Shaping the founders: naïve CD4 T cell heterogeneity in people with HIV-1 or HIV-2

Naïve CD4 T cells harbour functional subsets that influence the quality of immune reconstitution and the persistent viral reservoirs in people with HIV (PWH) under antiretroviral therapy (ART). Here, we profiled the circulating naïve CD4 T cells from PWH under effective ART with distinct past histories of viral burden, namely starting treatment early in acute or late in chronic stage HIV-1 infection, and people with HIV-2 (PWH2), who feature low to undetectable viremia before ART and slow disease progression. Spectral flow cytometry enabled us to capture the heterogeneity of this overlooked T cell compartment. Early-treated PWH1 maintained a naïve CD4 T cell profile comparable to that of age-matched seronegative individuals. Late-treated PWH1 and PWH2 showed distinct imbalances in conventional and regulatory subpopulations, yet both exhibited a relative expansion of CD31-expressing naïve cells, consistent with an IL-7-mediated homeostatic response. The ability of purified naïve CD4 T cells to respond to IL-7 was evaluated in additional cohorts of untreated PWH, revealing reduced proliferation and increased p21 transcription in PWH1 elite controllers. Additionally, a significant decline in proviral DNA was found in PWH2, suggesting an impact of IL-7 on HIV-2-infected naïve CD4 T cells that was not observed in the case of HIV-1 infection. Unravelling the homeostatic pathways and functional implications of naïve CD4 T cell heterogeneity will help clarify viral reservoir dynamics and inflammation in PWH and define strategies to prevent immune senescence.