IL-2-mediated CD4 T-cell activation correlates highly with effective serological and T-cell responses to SARS-CoV-2 vaccination in people living with HIV (PLWH)

People living with HIV (PLWH) despite having appreciable depletion of CD4 ⁺ T-cell show a good SARS- CoV-2 vaccination response. The underlying mechanism(s) are currently not understood. We studied serological and polyfunctional T-cell responses in PLWH receiving anti-retroviral therapy stratified on CD4 ⁺ counts as PLWH-high (CD4 ≥500 cells/μL) and PLWH-low (<500 cells/μL). Responses were assessed longitudinally before the first vaccination (T0), 1-month after the first dose (T1), and 3- months (T2), and 6-months (T3) after the second dose. Expectedly, both PLWH-high and -low groups developed similar serological responses after T2, which were also non-significantly different to age and vaccination-matched HIV-negative controls at T3. The IgG titers were also protective showing a good correlation with ACE2-neutralizations (R=0.628, P=0.005). While no difference at T3 was observed between PLWH and controls in activated CD4 ⁺ CD154 ⁺ and CD4 ⁺ memory T-cells, spike- specific CD4 ⁺ polyfunctional cytokine expression analysis showed that PLWH preferentially express IL-2 (P<0.001) and controls, IFN-γ (P=0.017). CD4 ⁺ T-cell counts negatively correlated with IL-2- expressing CD4 ⁺ T-cells including CD4 ⁺ memory T-cells (Spearman ρ: -0.85 and -0.80, respectively; P<0.001). Our results suggest that the durable serological and CD4 ⁺ T-cell responses developing in vaccinated PLWH are associated with IL-2-mediated CD4 ⁺ T-cell activation that likely compensates for CD4 ⁺ T-cell depletion in PLWH.