HIV-1 manipulates CD96 on CD4 + T cells to subvert antiviral immunity
- Sandra Dehn
- Rabea Burkhard
- Johanna Leyens
- Tabea Kaiser
- Simone Brandimarte
- Dinah Heiligensetzer
- Herwig Koppensteiner
- Baubak Bajoghli
- Stephan Hailfinger
- Karin Schilbach
- Michael Schindler
2025-09-05
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 H 1/T H 17 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 H 1/T H 17-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.