CD8⁺ T-cell effector function is associated with reduced inducible HIV transcription in adults on long-term suppressive ART in Uganda

Ongoing transcription from the latent HIV reservoir has been proposed as a potential driver of immune dysfunction among individuals on long-term suppressive antiretroviral therapy (ART). The relationship between induced HIV transcriptional output, HIV-specific T-cell function, and viral subtype is not well understood, particularly in African settings where non-B subtypes predominate. We examined the interplay between induced HIV transcriptional output, viral subtypes, and HIV-specific CD4⁺ and CD8⁺ T-cell responses during long-term suppressive ART. We conducted a cross-sectional study among adults enrolled in the Infectious Diseases Institute HIV treatment cohort in Kampala, Uganda, who had maintained ≥12 years of suppressive antiretroviral therapy (ART). Induced HIV transcriptional output was quantified by measuring bulk HIV RNA following ex vivo PMA/ionomycin stimulation of peripheral blood mononuclear cells. HIV-1 subtyping was performed using next-generation sequencing of the pol, env, gag, and integrase regions. HIV-specific CD4⁺ and CD8⁺ T-cell immune responses were assessed using multiparameter flow cytometry following antigen-specific stimulation. Stronger HIV-specific CD8⁺ T-cell responses were associated with lower induced HIV transcriptional output, particularly for cytolytic perforin⁺/granzyme B⁺ cells (r = − 0.349, p = 0.0129) and TNF-α–producing cells (r = − 0.290, p = 0.041), with a similar trend observed for IFN-γ production. HIV-1 subtype did not significantly influence induced HIV transcriptional output. In this cohort of Ugandan adults with more than a decade of sustained viral suppression on ART, stronger CD8⁺ T-cell effector responses; particularly cytolytic (perforin⁺/granzyme B⁺) and TNF-α–producing cells were associated with lower levels of inducible HIV RNA. These findings support a potential relationship between functional antiviral immune responses and the transcriptionally active HIV reservoir, Longitudinal and mechanistic studies are needed to determine whether these immune responses contribute to reservoir control.