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Single-cell TCR profiling of CSF and blood cells of PWH reveals persistent and shared infected T cell clones across tissue compartments even after ART

ABSTRACT: The brain is a site of persistent infected cells during HIV infection. However, the dynamics of central nervous system (CNS) infection and T cell trafficking in people living with HIV (PWH) are incompletely understood. We profiled the single cell T cell repertoire and host transcriptome from paired blood and cerebrospinal fluid (CSF) from PWH and uninfected controls. We detected HIV RNA-producing cells in 8/11 (72.7 %) CSF samples and 6/11 (54.5 %) blood samples, with a higher frequency of infected single CD4 T cells in CSF than in blood. Infected CSF T cells displayed a unique transcriptional profile compared to uninfected CSF T cells. Most infected T cell clones were not shared across tissue; however, in a subset of participants we detected identical T cell clones that were infected in both CSF and blood. Longitudinally following one PWH before and at three time points after initiating ART, we found infected T cell clones that persisted after ART initiation, in both CSF and blood, including a T cell clone that expanded in the CSF several months after ART initiation. Our findings suggest that infected T cells traffic to the CNS where they undergo clonal expansion despite ART, contributing to the CNS reservoir.

ORGANISM(S): Homo sapiens

PROVIDER: GSE243905 | GEO | 2024/04/15

REPOSITORIES: GEO

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Project description:Recently, several neutralizing anti-HIV antibodies have been isolated from memory B cells of HIV-infected individuals. However, despite extensive evidence of B-cell dysfunction in HIV disease, little is known about the cells from which these rare HIV-specific antibodies originate. Accordingly, HIV envelope gp140 and CD4 or co-receptor (CoR) binding site (bs) mutant probes were used to evaluate HIV-specific responses in the peripheral blood B cells of individuals at various stages of infection. In contrast to non-HIV responses, HIV-specific responses against gp140 were enriched within abnormal B cells, namely activated and exhausted memory subsets, which are largely absent in the blood of uninfected individuals. Responses against the CoRbs (a poorly-neutralizing epitope) arose early whereas those against the CD4bs (a well-characterized neutralizing epitope) were delayed and infrequent. Enrichment of the HIV-specific response within resting memory B cells, the predominant subset in uninfected individuals, did occur in certain infected individuals who maintained low levels of plasma viremia and immune activation with or without antiretroviral therapy. These findings were corroborated by transcriptional profiles. Taken together, our findings provide valuable insight into virus-specific B-cell responses in HIV infection and demonstrate that memory B-cell abnormalities may contribute to the ineffectiveness of the antibody response in infected individuals. HIV-specific responses against gp140 were enriched within abnormal B cells, namely activated (AM) and exhausted (tissue-like; TLM) memory subsets, which are largely absent in the blood of uninfected individuals. These responses are highest during the early stage of HIV infection, significantly decreased following the initiation of antiretroviral therapy (ART), and most importantly, enriched in normal resting memory B cells (RM) when HIV viremia and immune activation are controlled either naturally or as a result of ART. These HIV-specific B cells (AM and TLM) and resting memory B cells (RM) were sorted from peripheral blood mononuclear cells (PBMCs) of 6 HIV infected individuals. In addition, gp140-specific IgG+ B cells were sorted from individuals with either a strong (n= 6) or weak (n= 6) pro-resting memory profile. TaqMan gene expression assay was performed on these HIV-specific B cells and B cell subset. The array consisted of 29 genes.

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Single-cell TCR profiling of CSF and blood cells of PWH reveals persistent and shared infected T cell clones across tissue compartments even after ART

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