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Origin and Correlates of Viral Rebound in SIV-Infected Rhesus Macaques Following ART Discontinuation

ABSTRACT: 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.

ORGANISM(S): Macaca mulatta

PROVIDER: GSE294867 | GEO | 2025/09/10

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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Origin and Correlates of Viral Rebound in SIV-Infected Rhesus Macaques Following ART Discontinuation

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