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Blocking PD-1 engagement rapidly upregulates innate antiviral and immune functions that associate with HIV reservoir decay [scRNA-seq]

ABSTRACT: The HIV reservoir, a small pool of PD-1+CD4+ T cells that carry integrated HIV genomes, remains a formidable obstacle to HIV cure. The clinical use of PD-1 inhibitors has shown promising results in curbing the HIV reservoir in people with HIV (PWH) and cancer, but the underlying mechanisms are unknown. Here, we demonstrate that anti-PD-1 therapy leads to a decay in the frequency of cells harboring HIV DNA at the end of a two-year follow-up in 9 of 14 PWH receiving pembrolizumab within the CITN-12 clinical trial (NCT02595866). This reduction correlates with an innate immune response, characterized by increased monocyte frequencies and enhanced myeloid cell-specific transcription of interferon-stimulated genes (ISGs), chemokines, antiviral restriction factors, and TLR signaling. These changes emerge as early as 24 hours post-treatment and persist until the end of therapy. Within 24 hours of treatment, we also observe an increase in proliferating effector HIV-specific CD8+ T cells, increased expression of effector T cell genes, and a decline in plasma TGF-β levels. We validate the generalizability of these ISG expression modules across >1,000 publicly available scRNA-seq samples, revealing a consistent association between high ISG expression in peripheral blood mononuclear cells (PBMCs) and lower expression of WNT pathway and Treg gene sets - pathways known to regulate immune quiescence and persistence of the HIV reservoir - in PBMCs from uninfected controls, as well as in samples from individuals with cancer or infections. Furthermore, we demonstrate that ISGs triggered by TLR ligands protect CD4+ T cells from HIV infection in vitro. These findings support a mechanism by which ISGs restrict the HIV reservoir in vivo and define a set of immune signaling pathways that can be used to identify PWH in whom the HIV reservoir may decay upon anti-PD-1 therapy.

ORGANISM(S): Homo sapiens

PROVIDER: GSE298838 | GEO | 2025/08/31

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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Blocking PD-1 engagement rapidly upregulates innate antiviral and immune functions that associate with HIV reservoir decay [scRNA-seq]

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