Postgraduate student University of Hong Kong Central and Western District, Hong Kong
Disclosure(s):
Tianyu Ma, MS: No financial relationships to disclose
Introduction/Rationale: 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 by IGHV4-34. 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.
