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 HIV-1 infection remain unclear. Here, we identify a key role for ?42PD-1, an isoform of PD-1, in human B cells. Chronic HIV-1 infection selectively upregulates ?42PD-1, but not PD-1, on up to 28% of B cells. BCR stimulation induces ?42PD-1 expression, resulting in B cell cycle arrest and apoptosis. Mechanistically, ?42PD-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 ?42PD-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 ?42PD-1-SHP1 axis and support ?42PD-1 as a therapeutic target to restore B cell responses in HIV-1 infection. Overall design: Sorted ?42PD-1+, PD-1+ and double negative B cells at 48 hours after the treatment with a-IgM/G F(ab')2 and CH34 or isotype control IgG2b.