -- Dosage and administration -- Evaluation -- Complications and side effects ,Viremia -- Risk factors -- Development and progression ,Drug resistance -- Analysis ,HIV infection -- Drug therapy ,Health care industry - 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.sup.+] 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 undertook 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 approximately [10.sup.3] copies/ mL. These proviruses had small, often identical deletions or point mutations involving the major splicing donor (MSD) site and showed partially reduced RNA dimerization and nucleocapsid binding. Nevertheless, they were inducible and produced noninfectious virions containing viral RNA, but lacking envelope. CONCLUSION. These findings show that proviruses with 5'-leader defects in [CD4.sup.+] T cell clones can give rise to NSV, affecting clinical care. Sequencing of the 5'-leader can help in understanding failure to completely suppress viremia. FUNDING. Office of the NIH Director and National Institute of Dental and Craniofacial Research, NIH; Howard Hughes Medical Institute; Johns Hopkins University Center for AIDS Research; National Institute for Allergy and Infectious Diseases (NIAID), NIH, to the PAVE, BEAT-HIV, and DARE Martin Delaney collaboratories., Introduction Treatment with antiretroviral therapy (ART) rapidly reduces plasma HIV-1 to below the detection limit of clinical assays, prevents infection of new cells, and dramatically reduces HIV-1-associated morbidity and mortality [...]
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- 2023
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29. The mTOR Complex Controls HIV Latency
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Besnard, Emilie, Hakre, Shweta, Kampmann, Martin, Lim, Hyung W, Hosmane, Nina N, Martin, Alyssa, Bassik, Michael C, Verschueren, Erik, Battivelli, Emilie, Chan, Jonathan, Svensson, J Peter, Gramatica, Andrea, Conrad, Ryan J, Ott, Melanie, Greene, Warner C, Krogan, Nevan J, Siliciano, Robert F, Weissman, Jonathan S, and Verdin, Eric
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Medical Microbiology ,Biomedical and Clinical Sciences ,Immunology ,Genetics ,Infectious Diseases ,Sexually Transmitted Infections ,HIV/AIDS ,Infection ,Adaptor Proteins ,Signal Transducing ,CD4-Positive T-Lymphocytes ,Cell Line ,Clustered Regularly Interspaced Short Palindromic Repeats ,Cyclin-Dependent Kinase 9 ,Gene Expression Regulation ,Viral ,Gene Knockdown Techniques ,Genes ,Viral ,HIV Infections ,HIV-1 ,Humans ,K562 Cells ,Phosphorylation ,Positive Transcriptional Elongation Factor B ,RNA ,Small Interfering ,Signal Transduction ,TOR Serine-Threonine Kinases ,Transcription ,Genetic ,Virus Latency ,mTOR Associated Protein ,LST8 Homolog ,tat Gene Products ,Human Immunodeficiency Virus ,MTOR Associated Protein ,LST8 Homolog ,HIV LTR ,HIV latency ,HIV transcription ,genome-wide shRNA screen ,latency reversal ,mTOR inhibition ,reactivation from latency ,Microbiology ,Biochemistry and cell biology ,Medical microbiology - Abstract
A population of CD4 T lymphocytes harboring latent HIV genomes can persist in patients on antiretroviral therapy, posing a barrier to HIV eradication. To examine cellular complexes controlling HIV latency, we conducted a genome-wide screen with a pooled ultracomplex shRNA library and in vitro system modeling HIV latency and identified the mTOR complex as a modulator of HIV latency. Knockdown of mTOR complex subunits or pharmacological inhibition of mTOR activity suppresses reversal of latency in various HIV-1 latency models and HIV-infected patient cells. mTOR inhibitors suppress HIV transcription both through the viral transactivator Tat and via Tat-independent mechanisms. This inhibition occurs at least in part via blocking the phosphorylation of CDK9, a p-TEFb complex member that serves as a cofactor for Tat-mediated transcription. The control of HIV latency by mTOR signaling identifies a pathway that may have significant therapeutic opportunities.
