Protein-dependent CD4⁺ T cell specialization and CD8⁺ T cell-driven IL-2 production in HIV

Chronic HIV infection alters antiviral T cell responses and shapes their functional profiles. We combined HLA peptide tetramers with functional stimulation assays to characterize HIV-specific CD4⁺ and CD8⁺ T cells targeting immunodominant epitopes in chronically infected individuals. CD4⁺ and CD8⁺ T cells were present at comparable frequencies but showed distinct functional programs. CD4⁺ T cells displayed helper-associated features and were often functionally unresponsive, whereas CD8⁺ T cells exhibited cytotoxic profiles and were a major source of IL-2. CD4⁺ T cell functions were protein dependent: p24-specific cells were more cytotoxic and responsive, whereas gp120-specific cells preferentially expressed CXCR5. CD8⁺ T cell functions, particularly IL-2 and IFN-γ production inversely associated with viral load and positively associated with CD4⁺ T cell counts and the CD4/CD8 ratio. Collectively, these findings show CD8⁺ T cells as major IL-2 producers and protein-specific CD4⁺ T cell specialization, informing HIV vaccine and cure strategies.