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Single-cell multiomics reveals persistence of HIV-1 in expanded cytotoxic T cell clones.

ABSTRACT: Understanding the drivers and markers of clonally expanding HIV-1-infected CD4⁺ T cells is essential for HIV-1 eradication. We used single-cell ECCITE-seq, which captures surface protein expression, cellular transcriptome, HIV-1 RNA, and TCR sequences within the same single cell to track clonal expansion dynamics in longitudinally archived samples from six HIV-1-infected individuals (during viremia and after suppressive antiretroviral therapy) and two uninfected individuals, in unstimulated conditions and after CMV and HIV-1 antigen stimulation. Despite antiretroviral therapy, persistent antigen and TNF responses shaped T cell clonal expansion. HIV-1 resided in Th1-polarized, antigen-responding T cells expressing BCL2 and SERPINB9 that may resist cell death. HIV-1 RNA⁺ T cell clones were larger in clone size, established during viremia, persistent after viral suppression, and enriched in GZMB⁺ cytotoxic effector memory Th1 cells. Targeting HIV-1-infected cytotoxic CD4⁺ T cells and drivers of clonal expansion provides another direction for HIV-1 eradication.

SUBMITTER: Collora JA

PROVIDER: S-EPMC9203927 | biostudies-literature | 2022 Jun

REPOSITORIES: biostudies-literature

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Single-cell multiomics reveals persistence of HIV-1 in expanded cytotoxic T cell clones.

Collora Jack A JA Liu Runxia R Pinto-Santini Delia D Ravindra Neal N Ganoza Carmela C Lama Javier R JR Alfaro Ricardo R Chiarella Jennifer J Spudich Serena S Mounzer Karam K Tebas Pablo P Montaner Luis J LJ van Dijk David D Duerr Ann A Ho Ya-Chi YC

Immunity 20220322 6

Understanding the drivers and markers of clonally expanding HIV-1-infected CD4<sup>+</sup> T cells is essential for HIV-1 eradication. We used single-cell ECCITE-seq, which captures surface protein expression, cellular transcriptome, HIV-1 RNA, and TCR sequences within the same single cell to track clonal expansion dynamics in longitudinally archived samples from six HIV-1-infected individuals (during viremia and after suppressive antiretroviral therapy) and two uninfected individuals, in unstim ...[more]

PMID: 35320704

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Project description:Little is known about the emergence and persistence of human immunodeficiency virus (HIV)-infected T-cell clones in perinatally infected children. We analyzed peripheral blood mononuclear cells (PBMCs) for clonal expansion in 11 children who initiated antiretroviral therapy (ART) between 1.8 and 17.4 months of age and with viremia suppressed for 6 to 9 years. We obtained 8,662 HIV type 1 (HIV-1) integration sites from pre-ART samples and 1,861 sites from on-ART samples. Expanded clones of infected cells were detected pre-ART in 10/11 children. In 8 children, infected cell clones detected pre-ART persisted for 6 to 9 years on ART. A comparison of integration sites in the samples obtained on ART with healthy donor PBMCs infected ex vivo showed selection for cells with proviruses integrated in BACH2 and STAT5B Our analyses indicate that, despite marked differences in T-cell composition and dynamics between children and adults, HIV-infected cell clones are established early in children, persist for up to 9 years on ART, and can be driven by proviral integration in proto-oncogenes.IMPORTANCE HIV-1 integrates its genome into the DNA of host cells. Consequently, HIV-1 genomes are copied with the host cell DNA during cellular division. Pediatric immune systems differ significantly from adults, consisting primarily of naive T cells, which have low expression of the HIV-1 coreceptor CCR5. This difference may result in variances in the number or size of infected cell clones that persist in children on ART. Here, we provide the most extensive analysis of the integration landscape of HIV-1 in children. We found that, despite the largely naive cell populations in neonatal immune systems, patterns of HIV-1 integration and the size of infected cell clones are as large and widespread as those in adults. Furthermore, selection for integration events in proto-oncogenes were observed in children despite early ART. If such cell clones persist for the life span of these individuals, there may be long-term consequences that have yet to be realized.

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Single-cell multiomics reveals persistence of HIV-1 in expanded cytotoxic T cell clones.

Publications

Single-cell multiomics reveals persistence of HIV-1 in expanded cytotoxic T cell clones.

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