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Premature skewing of T cell receptor clonality and delayed memory expansion in HIV-exposed infants

ABSTRACT: While preventing vertical HIV transmission has been very successful, HIV-exposed uninfected infants (iHEU) experience an elevated risk to infections compared to HIV-unexposed and uninfected infants (iHUU). Here we present a longitudinal multimodal analysis of infant immune ontogeny that highlights the impact of HIV/ARV exposure. Using mass cytometry, we show alterations in T cell memory differentiation between iHEU and iHUU being significant from week 15 of life. The altered memory T cell differentiation in iHEU was preceded by lower TCR Vβ clonotypic diversity and linked to TCR clonal depletion within the naïve T cell compartment. Compared to iHUU, iHEU had elevated CD56loCD16loPerforin+CD38+CD45RA+FcεRIγ+ NK cells at 1 month postpartum and whose abundance pre-vaccination were predictive of vaccine-induced pertussis and rotavirus antibody responses post 3 months of life. Collectively, HIV/ARV exposure disrupted the trajectory of innate and adaptive immunity from birth which may underlie relative vulnerability to infections in iHEU.

ORGANISM(S): Homo sapiens

PROVIDER: GSE256410 | GEO | 2024/02/23

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.