No evidence that circulating HIV-specific immune responses contribute to persistent inflammation and immune activation in persons on long-term ART

Objective: People with HIV (PWH) have persistently elevated levels of inflammation and immune activation despite suppressive antiretroviral therapy (ART), with specific biomarkers showing associations with non-AIDS-defining morbidities and mortality. We investigated the potential role of the HIV-specific adaptive immune response, which also persists under ART, in driving levels of these clinically relevant biomarkers. Design: Cohort-based study. Methods: HIV-specific IFN-gamma-producing T-cell responses and antibody concentrations were measured in blood at study entry in the ACTG A5321 cohort, following a median of 7 years of suppressive ART. HIV persistence measures including cell-associated (CA)-DNA, CA-RNA, and plasma HIV RNA (single-copy assay) were also assessed at study entry. Plasma inflammatory biomarkers and T-cell activation and cycling were measured at a pre-ART time point and at study entry. Results: Neither the magnitudes of HIV-specific T-cell responses nor HIV antibody levels were correlated with levels of the inflammatory or immune activation biomarkers, including hs-CRP, IL-6, neopterin, sCD14, sCD163, TNF-alpha, %CD38(+)HLA-DR+ CD8(+) and CD4(+) cells, and %Ki67(+) CD8(+) and CD4(+) cells - including after adjustment for pre-ART biomarker level. Plasma HIV RNA levels were modestly correlated with CD8(+) T-cell activation (r = 0.25, P = 0.027), but other HIV persistence parameters were not associated with these biomarkers. In mediation analysis, relationships between HIV persistence parameters and inflammatory biomarkers were not influenced by either HIV-specific T-cell responses or antibody levels. Conclusion: Adaptive HIV-specific immune responses do not appear to contribute to the elevated inflammatory and immune activation profile in persons on long-term ART.