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- 2016
30. Allogeneic bone marrow transplantation with post-transplant cyclophosphamide for patients with HIV and haematological malignancies: a feasibility study
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Durand, Christine M, Capoferri, Adam A, Redd, Andrew D, Zahurak, Marianna, Rosenbloom, Daniel I S, Cash, Ayla, Avery, Robin K, Bolaños-Meade, Javier, Bollard, Catherine M, Bullen, C Korin, Flexner, Charles, Fuchs, Ephraim J, Gallant, Joel, Gladstone, Doug E, Gocke, Christopher D, Jones, Richard J, Kasamon, Yvette L, Lai, Jun, Levis, Mark, Luznik, Leo, Marr, Kieren A, McHugh, Holly L, Mehta Steinke, Seema, Pham, Paul, Pohlmeyer, Christopher, Pratz, Keith, Shoham, Shmuel, Wagner-Johnston, Nina, Xu, Daniel, Siliciano, Janet D, Quinn, Thomas C, Siliciano, Robert F, and Ambinder, Richard F
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- 2020
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31. Defective proviruses rapidly accumulate during acute HIV-1 infection
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Bruner, Katherine M, Murray, Alexandra J, Pollack, Ross A, Soliman, Mary G, Laskey, Sarah B, Capoferri, Adam A, Lai, Jun, Strain, Matthew C, Lada, Steven M, Hoh, Rebecca, Ho, Ya-Chi, Richman, Douglas D, Deeks, Steven G, Siliciano, Janet D, and Siliciano, Robert F
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Medical Microbiology ,Biomedical and Clinical Sciences ,Immunology ,HIV/AIDS ,Infectious Diseases ,Health Disparities ,Pediatric ,Minority Health ,Sexually Transmitted Infections ,Pediatric AIDS ,Infection ,Acute Disease ,Adult ,Aged ,Anti-HIV Agents ,Bayes Theorem ,CD4-Positive T-Lymphocytes ,Cohort Studies ,Disease Progression ,Female ,HIV Infections ,HIV-1 ,Humans ,Male ,Middle Aged ,Polymerase Chain Reaction ,Proviruses ,Viral Load ,Virus Latency ,Virus Replication ,Young Adult ,Medical and Health Sciences ,Biomedical and clinical sciences ,Health sciences - Abstract
Although antiretroviral therapy (ART) suppresses viral replication to clinically undetectable levels, human immunodeficiency virus type 1 (HIV-1) persists in CD4(+) T cells in a latent form that is not targeted by the immune system or by ART. This latent reservoir is a major barrier to curing individuals of HIV-1 infection. Many individuals initiate ART during chronic infection, and in this setting, most proviruses are defective. However, the dynamics of the accumulation and the persistence of defective proviruses during acute HIV-1 infection are largely unknown. Here we show that defective proviruses accumulate rapidly within the first few weeks of infection to make up over 93% of all proviruses, regardless of how early ART is initiated. By using an unbiased method to amplify near-full-length proviral genomes from HIV-1-infected adults treated at different stages of infection, we demonstrate that early initiation of ART limits the size of the reservoir but does not profoundly affect the proviral landscape. This analysis allows us to revise our understanding of the composition of proviral populations and estimate the true reservoir size in individuals who were treated early versus late in infection. Additionally, we demonstrate that common assays for measuring the reservoir do not correlate with reservoir size, as determined by the number of genetically intact proviruses. These findings reveal hurdles that must be overcome to successfully analyze future HIV-1 cure strategies.
