Origin and Correlates of Viral Rebound in SIV-Infected Rhesus Macaques Following ART Discontinuation
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PROVIDER: PRJNA1251882 | ENA |
REPOSITORIES: ENA
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Project description:The earliest events of viral rebound following discontinuation of ART in persons living with HIV-1 (PLWH) remain largely unknown. Here we show that viral rebound in SIV-infected rhesus macaques following ART discontinuation involves serial clonal reactivation in gastrointestinal (GI) and lymph node (LN) tissues followed by rapid local and systemic spread. We investigated viral rebound dynamics in 18 SIV-infected rhesus macaques treated with antiretroviral therapy (ART) for 70 weeks and necropsied on day 12 after ART discontinuation. Using molecularly barcoded SIVmac239M, we tracked viral clonotypes following ATI in both peripheral blood and necropsy tissues. Viral rebound originated by reactivation of a single or a few clonotypes from a limited number of GI tissues and deep LNs, followed by replication of each clonotype and then serial reactivation of additional clonotypes from different anatomic sites, resulting in oligoclonal plasma viremia. Daily transcriptomic and proteomics profiling in peripheral blood identified early upregulation of pathways related to T cell signaling, cytokine responses, and cellular metabolism prior to detectable plasma viremia, presumably reflecting initial viral replication in tissues. Taken together, these data demonstrate the early clonal dynamics of viral rebound in SIV-infected macaques following ART discontinuation, which provides critical information for the development of next generation HIV-1 cure strategies.
2025-09-10 | GSE294867 | GEO
Project description:The development of biomarkers that can predict viral rebound following discontinuation of antiretroviral therapy (ART) in HIV-1-infected humans would be an important advance in HIV-1 cure research. In a prior study, we initiated ART in 20 rhesus macaques on days 0, 1, 2, and 3 following SIVmac251 infection prior to plasma viremia1. Following 6 months of suppressive ART, we discontinued ART and observed viral rebound in 9 of 20 animals. Here we show that transcriptomic and proteomic signatures of inflammation and immune activation in peripheral blood during ART suppression predicted viral rebound following ART discontinuation. Higher levels of proinflammatory and cellular immune activation pathways, including TNF, IL-1, IL-6, monocyte, and T cell activation signaling pathways, correlated with viral rebound following ART discontinuation. Immune modulatory IL-10 and TGF-b signaling also correlated with viral rebound. We then validated these candidate biomarkers of viral rebound in a second cohort of SIV-infected, ART-suppressed macaques. Taken together, these data suggest that persistent upregulation of inflammatory and immune activation pathways despite suppressive ART may represent a peripheral blood biomarker signature of the rebound-competent viral reservoir. The development of interventions that target the viral reservoir and modulate this signature may open new avenues in HIV-1 cure research.
2023-08-30 | GSE203603 | GEO
Project description:Peripheral Blood Biomarkers in ART-Suppressed, SIV-Infected Rhesus Macaques Predict Viral Rebound Following ART Discontinuation
| PRJNA841577 | ENA
Project description:Unlike HIV infection, which progresses to AIDS absent suppressive anti-retroviral therapy (ART), nonpathogenic infections in natural hosts, such African green monkeys (AGMs), are characterized by a lack of gut microbial translocation and robust secondary lymphoid Natural Killer (NK) cell responses resulting in absence of chronic inflammation and limited SIV dissemination in lymph nodes (LN) B-cell-follicles, respectively. In a pathogenic infection model (i.e. ART-treated, SIVmac239-infected rhesus macaques; RMs), sequential Interleukin (IL)-21 and interferon (IFN)-alpha therapy generated terminally-differentiated blood NK cells (NKG2a/clowCD16+) with potent HLA-E-restricted activity in response to SIV-ENV peptides in contrast to control RMs, where less differentiated, IFN-gamma+ NK cells predominated. The frequency and cytolytic activity of NKG2a/clowCD16+ NK cells correlated with a reduction of replication-competent SIV in LN during ART and viral rebound delay following analytical treatment interruption. These data demonstrate that AGM-like NK cell differentiation profiles can be rescued in RMs to promote viral clearance in tissues.
2021-02-22 | GSE163442 | GEO
Project description:Unlike HIV infection, which progresses to AIDS absent suppressive anti-retroviral therapy (ART), nonpathogenic infections in natural hosts, such African green monkeys (AGMs), are characterized by a lack of gut microbial translocation and robust secondary lymphoid Natural Killer (NK) cell responses resulting in absence of chronic inflammation and limited SIV dissemination in lymph nodes (LN) B-cell-follicles, respectively. In a pathogenic infection model (i.e. ART-treated, SIVmac239-infected rhesus macaques; RMs), sequential Interleukin (IL)-21 and interferon (IFN)-alpha therapy generated terminally-differentiated blood NK cells (NKG2a/clowCD16+) with potent HLA-E-restricted activity in response to SIV-ENV peptides in contrast to control RMs, where less differentiated, IFN-gamma+ NK cells predominated. The frequency and cytolytic activity of NKG2a/clowCD16+ NK cells correlated with a reduction of replication-competent SIV in LN during ART and viral rebound delay following analytical treatment interruption. These data demonstrate that AGM-like NK cell differentiation profiles can be rescued in RMs to promote viral clearance in tissues.
