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Isoformic PD-1 impedes B cell activation and function in HIV-1 infection

ABSTRACT: The interaction between PD-1 and PD-L1 inhibits activation of HIV-1-specific CD8+ T cells, yet mechanisms underlying B cell dysfunction in HIV-1 infection remain unclear. Here, we identify a key role for Δ42PD-1, an isoform of PD-1, in human B cells. Chronic HIV-1 infection selectively upregulates Δ42PD-1, but not PD-1, on up to 28% of B cells. BCR stimulation induces Δ42PD-1 expression, resulting in B cell cycle arrest and apoptosis. Mechanistically, Δ42PD-1 recruits SHP1 via its intracellular immunoreceptor tyrosine-based switch motif, leading to AKT1 inhibition and suppression of the AKT1/FOXO1 pathway, thus promoting B cell apoptosis. Notably, targeting Δ42PD-1 with a specific antibody or gene knock-down reduces SHP1 recruitment, restores AKT1/FOXO1 activation, and enhances B cell proliferation and function, including in HIV-1 ENV-specific memory B cells. These findings reveal a novel inhibitory Δ42PD-1-SHP1 axis and support Δ42PD-1 as a therapeutic target to restore B cell responses in HIV-1 infection.

ORGANISM(S): Homo sapiens

PROVIDER: GSE305753 | GEO | 2025/08/18

REPOSITORIES: GEO

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Project description:Despite the critical role antigen-specific T cells play in containing viral infections, their aggregate frequencies in peripheral blood have not correlated with clinical protection during HIV infection. However, a subset of HIV-specific T cells, which are capable of simultaneously producing multiple effector cytokines, termed polyfunctional T cells, have correlated with delayed disease progression. HIV-specific polyfunctional T cells have been enumerated and characterized using the intracellular cytokine staining (ICS) assay, which allows for simultaneous multiplexed analysis of cytokine expression at the single-cell level. In addition, using an unbiased computational analysis of ICS data generated through the RV144 HIV vaccine case-control study, we identified vaccine-induced HIV envelope (Env)-specific polyfunctional CD4 T cells as a novel correlate of reduced risk of HIV infection. However, very little is known about these cells and what differentiates them from other vaccine-elicited T cells. In addition, the use of sample fixation in the ICS assay prevents those cells from being further interrogated for transcriptional differences. Thus, we developed a novel live-cell multiplexed cytokine capture assay which allows for identification, sorting and transcriptional profiling of individual antigen-specific polyfunctional T cells by single-cell RNA-sequencing (scRNA-seq). We applied these methods to peripheral blood samples from participants who had received the RV144 vaccine regimen as part of the HVTN 097 clinical trial. Using this approach, we discovered transcriptional signatures that specifically identify the single-cell Env-specific CD4 T-cell functional profiles which had correlated with reduced risk of HIV infection in RV144. Interestingly, this signature is particularly characterized by upregulation of Th2 cytokines, supporting the hypothesis that the vaccine-induced Env-specific CD4 T cells likely contributed to the reduced risk of infection by providing T cell help to the Env-specific antibody responses. By interrogating the gene signatures that correlated with polyfunctionality, we have identified potential mechanisms of how vaccine-elicited polyfunctional T cells may contribute to reduced risk of HIV infection.

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Isoformic PD-1 impedes B cell activation and function in HIV-1 infection

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