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- 2016
32. Real-Time Predictions of Reservoir Size and Rebound Time during Antiretroviral Therapy Interruption Trials for HIV.
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Hill, Alison L, Rosenbloom, Daniel IS, Goldstein, Edward, Hanhauser, Emily, Kuritzkes, Daniel R, Siliciano, Robert F, and Henrich, Timothy J
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Humans ,HIV Infections ,Anti-HIV Agents ,Viral Load ,Bayes Theorem ,Virus Latency ,Models ,Theoretical ,Adult ,Female ,Male ,Virology ,Microbiology ,Immunology ,Medical Microbiology - Abstract
Monitoring the efficacy of novel reservoir-reducing treatments for HIV is challenging. The limited ability to sample and quantify latent infection means that supervised antiretroviral therapy (ART) interruption studies are generally required. Here we introduce a set of mathematical and statistical modeling tools to aid in the design and interpretation of ART-interruption trials. We show how the likely size of the remaining reservoir can be updated in real-time as patients continue off treatment, by combining the output of laboratory assays with insights from models of reservoir dynamics and rebound. We design an optimal schedule for viral load sampling during interruption, whereby the frequency of follow-up can be decreased as patients continue off ART without rebound. While this scheme can minimize costs when the chance of rebound between visits is low, we find that the reservoir will be almost completely reseeded before rebound is detected unless sampling occurs at least every two weeks and the most sensitive viral load assays are used. We use simulated data to predict the clinical trial size needed to estimate treatment effects in the face of highly variable patient outcomes and imperfect reservoir assays. Our findings suggest that large numbers of patients-between 40 and 150-will be necessary to reliably estimate the reservoir-reducing potential of a new therapy and to compare this across interventions. As an example, we apply these methods to the two "Boston patients", recipients of allogeneic hematopoietic stem cell transplants who experienced large reductions in latent infection and underwent ART-interruption. We argue that the timing of viral rebound was not particularly surprising given the information available before treatment cessation. Additionally, we show how other clinical data can be used to estimate the relative contribution that remaining HIV+ cells in the recipient versus newly infected cells from the donor made to the residual reservoir that eventually caused rebound. Together, these tools will aid HIV researchers in the evaluating new potentially-curative strategies that target the latent reservoir.
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- 2016
33. Last in first out: SIV proviruses seeded later in infection are harbored in short-lived CD4+T cells
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Sambaturu, Narmada, primary, Fray, Emily J., additional, Wu, Fengting, additional, Zitzmann, Carolin, additional, Simonetti, Francesco R., additional, Barouch, Dan H., additional, Siliciano, Janet D., additional, Siliciano, Robert F., additional, Ribeiro, Ruy M., additional, Perelson, Alan S., additional, Molina-París, Carmen, additional, and Leitner, Thomas, additional
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- 2023
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34. Predicting the outcomes of treatment to eradicate the latent reservoir for HIV-1
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Hill, Alison L., Rosenbloom, Daniel I. S., Fu, Feng, Nowak, Martin A., and Siliciano, Robert F.
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Quantitative Biology - Populations and Evolution - Abstract
Massive research efforts are now underway to develop a cure for HIV infection, allowing patients to discontinue lifelong combination antiretroviral therapy (ART). New latency-reversing agents (LRAs) may be able to purge the persistent reservoir of latent virus in resting memory CD4+ T cells, but the degree of reservoir reduction needed for cure remains unknown. Here we use a stochastic model of infection dynamics to estimate the efficacy of LRA needed to prevent viral rebound after ART interruption. We incorporate clinical data to estimate population-level parameter distributions and outcomes. Our findings suggest that approximately 2,000-fold reductions are required to permit a majority of patients to interrupt ART for one year without rebound and that rebound may occur suddenly after multiple years. Greater than 10,000-fold reductions may be required to prevent rebound altogether. Our results predict large variation in rebound times following LRA therapy, which will complicate clinical management. This model provides benchmarks for moving LRAs from the lab to the clinic and can aid in the design and interpretation of clinical trials. These results also apply to other interventions to reduce the latent reservoir and can explain the observed return of viremia after months of apparent cure in recent bone marrow transplant recipients and an immediately-treated neonate., Comment: 8 pages main text (4 figures). In PNAS Early Edition http://www.pnas.org/content/early/2014/08/05/1406663111. Ancillary files: SI, 24 pages SI (7 figures). File .htm opens a browser-based application to calculate rebound times (see SI). Or, the .cdf file can be run with Mathematica. The most up-to-date version of the code is available at http://www.danielrosenbloom.com/reboundtimes/
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- 2014
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35. Persistence of viral RNA in lymph nodes in ART-suppressed SIV/SHIV-infected Rhesus Macaques
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Cadena, Anthony M., Ventura, John D., Abbink, Peter, Borducchi, Erica N., Tuyishime, Hubert, Mercado, Noe B., Walker-Sperling, Victoria, Siamatu, Mazuba, Liu, Po-Ting, Chandrashekar, Abishek, Nkolola, Joseph P., McMahan, Katherine, Kordana, Nicole, Hamza, Venous, Bondzie, Esther A., Fray, Emily, Kumar, Mithra, Fischinger, Stephanie, Shin, Sally A., Lewis, Mark G., Siliciano, Robert F., Alter, Galit, and Barouch, Dan H.
