Study on HIV Reservoir Size, HIV-Specific Immune Response Trends, and Inflammation, and their Relationships, in People Living with HIV on Long-Term Antiretroviral Therapy
Open Access DepositedAnalysis 1 Abstract: HIV persists in a reservoir of infected cells in people living with HIV (PLWH), necessitating lifelong antiretroviral therapy (ART) to prevent viral rebound and disease progression. Multiple methods have been developed to measure and quantify aspects of the size of the HIV reservoir and its persistence on ART, each providing different but complementary information. Understanding host and viral factors that impact the size of the reservoir is important towards explaining interindividual variability, and is relevant to cure studies. Here, we measure HIV cell-associated (CA)-DNA and RNA levels, as well as plasma HIV RNA levels by single copy assay, in 295 PLWH from the ACTG A5321 cohort on suppressive ART for a median of 7.3 years, and we perform quantitative viral outgrowth assays and measure CA-DNA levels in 61 PLWH from the BELIEVE cohort on ART for a median of 7.6 years. We construct univariable and multivariable models to evaluate host and viral factors associated with these HIV persistence measures, allowing for comparisons of relative effects across factors and measures. Pre-ART viral load was the most consistent factor positively associated with HIV persistence measures, but viral blips had the greatest impact on both CA-RNA and plasma HIV RNA levels in the ACTG A5321 cohort. The CD4/CD8 T-cell ratio was found positively associated with the CA-RNA/DNA ratio cross-sectionally in the ACTG A5321 cohort, and CA-DNA levels were substantially lower in participants from Canada and Brazil compared to the USA in the BELIEVE cohort – including after controlling for other measured factors. These results add to the literature on host and viral factors impacting HIV persistence, including on the role of viral blips, and warrant further comparative studies on differences in persistence measures in PLWH from varied geographic regions, which may be of importance to HIV cure efforts focused on reservoir reduction. Analysis 2 Abstract: Antiretroviral therapies (ARTs) abrogate HIV replication; however, infection persists as long-lived reservoirs of infected cells with integrated proviruses, which reseed replication if ART is interrupted. A central tenet of our current understanding of this persistence is that infected cells are shielded from immune recognition and elimination through a lack of antigen expression from proviruses. Efforts to cure HIV infection have therefore focused on reactivating latent proviruses to enable immune-mediated clearance, but these have yet to succeed in reducing viral reservoirs. Here, we revisited the question of whether HIV reservoirs are predominately immunologically silent from a new angle: by querying the dynamics of HIV-specific T-cell responses over long-term ART for evidence of ongoing recognition of HIV-infected cells. In longitudinal assessments, we show that the rates of change in persisting HIV Nef-specific responses, but not responses to other HIV gene products, were associated with residual frequencies of infected cells. These Nef-specific responses were highly stable over time and disproportionately exhibited a cytotoxic, effector functional profile, indicative of recent in vivo recognition of HIV antigens. These results indicate substantial visibility of the HIV-infected cells to T-cells on stable ART, presenting both opportunities and challenges for the development of therapeutic approaches to curing infection. Analysis 3 Abstract: Background: 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. 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. Conclusions: Adaptive HIV-specific immune responses do not appear to contribute to the elevated inflammatory and immune activation profile in persons on long-term ART.
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