HIV-1 manipulates CD96 on CD4⁺ T cells to subvert antiviral immunity

HIV-1 evades immune responses by modulating plasma membrane receptors. Using a flow cytometry-based screening, we profiled 332 surface receptors on HIV-1-infected primary CD4⁺ T cells and identified 23 down-regulated receptors, including known targets such as CD4, MHCI, CCR7, and CD62L. CD96, an inhibitory natural killer (NK) cell receptor poorly studied in human CD4⁺ T cells, was markedly down-regulated. This modulation, mediated by the viral proteins Nef and Vpu, surpassed that of other NK-associated receptors such as CD155 and NTB-A and is conserved across lentiviruses. CD96^Hi CD4⁺ T cells exhibited a proinflammatory T_H1/T_H17 phenotype characterized by IFN-γ and IL-17 secretion and displayed impaired migration in vivo. Furthermore, CD96 ligation enhanced IFN-γ release upon viral peptide stimulation and promoted the secretion of T_H1/T_H17-associated cytokines. Our findings suggest that CD96 regulates antiviral immune responses and maintains proinflammatory properties in CD4⁺ T cells. Thus, its down-regulation represents a previously unknown HIV-1 immune evasion strategy, with implications for exploiting CD96 as immunotherapeutic target.