No Evidence that Ongoing HIV-Specific Immune Responses Contribute to Persistent Inflammation and Immune Activation in Persons on Long-Term ART

Abstract

AbstractBackgroundPeople 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.MethodsHIV-specific T-cell responses and antibody concentrations were measured 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. Plasma inflammatory biomarkers and T-cell activation and cycling were measured at a pre-ART time point and at study entry.ResultsNeither 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, %CD38+HLA-DR+ CD8+ and CD4+ cells, and %Ki67+ CD8+ and CD4+ cells – including after adjustment for pre-ART biomarker level. Magnitudes of T-cell responses to HIV-Pol were correlated with TNF-α levels, but this was confounded by several factors. Plasma HIV RNA levels were 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.ConclusionsAdaptive HIV-specific immune responses do not appear to contribute to the elevated inflammatory and immune activation profile associated with morbidity and mortality under long-term ART.SummaryHIV-specific T-cell and antibody responses persist over years of suppressive ART, but there is no evidence that these ongoing immune responses contribute to elevated levels of inflammation and immune activation in people living with HIV on long-term ART.