Resident CD49a + CD103 + NKG2C + NK cells restrict HIV infection in human lymphoid tissue explants

Natural killer (NK) cells are pivotal effectors in antiviral immunity, yet their tissue-specific roles during acute HIV infection remain poorly defined. Using an ex vivo human tonsillar tissue model, we profile NK cell responses to early HIV infection and uncover distinct subsets with specialized functions. We identify a previously uncharacterized memory-like NK population (CD16 +/− CD69 + CD49a + CD103 + NKG2C + ) associated with reduced viral burden and enriched in cytotoxic mediators (GNLY, PRF1, and GZMB), apoptotic ligands (FASLG and TRAIL), cytokine receptors (IL2RA, IL2RB, IL2RG, IL12RB2, and IL18R1) and trafficking molecules (CCL3–5, CCR7, and SELL). Although functionally capable of clearing HIV-infected CD4 + T cells in a tissue-mimetic environment, they show impaired cytotoxicity and transcriptional signs of exhaustion after infection. Conversely, HIV drives the reprogramming of immature CD16 − CD69 + NK cells toward a more cytotoxic and migratory effector phenotype. These findings reveal dynamic NK cell adaptations in lymphoid tissue during early HIV infection and highlight tissue-resident NK cells as promising targets for immunotherapeutic intervention.