Viral and Host Mediators of Non-Suppressible HIV-1 Viremia

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

doi:10.1101/2023.03.30.23287124

Viral and Host Mediators of Non-Suppressible HIV-1 Viremia

medRxiv [Preprint]. 2023 Mar 31:2023.03.30.23287124. doi: 10.1101/2023.03.30.23287124.

Authors

Abbas Mohammadi¹, Behzad Etemad¹, Xin Zhang¹, Yijia Li², Gregory J Bedwell³, Radwa Sharaf¹, Autumn Kittilson¹, Meghan Melberg¹, Colline Wong¹, Jesse Fajnzylber¹, Daniel P Worrall⁴, Alex Rosenthal¹, Hannah Jordan¹, Nikolaus Jilg^{1

5}, Clarety Kaseke⁴, Francoise Giguel⁵, Xiaodong Lian^{5

4}, Rinki Deo¹, Elisabeth Gillespie¹, Rida Chishti¹, Sara Abrha¹, Taylor Adams¹, Abigail Siagian¹, Peter L Anderson⁶, Steven G Deeks⁷, Michael M Lederman⁸, Sigal Yawetz¹, Daniel R Kuritzkes¹, Mathias D Lichterfeld^{5

4}, Athe Tsibris¹, Mary Carrington^{4

9}, Zabrina L Brumme^{10

11}, Jose R Castillo-Mancilla⁶, Alan N Engelman³, Gaurav D Gaiha^{4

12}, Jonathan Z Li¹

Affiliations

¹ Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
² University of Pittsburgh, Pittsburgh, PA, USA.
³ Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
⁴ Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA 02139, USA.
⁵ Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
⁶ Division of Infectious Diseases, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
⁷ Division of HIV, Infectious Diseases, and Global Medicine, University of California, San Francisco, CA, USA.
⁸ Center for AIDS Research, Division of Infectious Diseases and HIV Medicine, Department of Medicine, Case Western Reserve University/University Hospitals Cleveland Medical Center, Cleveland, OH, USA.
⁹ Basic Science Program, Frederick National Laboratory for Cancer Research, National Cancer Institute, Frederick, MD, USA and Laboratory of Integrative Cancer Immunology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
¹⁰ Faculty of Health Sciences, Simon Fraser University, Burnaby, Canada.
¹¹ British Columbia Centre for Excellence in HIV/AIDS, Vancouver, Canada.
¹² Division of Gastroenterology, Massachusetts General Hospital, Boston, MA 02114, USA.

Abstract

Non-suppressible HIV-1 viremia (NSV) can occur in persons with HIV despite adherence to combination antiretroviral therapy (ART) and in the absence of significant drug resistance. Here, we show that plasma NSV sequences are comprised primarily of large clones without evidence of viral evolution over time. We defined proviruses that contribute to plasma viremia as "producer", and those that did not as "non-producer". Compared to ART-suppressed individuals, NSV participants had a significantly larger producer reservoir. Producer proviruses were enriched in chromosome 19 and in proximity to the activating H3K36me3 epigenetic mark. CD4⁺ cells from NSV participants demonstrated upregulation of anti-apoptotic genes and downregulation of pro-apoptotic and type I/II interferon-related pathways. Furthermore, NSV participants showed no elevation in HIV-specific CD8⁺ cell responses and producer proviruses were enriched for HLA escape mutations. We identified critical host and viral mediators of NSV that represent potential targets to disrupt HIV persistence and promote viral silencing.

Keywords: CD8 immune response; HIV; integration; non-suppressible viremia; persistent low-level viremia; producer provirus.

Publication types

Preprint

Abstract

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