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Viral rebound in SHIV-infected infant macaques is predicted by immunovirologic features measured before and after antiretroviral therapy

ABSTRACT: 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.

ORGANISM(S): Macaca mulatta

PROVIDER: GSE261049 | GEO | 2025/09/11

REPOSITORIES: GEO

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Project description:Therapeutic strategies that enhance anti-viral immunity and reduce the viral reservoir are critical to achieving durable remission of HIV. The co-inhibitory receptor programmed death-1 (PD-1) regulates CD8+ T cell dysfunction during chronic HIV and SIV infections 1-4. In addition, PD-1+ CD4+ T cells constitute a significant fraction of the HIV/SIV viral reservoir5-7. We previously demonstrated that in vivo blockade of PD-1 during chronic SIV infection improves the function of anti-viral CD8+ T cells and B cells 4,8. However, the immunological effects of PD-1 blockade during anti-retroviral therapy (ART) and the potential to destabilize the persistent HIV/SIV reservoir have not been studied. Here, we show that administration of anti-PD-1 antibody (PD-1 Ab) 10 days prior to initiation of ART rapidly enhanced anti-viral CD8+ T cell function and diminished interferon stimulated genes (ISGs) that resulted in markedly improved viral suppression in plasma and better Th17 cell reconstitution in the rectal mucosa following ART initiation. In addition, PD-1 blockade during suppressive ART resulted in transient increases in plasma viremia, induction of gene signatures associated with effector CD8+ T cell function and ISGs, and lower levels of cell associated replication-competent virus suggesting destabilization of the viral reservoir. Following ART interruption, PD-1 Ab treated animals showed markedly higher expansion of proliferating CXCR5+ Perforin+ Granzyme B+ effector CD8+ T cells and lower regulatory T cells that resulted in delayed viral rebound and better control of viremia. PD-1 blockade administered only during suppressive ART however was only partially effective. Our results indicate an optimal regimen of PD-1 blockade administered in combination with ART, that augments anti-viral CD8+ T cell function and reduces the viral reservoir leading to improved control of viral rebound after ART interruption. These results have important implications for developing novel therapeutic interventions to achieve durable remission of HIV.

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Viral rebound in SHIV-infected infant macaques is predicted by immunovirologic features measured before and after antiretroviral therapy

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