학술논문
Viral and host mediators of non-suppressible HIV-1 viremia
Document Type
article
Author
Mohammadi, Abbas; Etemad, Behzad; Zhang, Xin; Li, Yijia; Bedwell, Gregory J; Sharaf, Radwa; Kittilson, Autumn; Melberg, Meghan; Crain, Charles R; Traunbauer, Anna K; Wong, Colline; Fajnzylber, Jesse; Worrall, Daniel P; Rosenthal, Alex; Jordan, Hannah; Jilg, Nikolaus; Kaseke, Clarety; Giguel, Francoise; Lian, Xiaodong; Deo, Rinki; Gillespie, Elisabeth; Chishti, Rida; Abrha, Sara; Adams, Taylor; Siagian, Abigail; Dorazio, Dominic; Anderson, Peter L; Deeks, Steven G; Lederman, Michael M; Yawetz, Sigal; Kuritzkes, Daniel R; Lichterfeld, Mathias D; Sieg, Scott; Tsibris, Athe; Carrington, Mary; Brumme, Zabrina L; Castillo-Mancilla, Jose R; Engelman, Alan N; Gaiha, Gaurav D; Li, Jonathan Z
Source
Nature Medicine. 29(12)
Subject
Language
Abstract
Non-suppressible HIV-1 viremia (NSV) is defined as persistent low-level viremia on antiretroviral therapy (ART) without evidence of ART non-adherence or significant drug resistance. Unraveling the mechanisms behind NSV would broaden our understanding of HIV-1 persistence. Here we analyzed plasma virus sequences in eight ART-treated individuals with NSV (88% male) and show that they are composed of large clones without evidence of viral evolution over time in those with longitudinal samples. We defined proviruses that match plasma HIV-1 RNA sequences as 'producer proviruses', and those that did not as 'non-producer proviruses'. Non-suppressible viremia arose from expanded clones of producer proviruses that were significantly larger than the genome-intact proviral reservoir of ART-suppressed individuals. Integration sites of producer proviruses were enriched in proximity to the activating H3K36me3 epigenetic mark. CD4+ T cells from participants with NSV demonstrated upregulation of anti-apoptotic genes and downregulation of pro-apoptotic and type I/II interferon-related pathways. Furthermore, participants with NSV showed significantly lower HIV-specific CD8+ T cell responses compared with untreated viremic controllers with similar viral loads. We identified potential critical host and viral mediators of NSV that may represent targets to disrupt HIV-1 persistence.