T-cell responses to ancestral SARS-CoV-2 and Omicron in unvaccinated hospitalised adults living with and without HIV in South Africa

HIV-associated immune dysfunction may impact SARS-CoV-2–specific T-cell responses, yet data in COVID-19–unvaccinated people living with HIV (PLWH) remain limited. We evaluated virus-specific T-cell responses one month after COVID-19–related hospitalisation in antiretroviral-treated PLWH and HIV-uninfected adults recovering from ancestral (Wuhan-Hu-1), Beta (B.1.351), or Delta (B.1.617.2) variant infection. Flow cytometry assessed the magnitude, polyfunctionality, and activation (HLA-DR, CD38, and CD26) of CD4 ⁺ , CD8 ⁺ , and CD4 ⁺ CD8 ⁺ (double positive, DP) T-cell subsets, as well as cross-reactivity to Omicron (BA.4/BA.5). Seventeen PLWH and 21 HIV-uninfected black African adults were enrolled. SARS-CoV-2–specific CD4 ⁺ , CD8 ⁺ , and DP T-cell response magnitudes, responder frequencies, and cytokine production profiles (IFN-γ, IL-2, and TNF-α) were comparable between groups. Spike- and nucleocapsid-specific responses correlated strongly in PLWH (CD4 ⁺ : r = 0.914, p < 0.001; CD8 ⁺ : r = 0.789; p < 0.001), whereas correlations were weaker in HIV-uninfected participants (CD4 ⁺ : r = 0.512, p < 0.05; CD8 ⁺ : r = 0.427; p = 0.069). CD26 expression and most activation phenotypes (HLA-DR/CD38 subsets) did not differ by HIV status, though PLWH had fewer CD8 ⁺ HLA-DR ⁺ CD38 ^- T cells (adjusted p = 0.013). Both groups demonstrated cross-recognition of Omicron, irrespective of the infecting SARS-CoV-2 variant. Our results demonstrate comparable SARS-CoV-2–specific T-cell responses and activation profiles between PLWH on antiretroviral therapy and HIV-uninfected adults, with preserved cross-reactive T-cell responses to Omicron.