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- 2021
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36. Assays to Measure Latency, Reservoirs, and Reactivation
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Siliciano, Janet D., Siliciano, Robert F., Compans, Richard W, Series Editor, Malissen, Bernard, Series Editor, Aktories, Klaus, Series Editor, Rappuoli, Rino, Series Editor, Galan, Jorge E, Series Editor, Ahmed, Rafi, Series Editor, Palme, Klaus, Series Editor, Casadevall, Arturo, Series Editor, Garcia-Sastre, Adolfo, Series Editor, Iwasaki, Akiko, Series Editor, Akira, Shizuo, Series Editor, Silvestri, Guido, editor, and Lichterfeld, Mathias, editor
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- 2018
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37. Screening for noise in gene expression identifies drug synergies
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Dar, Roy D, Hosmane, Nina N, Arkin, Michelle R, Siliciano, Robert F, and Weinberger, Leor S
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Medical Microbiology ,Biomedical and Clinical Sciences ,Medicinal and Biomolecular Chemistry ,Chemical Sciences ,Infectious Diseases ,Genetics ,HIV/AIDS ,Sexually Transmitted Infections ,Infection ,Anti-HIV Agents ,Drug Discovery ,Drug Evaluation ,Preclinical ,Drug Synergism ,Gene Expression ,Genetic Testing ,HIV ,Humans ,Promoter Regions ,Genetic ,Small Molecule Libraries ,Stochastic Processes ,Virus Activation ,General Science & Technology - Abstract
Stochastic fluctuations are inherent to gene expression and can drive cell-fate specification. We used such fluctuations to modulate reactivation of HIV from latency-a quiescent state that is a major barrier to an HIV cure. By screening a diverse library of bioactive small molecules, we identified more than 80 compounds that modulated HIV gene-expression fluctuations (i.e., "noise"), without changing mean expression. These noise-modulating compounds would be neglected in conventional screens, and yet, they synergized with conventional transcriptional activators. Noise enhancers reactivated latent cells significantly better than existing best-in-class reactivation drug combinations (and with reduced off-target cytotoxicity), whereas noise suppressors stabilized latency. Noise-modulating chemicals may provide novel probes for the physiological consequences of noise and an unexplored axis for drug discovery, allowing enhanced control over diverse cell-fate decisions.
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- 2014
38. A Pilot Study Assessing the Safety and Latency-Reversing Activity of Disulfiram in HIV-1–Infected Adults on Antiretroviral Therapy
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Spivak, Adam M, Andrade, Adriana, Eisele, Evelyn, Hoh, Rebecca, Bacchetti, Peter, Bumpus, Namandjé N, Emad, Fatemeh, Buckheit, Robert, McCance-Katz, Elinore F, Lai, Jun, Kennedy, Margene, Chander, Geetanjali, Siliciano, Robert F, Siliciano, Janet D, and Deeks, Steven G
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Medical Microbiology ,Biomedical and Clinical Sciences ,Immunology ,Clinical Research ,HIV/AIDS ,Infectious Diseases ,Sexually Transmitted Infections ,2.2 Factors relating to the physical environment ,Evaluation of treatments and therapeutic interventions ,Aetiology ,6.1 Pharmaceuticals ,Infection ,Good Health and Well Being ,Adult ,Anti-Retroviral Agents ,Disulfiram ,Female ,HIV Infections ,HIV-1 ,Humans ,Male ,Middle Aged ,Pilot Projects ,Transcription ,Genetic ,Viral Load ,Virus Latency ,Young Adult ,HIV-1 latent reservoir ,disulfiram ,latency-reversing agents ,Biological Sciences ,Medical and Health Sciences ,Microbiology ,Clinical sciences - Abstract
BackgroundTranscriptionally silent human immunodeficiency virus type 1 (HIV-1) DNA persists in resting memory CD4(+) T cells despite antiretroviral therapy. In a primary cell model, the antialcoholism drug disulfiram has been shown to induce HIV-1 transcription in latently infected resting memory CD4(+) T cells at concentrations achieved in vivo.MethodsWe conducted a single-arm pilot study to evaluate whether 500 mg of disulfiram administered daily for 14 days to HIV-1-infected individuals on stable suppressive antiretroviral therapy would result in reversal of HIV-1 latency with a concomitant transient increase in residual viremia or depletion of the latent reservoir in resting memory CD4(+) T cells.ResultsDisulfiram was safe and well tolerated. There was a high level of subject-to-subject variability in plasma disulfiram levels. The latent reservoir did not change significantly (1.16-fold change; 95% confidence interval [CI], .70- to 1.92-fold; P = .56). During disulfiram administration, residual viremia did not change significantly compared to baseline (1.53-fold; 95% CI, .88- to 2.69-fold; P = .13), although residual viremia was estimated to increase by 1.88-fold compared to baseline during the postdosing period (95% CI, 1.03- to 3.43-fold; P = .04). In a post hoc analysis, a rapid and transient increase in viremia was noted in a subset of individuals (n = 6) with immediate postdose sampling (HIV-1 RNA increase, 2.96-fold; 95% CI, 1.29- to 6.81-fold; P = .01).ConclusionsAdministration of disulfiram to patients on antiretroviral therapy does not reduce the size of the latent reservoir. A possible dose-related effect on residual viremia supports future studies assessing the impact of higher doses on HIV-1 production. Disulfiram affects relevant signaling pathways and can be safely administered, supporting future studies of this drug.
