Loss of HIV-1-specific neutralizing antibodies via Δ42PD-1 positive B cells 2333776

Abstract Introduction Δ42PD-1, an isoform of PD-1, abolishes PD-L1/PD-L2 binding and confers T cell resistance to anti-PD-1 immunotherapy. Δ42PD-1 modulates B cell function in people living with HIV (PLWH) through functional exhaustion, cell cycle arrest, and apoptosis. We then hypothesized that HIV-1-induced Δ42PD-1 affects the induction of broad neutralizing antibodies (bnAbs). Methods We analyzed primary B cells from nine PLWH, comprising three acute cases, three chronic untreated cases and three chronic cases on ART. Δ42PD-1+ and Δ42PD-1⁻ B cells, including Env-specific subsets by oligo-tagged BG505 SOSIP.664 (BG505), were sorted for 10x single-cell sequencing and functional analysis. Results A total of 22,999 B cells were sequenced, comprising 6,245 Δ42PD-1+ and 16,754 Δ42PD-1⁻ cells. Of these, 1,113 were BG505 reactive, including 820 Δ42PD-1+ cells and 293 Δ42PD-1⁻ cells, corresponding to overall frequencies of 13.1% (820/6,245) and 1.7% (293/16,754), respectively. Although overall B cell clonotype diversity was similar between the two groups, BG505 reactive heavy chains were predominantly encoded byIGHV4-34. Among 181 highly BG505 reactive B cell receptors cloned for functional analysis, 111 originated from the Δ42PD-1+ subset and 70 from the Δ42PD-1⁻ subset, with the majority recognizing gp41 (85.6% vs. 78.6%). Five bnAbs (2 from Δ42PD-1+ and 3 from Δ42PD-1⁻ cells) neutralized pseudoviruses from multiple HIV-1 subtypes. Their potency was associated with somatic hypermutation (SHM; range, 0.75—22.01%) and extended CDR3 regions (19—24 amino acids). Δ42PD-1+ B cells exhibited impaired SHM maturation and antibody secreting cell differentiation due to increased functional exhaustion and apoptosis. Conclusion Most HIV-1—activated B cells differentiate into the Δ42PD-1+ subset, leading to impaired maturation of neutralizing antibodies. Δ42PD-1 may serve as a therapeutic target for enhancing functional B cells for generating bnAbs. Funding Source RGC No. 17119723 Topic Categories Viral Immunology (VIR)