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Barcode and integration-site sequencing of HIV-infected humanized mice following NK cell treatment

ABSTRACT: Latently infected cells persist during antiretroviral therapy (ART) and drive viral rebound upon treatment interruption. This study profiles the composition of the rebound-competent HIV reservoir in humanized mice following adoptive transfer of allogeneic human primary NK cells engineered with a truncated CD4-based chimeric antigen receptor (D1D2-CAR) targeting the CD4 binding site on HIV Env. Humanized NSG mice infected with barcoded CCR5-tropic HIV were ART-suppressed and infused with D1D2-CAR NK cells, GFP-expressing control NK cells, or PBS vehicle prior to analytical treatment interruption (ATI). Tissues were collected after rebound, and genomic DNA was used to generate libraries measuring both HIV barcode lineages and integration sites in proviral DNA. The dataset supports comparison of clonal composition, lineage diversity, inter-organ lineage sharing, intra-organ clonal expansion, and integration-site chromatin context across the three treatment arms and across tissues.

ORGANISM(S): Homo sapiens

PROVIDER: GSE335409 | GEO | 2026/09/30

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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Barcode and integration-site sequencing of HIV-infected humanized mice following NK cell treatment

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