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- 2014
39. CD4+ and CD8+ T Cell Activation Are Associated with HIV DNA in Resting CD4+ T Cells
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Cockerham, Leslie R, Siliciano, Janet D, Sinclair, Elizabeth, O'Doherty, Una, Palmer, Sarah, Yukl, Steven A, Strain, Matt C, Chomont, Nicolas, Hecht, Frederick M, Siliciano, Robert F, Richman, Douglas D, and Deeks, Steven G
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Medical Microbiology ,Biomedical and Clinical Sciences ,Immunology ,Sexually Transmitted Infections ,HIV/AIDS ,Infectious Diseases ,2.1 Biological and endogenous factors ,Evaluation of treatments and therapeutic interventions ,Aetiology ,6.1 Pharmaceuticals ,Infection ,ADP-ribosyl Cyclase 1 ,Adult ,Biomarkers ,CD4-Positive T-Lymphocytes ,CD8-Positive T-Lymphocytes ,DNA ,Viral ,Disease Reservoirs ,Female ,HIV Infections ,HLA-DR Antigens ,Humans ,Lymphocyte Activation ,Male ,Middle Aged ,Species Specificity ,General Science & Technology - Abstract
The association between the host immune environment and the size of the HIV reservoir during effective antiretroviral therapy is not clear. Progress has also been limited by the lack of a well-accepted assay for quantifying HIV during therapy. We examined the association between multiple measurements of HIV and T cell activation (as defined by markers including CD38, HLA-DR, CCR5 and PD-1) in 30 antiretroviral-treated HIV-infected adults. We found a consistent association between the frequency of CD4+ and CD8+ T cells expressing HLA-DR and the frequency of resting CD4+ T cells containing HIV DNA. This study highlights the need to further examine this relationship and to better characterize the biology of markers commonly used in HIV studies. These results may also have implications for reactivation strategies.
- Published
- 2014
40. Biphasic decay of intact SHIV genomes following initiation of antiretroviral therapy complicates analysis of interventions targeting the reservoir
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Kumar, Mithra R., primary, Fray, Emily J., additional, Bender, Alexandra M., additional, Zitzmann, Carolin, additional, Ribeiro, Ruy M., additional, Perelson, Alan S., additional, Barouch, Dan H., additional, Siliciano, Janet D., additional, and Siliciano, Robert F., additional
- Published
- 2023
- Full Text
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41. Expanded cellular clones carrying replication-competent HIV-1 persist, wax, and wane
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Wang, Zheng, Gurule, Evelyn E., Brennan, Timothy P., Gerold, Jeffrey M., Kwon, Kyungyoon J., Hosmane, Nina N., Kumar, Mithra R., Beg, Subul A., Capoferri, Adam A., Ray, Stuart C., Ho, Ya-Chi, Hill, Alison L., Siliciano, Janet D., and Siliciano, Robert F.
