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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.Cohort-based study.HIV-specific IFN-γ-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.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-α, %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.Adaptive HIV-specific immune responses do not appear to contribute to the elevated inflammatory and immune activation profile in persons on long-term ART.

The latent HIV-1 reservoir represents a major barrier to achieving a long-term antiretroviral therapy (ART)-free remission or cure for HIV-1. Natural Killer (NK) cells are innate immune cells that play a critical role in controlling viral infections and have been shown to be involved in preventing HIV-1 infection and, in those who are infected, delaying time to progression to AIDS. However, their role in limiting HIV-1 persistence on long term ART is still uncharacterized. To identify associations between markers of HIV-1 persistence and the NK cell receptor-ligand repertoire, we used twin mass cytometry panels to characterize the peripheral blood NK receptor-ligand repertoire in individuals with long-term antiretroviral suppression enrolled in the AIDS Clinical Trial Group A5321 study. At the time of testing, participants had been on ART for a median of 7 years, with virological suppression +CD56dimCD57-LILRB1-NKG2C-) was associated with lower HIV-1 cell associated DNA. Finally, we found that surface expression of HLA-Bw6 measured by CyTOF was associated with lower HIV-1 persistence. Genetic analysis revealed that this was driven by lower HIV-1 persistence in HLA-Bw4/6 heterozygotes. These findings suggest that there may be a role for NK cells in controlling HIV-1 persistence in individuals on long-term ART, which must be corroborated by future studies.

The ability of automated, FDA-cleared plasma HIV-1 RNA assays to detect low-level viremia, compared to manual, highly sensitive research-only methods, is not well-defined. We therefore tested paired plasma samples from people with HIV-1 (PWH) on long-term antiretroviral therapy (ART) with both the Abbott M2000 RealTime HIV-1 Viral Load assay (Abbott) and a quantitative reverse transcriptase (RT)-initiated PCR assay that has a reported 95% detection limit of 1 HIV-1 RNA copy/ml (single copy assay, SCA).Plasma samples from 309 participants in the AIDS Clinical Trials Group study A5321 were tested by both Abbott and SCA. Participants were mostly men (82%). All were on stable ART for a median of 7 years with HIV-1 RNA40 copies/mL by Abbott. Pooled plasma from each donor was divided and tested. Abbott results were reported as target detected40 copies/mL but not quantifiable (target detected40) or target not detected (TND), and SCA results were classified as HIV-1 RNA detected or not detected.By Abbott, 17% (51/309) of sample results were target detected40, whereas 83% (258/309) were TND. Of the samples that were target detected40 by Abbott, 73% (37/51) had HIV-1 RNA detected by SCA. By contrast, 43% of samples that were TND by Abbott (110/258) had HIV-1 RNA detected by SCA (p 0.001).Plasma samples from PWH with HIV-1 RNA detected but40 copies/ml by the automated Abbott M2000 assay are likely (73% of 51 samples) to have HIV-1 RNA detected by an optimized manual assay with single copy sensitivity. An Abbott HIV-1 RNA result of target not detected did not exclude low-level viremia: 43% of 258 samples had HIV-1 RNA detected by the single copy assay. These findings indicate that the Abbott M2000 assay cannot exclude the persistence of viremia on ART and thus may have less utility, compared to a manual single copy assay, for assessing the impact of experimental interventions designed to eliminate low-level viremia as a step towards achieving ART-free HIV-1 remission.