2021-02-22 | GSE163441 | GEO
Project description:Unlike HIV infection, which progresses to AIDS absent suppressive anti-retroviral therapy (ART), nonpathogenic infections in natural hosts, such African green monkeys (AGMs), are characterized by a lack of gut microbial translocation and robust secondary lymphoid Natural Killer (NK) cell responses resulting in absence of chronic inflammation and limited SIV dissemination in lymph nodes (LN) B-cell-follicles, respectively. In a pathogenic infection model (i.e. ART-treated, SIVmac239-infected rhesus macaques; RMs), sequential Interleukin (IL)-21 and interferon (IFN)-alpha therapy generated terminally-differentiated blood NK cells (NKG2a/clowCD16+) with potent HLA-E-restricted activity in response to SIV-ENV peptides in contrast to control RMs, where less differentiated, IFN-gamma+ NK cells predominated. The frequency and cytolytic activity of NKG2a/clowCD16+ NK cells correlated with a reduction of replication-competent SIV in LN during ART and viral rebound delay following analytical treatment interruption. These data demonstrate that AGM-like NK cell differentiation profiles can be rescued in RMs to promote viral clearance in tissues.
2021-02-22 | GSE163440 | GEO
Project description:Interleukin-21 treatment during ART was able to decrease residual immune activation and viral burden in SIV-infected rhesus macaques
2017-02-28 | GSE73232 | GEO
Project description:Evaluation of HIV cure strategies requires antiretroviral therapy (ART) interruption, but ethical and clinical considerations make this difficult in children. Uncovering predictors of time to viral rebound (TTR) and post-treatment control (PTC) of rebound viremia in a pediatric preclinical model may inform the design of studies testing novel cure interventions in these populations. We thus assessed 141 variables in SHIV-infected infant rhesus macaques (RMs) where ART initiation was staggered then followed by analytical treatment interruption (ATI). Viral rebound occurred in 25/30 RMs within 7-98 d of ATI, with TTR significantly delayed in the Early ART group compared to the Intermediate and Late ART groups (median TTR 84, 18, and 17 d, respectively; p<0.001). Peak plasma viral load pre-ART best described TTR, with increased predictive strength through the successive inclusion of six additional variables. Increased peak viral load pre-ART decreased the odds of no rebound and elevated Ki67+ effector memory CD8+ T cells in lymph nodes pre-ATI increased the odds of PTC. RNA sequencing of CD4+ T cells pre-ATI showed heme metabolism and IFNg response pathways were most upregulated in RMs with sustained suppression of viremia during ATI. Analysis of only the Early ART group also implicated TGFb pathway genes in lack of viral rebound off ART. This comprehensive investigation reveals major determinants of viral rebound dynamics following ART interruption that should be validated and explored as biomarkers to screen children with HIV being considered for ATI.
2025-09-11 | GSE261049 | GEO
Project description:The discovery of biomarkers that predict viral rebound after discontinuation of antiretroviral therapy (ART) would significantly contribute to the HIV cure field. We previously initiated ART in 20 rhesus macaques on days 0, 1, 2, and 3 following SIVmac251 infection. After 6 months, we discontinued ART and observed viral rebound in 9 of 20 animals, which provided an opportunity to define peripheral biomarkers on ART that predicted viral rebound following ART discontinuation. We show that interleukin-1 (IL-1), IL-6_JAK_STAT3, IL-10, transforming growth factor β (TGF-β), IL-22, and IL-23 signaling and activation of monocyte, macrophage, and antigen processing and presentation pathways during ART suppression correlated with viral rebound. These signatures were validated in a second cohort of macaques. Our data suggest that low levels of antigen and proinflammatory signaling during ART suppression correlate with the presence of a rebound-competent viral reservoir. Interventions that modulate these peripheral biomarkers may be promising candidates to evaluate as potential HIV-1 cure strategies.
| S-EPMC10394255 | biostudies-literature
Project description:Objective: To evaluate the effect of short-term type I IFN treatment on the latent viral reservoir in SIV-infected rhesus macaques on ART; Methods: We infected twelve RMs intrarectally with 10,000 TCID of SIVmac239. After 6 weeks of infection, all RMs started a three-class, four-drug ART regimen. Once viral loads were consistently undetectable, six animals were administered 1 dose of pegylated IFN-α2a per week for 4 weeks with each weekly intramuscular application being 6 µg/kg.
2018-05-17 | GSE114561 | GEO