- Published
- 2018
42. HIV latency and integration site placement in five cell-based models
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Sherrill-Mix, Scott, Lewinski, Mary K, Famiglietti, Marylinda, Bosque, Alberto, Malani, Nirav, Ocwieja, Karen E, Berry, Charles C, Looney, David, Shan, Liang, Agosto, Luis M, Pace, Matthew J, Siliciano, Robert F, O’Doherty, Una, Guatelli, John, Planelles, Vicente, and Bushman, Frederic D
- Abstract
Abstract Background HIV infection can be treated effectively with antiretroviral agents, but the persistence of a latent reservoir of integrated proviruses prevents eradication of HIV from infected individuals. The chromosomal environment of integrated proviruses has been proposed to influence HIV latency, but the determinants of transcriptional repression have not been fully clarified, and it is unclear whether the same molecular mechanisms drive latency in different cell culture models. Results Here we compare data from five different in vitro models of latency based on primary human T cells or a T cell line. Cells were infected in vitro and separated into fractions containing proviruses that were either expressed or silent/inducible, and integration site populations sequenced from each. We compared the locations of 6,252 expressed proviruses to those of 6,184 silent/inducible proviruses with respect to 140 forms of genomic annotation, many analyzed over chromosomal intervals of multiple lengths. A regularized logistic regression model linking proviral expression status to genomic features revealed no predictors of latency that performed better than chance, though several genomic features were significantly associated with proviral expression in individual models. Proviruses in the same chromosomal region did tend to share the same expressed or silent/inducible status if they were from the same cell culture model, but not if they were from different models. Conclusions The silent/inducible phenotype appears to be associated with chromosomal position, but the molecular basis is not fully clarified and may differ among in vitro models of latency.
- Published
- 2013
43. Comparative analysis of measures of viral reservoirs in HIV-1 eradication studies.
- Author
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Eriksson, Susanne, Graf, Erin H, Dahl, Viktor, Strain, Matthew C, Yukl, Steven A, Lysenko, Elena S, Bosch, Ronald J, Lai, Jun, Chioma, Stanley, Emad, Fatemeh, Abdel-Mohsen, Mohamed, Hoh, Rebecca, Hecht, Frederick, Hunt, Peter, Somsouk, Ma, Wong, Joseph, Johnston, Rowena, Siliciano, Robert F, Richman, Douglas D, O'Doherty, Una, Palmer, Sarah, Deeks, Steven G, and Siliciano, Janet D
- Subjects
Leukocytes ,Mononuclear ,CD4-Positive T-Lymphocytes ,Humans ,Proviruses ,HIV ,HIV Infections ,DNA ,Viral ,RNA ,Viral ,Antiretroviral Therapy ,Highly Active ,Viral Load ,Longitudinal Studies ,Polymerase Chain Reaction ,Disease Reservoirs ,Virus Integration ,Adult ,Aged ,Middle Aged ,Female ,Male ,Infectious Diseases ,HIV/AIDS ,Clinical Research ,2.2 Factors relating to the physical environment ,Infection ,Virology ,Microbiology ,Immunology ,Medical Microbiology - Abstract
HIV-1 reservoirs preclude virus eradication in patients receiving highly active antiretroviral therapy (HAART). The best characterized reservoir is a small, difficult-to-quantify pool of resting memory CD4(+) T cells carrying latent but replication-competent viral genomes. Because strategies targeting this latent reservoir are now being tested in clinical trials, well-validated high-throughput assays that quantify this reservoir are urgently needed. Here we compare eleven different approaches for quantitating persistent HIV-1 in 30 patients on HAART, using the original viral outgrowth assay for resting CD4(+) T cells carrying inducible, replication-competent viral genomes as a standard for comparison. PCR-based assays for cells containing HIV-1 DNA gave infected cell frequencies at least 2 logs higher than the viral outgrowth assay, even in subjects who started HAART during acute/early infection. This difference may reflect defective viral genomes. The ratio of infected cell frequencies determined by viral outgrowth and PCR-based assays varied dramatically between patients. Although strong correlations with the viral outgrowth assay could not be formally excluded for most assays, correlations achieved statistical significance only for integrated HIV-1 DNA in peripheral blood mononuclear cells and HIV-1 RNA/DNA ratio in rectal CD4(+) T cells. Residual viremia was below the limit of detection in many subjects and did not correlate with the viral outgrowth assays. The dramatic differences in infected cell frequencies and the lack of a precise correlation between culture and PCR-based assays raise the possibility that the successful clearance of latently infected cells may be masked by a larger and variable pool of cells with defective proviruses. These defective proviruses are detected by PCR but may not be affected by reactivation strategies and may not require eradication to accomplish an effective cure. A molecular understanding of the discrepancy between infected cell frequencies measured by viral outgrowth versus PCR assays is an urgent priority in HIV-1 cure research.
