Long-term persistence of transcriptionally-active "defective" HIV-1 proviruses: Implications for persistent immune activation during antiretroviral therapy.

Abstract

People with HIV-1 (PWH) on effective antiretroviral therapy (ART) continue to exhibit chronic systemic inflammation, immune activation, and persistent elevations in markers of HIV-1 infection (including HIV-DNA, cell-associated (CA) HIV-RNA, and antibodies to HIV-1 proteins) despite prolonged suppression of plasma HIV-RNA levels <50 copies/mL. Here, we investigated the hypothesis that non-replicating but transcriptionally- and translationally-competent "defective" HIV-1 proviruses may be one of drivers of these phenomena. A combined cohort of 23 viremic and virologically suppressed individuals on ART were studied. HIV-DNA, CA HIV-RNA, western blot (WB) score (measure of anti-HIV-1 antibodies as a surrogate for viral protein expression in vivo), and key biomarkers of inflammation and coagulation (IL-6, hsCRP, TNF-alpha, tissue factor, and D-dimer) were measured in peripheral blood and analyzed using a combined cross-sectional and longitudinal approaches. Sequences of HIV-DNA and CA HIV-RNA obtained via 5'LTR-to-3'LTR PCR and single-genome sequencing were also analyzed. We observed similar long-term persistence of multiple, unique, transcriptionally-active "defective" HIV-1 provirus clones (average: 11 yrs., range: 4-20 yrs.) and antibody responses against HIV-1 viral proteins among all ART-treated participants evaluated. A direct correlation was observed between the magnitude of HIV-1 WB score and the levels of transcription of "defective" HIV-1 proviruses (r = 0.73, p < 0.01). Additional correlations were noted between total CD8+ T cell counts and HIV-DNA (r = 0.52, p = 0.01) or CA HIV-RNA (r = 0.65, p < 0.01). These findings suggest a novel interplay between transcription and translation of "defective" HIV-1 proviruses and the persistent immune activation seen in the setting of treated chronic HIV-1 infection.