Naïve CD4 T Cell Profiles Differ in HIV-1 and HIV-2 Patients, Influencing Viral Reservoirs

Despite effective antiretroviral therapy (ART), HIV infection persists due to latent viral reservoirs, primarily in memory CD4+ T cells. However, the role of naïve CD4 T cells, which are crucial for immune reconstitution and maintaining immune competence, in this persistence and overall disease progression is often overlooked. Understanding the heterogeneity within this compartment could reveal new insights into reservoir dynamics, inflammation, and immune senescence in people with HIV (PWH). This study explores how different HIV infection histories shape these critical founder cells.

Researchers profiled circulating naïve CD4 T cells from PWH under effective ART, categorizing them by past viral burden: early-treated HIV-1 (acute stage), late-treated HIV-1 (chronic stage), and people with HIV-2 (PWH2), known for low viremia and slow progression. Spectral flow cytometry was employed to analyze T cell heterogeneity. Additionally, the ability of purified naïve CD4 T cells to respond to IL-7 was assessed in separate cohorts of untreated PWH, including HIV-1 elite controllers, to evaluate proliferation and gene transcription (p21).

Early-treated PWH1 maintained a naïve CD4 T cell profile comparable to age-matched seronegative individuals. In contrast, late-treated PWH1 and PWH2 exhibited distinct imbalances in conventional and regulatory subpopulations. Both groups, however, showed a relative expansion of CD31-expressing naïve cells, consistent with an IL-7-mediated homeostatic response. This suggests a compensatory mechanism in response to chronic infection. The ability of purified naïve CD4 T cells to respond to IL-7 was further evaluated: > Untreated PWH1 elite controllers showed reduced proliferation and increased p21 transcription in response to IL-7, indicating altered cell cycle regulation. Crucially, a significant decline in proviral DNA was observed in PWH2, suggesting a beneficial impact of IL-7 on HIV-2-infected naïve CD4 T cells that was not observed in the case of HIV-1 infection. These findings highlight diverse immune responses and reservoir dynamics influenced by infection type and treatment timing.