- Published
- 2013
44. BET bromodomain-targeting compounds reactivate HIV from latency via a Tat-independent mechanism
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Boehm, Daniela, Calvanese, Vincenzo, Dar, Roy D, Xing, Sifei, Schroeder, Sebastian, Martins, Laura, Aull, Katherine, Li, Pao-Chen, Planelles, Vicente, Bradner, James E, Zhou, Ming-Ming, Siliciano, Robert F, Weinberger, Leor, Verdin, Eric, and Ott, Melanie
- Subjects
Biochemistry and Cell Biology ,Biological Sciences ,Sexually Transmitted Infections ,Infectious Diseases ,HIV/AIDS ,Genetics ,5.1 Pharmaceuticals ,Development of treatments and therapeutic interventions ,Infection ,Good Health and Well Being ,Azepines ,Benzodiazepines ,CD4-Positive T-Lymphocytes ,Cell Cycle Proteins ,Cells ,Cultured ,HEK293 Cells ,HIV Infections ,HIV-1 ,Heterocyclic Compounds ,4 or More Rings ,Humans ,Jurkat Cells ,Nuclear Proteins ,Positive Transcriptional Elongation Factor B ,Promoter Regions ,Genetic ,Protein Serine-Threonine Kinases ,RNA Interference ,RNA ,Small Interfering ,Transcription Factors ,Transcription ,Genetic ,Triazoles ,Virus Latency ,tat Gene Products ,Human Immunodeficiency Virus ,HIV ,latency ,Tat ,JQ1 ,MS417 ,I-BET ,I-BET151 ,P-TEFb ,BRD4 ,BRD2 ,Developmental Biology ,Biochemistry and cell biology - Abstract
The therapeutic potential of pharmacologic inhibition of bromodomain and extraterminal (BET) proteins has recently emerged in hematological malignancies and chronic inflammation. We find that BET inhibitor compounds (JQ1, I-Bet, I-Bet151 and MS417) reactivate HIV from latency. This is evident in polyclonal Jurkat cell populations containing latent infectious HIV, as well as in a primary T-cell model of HIV latency. Importantly, we show that this activation is dependent on the positive transcription elongation factor p-TEFb but independent from the viral Tat protein, arguing against the possibility that removal of the BET protein BRD4, which functions as a cellular competitor for Tat, serves as a primary mechanism for BET inhibitor action. Instead, we find that the related BET protein, BRD2, enforces HIV latency in the absence of Tat, pointing to a new target for BET inhibitor treatment in HIV infection. In shRNA-mediated knockdown experiments, knockdown of BRD2 activates HIV transcription to the same extent as JQ1 treatment, while a lesser effect is observed with BRD4. In single-cell time-lapse fluorescence microscopy, quantitative analyses across ~2,000 viral integration sites confirm the Tat-independent effect of JQ1 and point to positive effects of JQ1 on transcription elongation, while delaying re-initiation of the polymerase complex at the viral promoter. Collectively, our results identify BRD2 as a new Tat-independent suppressor of HIV transcription in latently infected cells and underscore the therapeutic potential of BET inhibitors in the reversal of HIV latency.
- Published
- 2013
45. Incentives for Viral Suppression in People Living with HIV: A Randomized Clinical Trial
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Silverman, Kenneth, Holtyn, August F., Rodewald, Andrew M., Siliciano, Robert F., Jarvis, Brantley P., Subramaniam, Shrinidhi, Leoutsakos, Jeannie-Marie, Getty, Carol-Ann, Ruhs, Sebastian, Marzinke, Mark A., and Fingerhood, Michael
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- 2019
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46. Nonsuppressible HIV-1 viremia: a reflection of how the reservoir persists
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Siliciano, Janet D. and Siliciano, Robert F.
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Health care industry - Abstract
Antiretroviral therapy (ART) generally reduces plasma HIV to undetectable levels, although virus persists in latently infected [CD4.sup.+] T cells. In some individuals, viremia remains detectable despite adherence to ART and the absence of drug resistance mutations. In this issue of theJCI, Halvas et al. describe HIV RNA sequences from plasma of 8 donors with persistent viremia. Residual viremia was dominated by identical HIV-1 RNA sequences that remained relatively constant over 4 years. Plasma virus matched replication-competent virus cultured from [CD4.sup.+] T cells. Integration site analysis confirmed the presence of large clones of infected cells. These results indicate that nonsuppressible viremia can be due to expanded clones of infected [CD4.sup.+] T cells carrying replication-competent virus. The individuals described here represent extreme examples of a phenomenon that is seen in all infected individuals and that is a major barrier to curing HIV infection, the in vivo proliferation of latently infected cells., Nonsuppressible HIV-1 viremia Rare is the paper that provides insight into a fundamental scientific issue while also solving a long-standing clinical dilemma. In this issue of the JCI, Halvas et [...]
