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

The interaction between PD-1 and PD-L1 inhibits activation of HIV-1-specific CD8⁺ T cells, yet mechanisms underlying B cell dysfunction in people living with HIV-1 (PLWHs) 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, in up to 28% of B cells. B cell receptor (BCR) stimulation induces Δ42PD-1 expression, resulting in B cell-cycle arrest and apoptosis. Mechanistically, Δ42PD-1 recruits SHP-1 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 knockdown reduces SHP-1 recruitment, restores AKT1/FOXO1 activation, and enhances B cell proliferation and function, including HIV-1 envelope (ENV)-specific memory B cells. These findings reveal an inhibitory Δ42PD-1-SHP-1 axis and support Δ42PD-1 as a therapeutic target to restore B cell responses in PLWHs.