Africa-specific human genetic variation near CHD1L associates with HIV-1 load

Paul J. McLaren*, Immacolata Porreca, Gennaro Iaconis, Hoi Ping Mok, Subhankar Mukhopadhyay, Emre Karakoc, Sara Cristinelli, Cristina Pomilla, István Bartha, Christian W. Thorball, Riley H. Tough, Paolo Angelino, Cher S. Kiar, Tommy Carstensen, Segun Fatumo, Tarryn Porter, Isobel Jarvis, William C. Skarnes, Andrew Bassett, Marianne K. DeGorterMohana Prasad Sathya Moorthy, Jeffrey F. Tuff, Eun Young Kim, Miriam Walter, Lacy M. Simons, Arman Bashirova, Susan Buchbinder, Mary Carrington, Andrea Cossarizza, Andrea De Luca, James J. Goedert, David B. Goldstein, David W. Haas, Joshua T. Herbeck, Eric O. Johnson, Pontiano Kaleebu, William Kilembe, Gregory D. Kirk, Neeltje A. Kootstra, Alex H. Kral, Olivier Lambotte, Ma Luo, Simon Mallal, Javier Martinez-Picado, Laurence Meyer, José M. Miro, Pravi Moodley, Ayesha A. Motala, James I. Mullins, Kireem Nam, Niels Obel, Fraser Pirie, Francis A. Plummer, Guido Poli, Matthew A. Price, Andri Rauch, Ioannis Theodorou, Alexandra Trkola, Bruce D. Walker, Cheryl A. Winkler, Jean François Zagury, Stephen B. Montgomery, Angela Ciuffi, Judd F. Hultquist, Steven M. Wolinsky, Gordon Dougan, Andrew M.L. Lever, Deepti Gurdasani, Harriet Groom, Manjinder S. Sandhu*, Jacques Fellay*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

HIV-1 remains a global health crisis1, highlighting the need to identify new targets for therapies. Here, given the disproportionate HIV-1 burden and marked human genome diversity in Africa2, we assessed the genetic determinants of control of set-point viral load in 3,879 people of African ancestries living with HIV-1 participating in the international collaboration for the genomics of HIV3. We identify a previously undescribed association signal on chromosome 1 where the peak variant associates with an approximately 0.3 log10-transformed copies per ml lower set-point viral load per minor allele copy and is specific to populations of African descent. The top associated variant is intergenic and lies between a long intergenic non-coding RNA (LINC00624) and the coding gene CHD1L, which encodes a helicase that is involved in DNA repair4. Infection assays in iPS cell-derived macrophages and other immortalized cell lines showed increased HIV-1 replication in CHD1L-knockdown and CHD1L-knockout cells. We provide evidence from population genetic studies that Africa-specific genetic variation near CHD1L associates with HIV replication in vivo. Although experimental studies suggest that CHD1L is able to limit HIV infection in some cell types in vitro, further investigation is required to understand the mechanisms underlying our observations, including any potential indirect effects of CHD1L on HIV spread in vivo that our cell-based assays cannot recapitulate.

Original languageEnglish (US)
Pages (from-to)1025-1030
Number of pages6
JournalNature
Volume620
Issue number7976
DOIs
StatePublished - Aug 31 2023

ASJC Scopus subject areas

  • General

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