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. No statistically significant differences were observed in 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) between groups following adjustment for multiple comparisons. Spike- and nucleocapsid-specific responses correlated strongly in PLWH, particularly among CD4 + and CD8 + T cells, with fewer significant correlations observed among HIV-uninfected participants. CD26 expression and T-cell activation phenotypes (HLA-DR/CD38 subsets) did not differ by HIV status after adjustment for multiple comparisons. Both groups demonstrated cross-recognition of Omicron, irrespective of the infecting SARS-CoV-2 variant. Overall, our results provide no evidence of substantial differences in SARS-CoV-2–specific T-cell responses and activation profiles between antiretroviral-treated PLWH and HIV-uninfected adults, while both groups demonstrated cross-reactive T-cell responses to Omicron.