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ACCELERATED CD8+ T CELL MATURATION IN INFANTS WITH PERINATAL HIV INFECTION

ABSTRACT: In perinatal HIV infection, early ART initiation is recommended but questions remain regarding infant immune responses to HIV and impact of HIV on immune development. Using single cell transcriptional and phenotypic analysis we evaluated the T cell compartment at pre-ART initiation of infants with perinatally acquired HIV from Maputo, Mozambique (TARA cohort). CD8+ T cell maturation subsets exhibited altered distribution in HIV exposed infected (HEI) infants relative to control infants (HIV exposed uninfected) with reduced naïve, increased effectors, higher frequencies of activated T cells, and lower frequencies of cells with markers of self-renewal. Additionally, a cluster of CD8+ T cells identified in HEI displayed gene profiles consistent with cytotoxic T lymphocytes (CTL) and showed evidence for hyper expansion. Longitudinal phenotypic analysis revealed accelerated maturation of CD8+ T cells was maintained in HEI despite viral control. The results point to a HIV directed immune response that is likely to influence reservoir establishment.

ORGANISM(S): Homo sapiens

PROVIDER: GSE254645 | GEO | 2024/04/16

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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ACCELERATED CD8+ T CELL MATURATION IN INFANTS WITH PERINATAL HIV INFECTION

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