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Gene dysregulation in acute HIV-1 infection – early transcriptomic analysis reveals the crucial biological functions affected

ABSTRACT: Transcriptomic analyses from early human immunodeficiency virus (HIV) infection have the potential to reveal how HIV causes widespread and lasting damage to biological functions, especially in the immune system. Previous studies have been hampered by difficulties in obtaining early specimens. We studied 29 HIV infected subjects 1 month from presentation and 46 contemporaneous uninfected controls. We used RNA-seq to examine circulating immune cells to describe in detail the profound gene dysregulation observed in early HIV infection. Correlations were sought between viral load and differential gene expression, and biological implications were examined. The most profoundly upregulated biological functions related to cell cycle regulation, DNA repair and replication, microtubule and spindle organization, and immune activation and response. Our findings provide insight into the pathogenic mechanisms of early HIV-induced immune damage, information important for timely interventions to prevent clinical progression, inhibit reservoir seeding, and enable vaccine development.

ORGANISM(S): Homo sapiens

PROVIDER: GSE199911 | GEO | 2022/05/30

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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Gene dysregulation in acute HIV-1 infection – early transcriptomic analysis reveals the crucial biological functions affected

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