Journal Article

Viral and host mediators of non-suppressible HIV-1 viremia

Jordan, Hannah, Abrha, Sara, Tsibris, Athe, Kittilson, Autumn, Yawetz, Sigal, Jilg, Nikolaus, Engelman, Alan N., Traunbauer, Anna K., Kaseke, Clarety, Li, Yijia, Gaiha, Gaurav D., Chishti, Rida, Lederman, Michael M., Wong, Colline, Rosenthal, Alex, Castillo-Mancilla, Jose R., Worrall, Daniel P., Zhang, Xin, Etemad, Behzad, Fajnzylber, Jesse, Giguel, Francoise, Dorazio, Dominic, Deeks, Steven G., Sharaf, Radwa, Gillespie, Elisabeth, Brumme, Zabrina L., Kuritzkes, Daniel R., Mohammadi, Abbas, Anderson, Peter L., Adams, Taylor, Carrington, Mary, Deo, Rinki, Sieg, Scott, Melberg, Meghan, Siagian, Abigail, Bedwell, Gregory J., Li, Jonathan Z., Lichterfeld, Mathias D., Crain, Charles R., Lian, Xiaodong

2023

Overview

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. Understanding the heterogeneity of HIV infection, such as in persons with non-suppressible HIV-1 viremia despite adherence to antiretroviral treatment, is crucial to better tailor therapeutic interventions to abrogate HIV-1 persistence.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 631/326/596/2557 / 631/326/596/2564 / 692/308/575 / 692/699/255/1901 / Antiretroviral agents / Antiretroviral drugs / Antiretroviral therapy / Apoptosis / Biomedical and Life Sciences / Biomedicine / Cancer Research / CD4 antigen / CD4-Positive T-Lymphocytes / CD8 antigen / Cloning / Drug resistance / Epigenetics / Female / Gene sequencing / Genomes / Heterogeneity / HIV / HIV Infections - drug therapy / HIV Seropositivity / HIV-1 - genetics / Human immunodeficiency virus / Humans / Infectious Diseases / Lymphocytes / Lymphocytes T / Male / Metabolic Diseases / Molecular Medicine / Neurosciences / Proviruses / Proviruses - genetics / Proviruses - metabolism / RNA, Viral / Therapeutic applications / Viral Load / Viremia