- Published
- 2020
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47. Reduced Frequency of Cells Latently Infected With Replication-Competent Human Immunodeficiency Virus-1 in Virally Suppressed Individuals Living in Rakai, Uganda
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Prodger, Jessica L., Lai, Jun, Reynolds, Steven J., Keruly, Jeanne C., Moore, Richard D., Kasule, Jingo, Kityamuweesi, Taddeo, Buule, Paul, Serwadda, David, Nason, Martha, Capoferri, Adam A., Porcella, Stephen F., Siliciano, Robert F., Redd, Andrew D., Siliciano, Janet D., and Quinn, Thomas C.
- Published
- 2017
48. Assessing the impact of autologous neutralizing antibodies on viral rebound in postnatally SHIV-infected ART-treated infant rhesus macaques
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Mainou, Ellie, primary, Berendam, Stella J, additional, Obregon-Perko, Veronica, additional, Uffman, Emilie A, additional, Phan, Caroline T, additional, Shaw, George M, additional, Bar, Katherine J, additional, Kumar, Mithra R, additional, Fray, Emily J, additional, Siliciano, Janet M, additional, Siliciano, Robert F, additional, Silvestri, Guido, additional, Permar, Sallie R, additional, Fouda, Genevieve G, additional, McCarthy, Janice, additional, Chahroudi, Ann, additional, Conway, Jessica M, additional, and Chan, Cliburn, additional
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- 2023
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49. Current HIV/SIV Reservoir Assays for Preclinical and Clinical Applications: Recommendations from the Experts 2022 NIAID Workshop Summary
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Sanders-Beer, Brigitte E., primary, Archin, Nancie M., additional, Brumme, Zabrina L., additional, Busch, Michael P., additional, Deleage, Claire, additional, O'Doherty, Una, additional, Hughes, Stephen H., additional, Jerome, Keith R., additional, Jones, R. Brad, additional, Karn, Jonathan, additional, Kearney, Mary F., additional, Keele, Brandon F., additional, Kulpa, Deanna A., additional, Laird, Gregory M., additional, Li, Jonathan Z., additional, Lichterfeld, Mathias D., additional, Nussenzweig, Michel C., additional, Persaud, Deborah, additional, Yukl, Steven A., additional, Siliciano, Robert F., additional, and Mellors, John W., additional
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- 2023
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50. Current HIV/SIV Reservoir Assays for Preclinical and Clinical Applications: Recommendations from the Experts 2022 NIAID Workshop Summary.
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Sanders-Beer, Brigitte E., Archin, Nancie M., Brumme, Zabrina L., Busch, Michael P., Deleage, Claire, O'Doherty, Una, Hughes, Stephen H., Jerome, Keith R., Jones, R. Brad, Karn, Jonathan, Kearney, Mary F., Keele, Brandon F., Kulpa, Deanna A., Laird, Gregory M., Li, Jonathan Z., Lichterfeld, Mathias D., Nussenzweig, Michel C., Persaud, Deborah, Yukl, Steven A., and Siliciano, Robert F.
- Abstract
Since the first HIV-cured person was reported in 2009, a strong interest in developing highly sensitive HIV and SIV reservoir assays has emerged. In particular, the question arose about the comparative value of state-of-the-art assays to measure and characterize the HIV reservoir, and how these assays can be applied to accurately detect changes in the reservoir during efforts to develop a cure for HIV infection. Second, it is important to consider the impact on the outcome of clinical trials if these relatively new HIV reservoir assays are incorporated into clinical trial endpoints and/or used for clinical decision-making. To understand the advantages and limitations and the regulatory implications of HIV reservoir assays, the National Institute of Allergy and Infectious Diseases (NIAID) sponsored and convened a meeting on September 16, 2022, to discuss the state of knowledge concerning these questions and best practices for selecting HIV reservoir assays for a particular research question or clinical trial protocol. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
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