학술논문
Long-term persistence of transcriptionally active ‘defective’ HIV-1 proviruses: implications for persistent immune activation during antiretroviral therapy
Document Type
Academic Journal
Author
Singh, Kanal; Natarajan, Ven; Dewar, Robin; Rupert, Adam; Badralmaa, Yuden; Zhai, Tracey; Winchester, Nicole; Scrimieri, Francesca; Smith, Mindy; Davis, Ivery; Lallemand, Perrine; Giglietti, Aude; Hensien, Jack; Buerkert, Thomas; Goshu, Bruktawit; Rehm, Catherine A.; Hu, Zonghui; Lane, H. Clifford; Imamichi, Hiromi
Source
AIDS. Nov 15, 2023 37(14):2119-2130
Subject
Language
English
ISSN
0269-9370
Abstract
OBJECTIVES:: 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 HIV-RNA (CA HIV-RNA), and antibodies to HIV-1 proteins] despite prolonged suppression of plasma HIV-RNA levels less than 50 copies/ml. Here, we investigated the hypothesis that nonreplicating but transcriptionally and translationally competent ‘defective’ HIV-1 proviruses may be one of drivers of these phenomena. DESIGN:: A combined cohort of 23 viremic and virologically suppressed individuals on ART were studied. METHODS:: HIV-DNA, CA HIV-RNA, western blot 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. RESULTS:: We observed similar long-term persistence of multiple, unique, transcriptionally active ‘defective’ HIV-1 provirus clones (average: 11 years., range: 4–20 years) 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 western blot 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). CONCLUSION:: 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.