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. DeGorter, Mohana Prasad Sathya Moorthy, Jeffrey F. Tuff, Eun-Young Kim, Miriam Walter, Lacy M. Simons, Arman Bashirova, Susan Buchbinder, Mary Carrington, Andrea Cossarizza, Andrea 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 () and Jacques Fellay ()
Additional contact information
Paul J. McLaren: Public Health Agency of Canada
Immacolata Porreca: Wellcome Trust Sanger Institute
Gennaro Iaconis: University of Cambridge
Hoi Ping Mok: University of Cambridge
Subhankar Mukhopadhyay: King’s College London
Emre Karakoc: Wellcome Trust Sanger Institute
Sara Cristinelli: Lausanne University Hospital and University of Lausanne
Cristina Pomilla: Wellcome Trust Sanger Institute
István Bartha: École Polytechnique Fédérale de Lausanne
Christian W. Thorball: École Polytechnique Fédérale de Lausanne
Riley H. Tough: Public Health Agency of Canada
Paolo Angelino: Swiss Institute of Bioinformatics
Cher S. Kiar: King’s College London
Tommy Carstensen: Wellcome Trust Sanger Institute
Segun Fatumo: MRC/UVRI and LSHTM Uganda Research Unit
Tarryn Porter: Wellcome Trust Sanger Institute
Isobel Jarvis: University of Cambridge
William C. Skarnes: The Jackson Laboratory for Genomic Medicine
Andrew Bassett: Wellcome Trust Sanger Institute
Marianne K. DeGorter: Stanford University School of Medicine
Mohana Prasad Sathya Moorthy: Stanford University School of Medicine
Jeffrey F. Tuff: Public Health Agency of Canada
Eun-Young Kim: Northwestern University
Miriam Walter: Northwestern University
Lacy M. Simons: Northwestern University
Arman Bashirova: National Cancer Institute
Susan Buchbinder: San Francisco Department of Public Health
Mary Carrington: National Cancer Institute
Andrea Cossarizza: University of Modena and Reggio Emilia
Andrea Luca: Siena University Hospital
James J. Goedert: National Cancer Institute, National Institutes of Health
David B. Goldstein: Columbia University
David W. Haas: Vanderbilt University School of Medicine
Joshua T. Herbeck: University of Washington
Eric O. Johnson: RTI International
Pontiano Kaleebu: Medical Research Council/Uganda Virus Research Institute & London School of Hygiene and Tropical Medicine, Uganda Research Unit
William Kilembe: Center for Family Health Research—Zambia
Gregory D. Kirk: Johns Hopkins University
Neeltje A. Kootstra: University of Amsterdam
Alex H. Kral: RTI International
Olivier Lambotte: Université Paris Saclay, Inserm UMR1184, CEA
Ma Luo: University of Manitoba
Simon Mallal: Vanderbilt University School of Medicine
Javier Martinez-Picado: University of Vic—Central University of Catalonia
Laurence Meyer: INSERM U1018, Université Paris-Saclay
José M. Miro: CIBERINFEC, Instituto de Salud Carlos III
Pravi Moodley: South Africa and University of KwaZulu-Natal
Ayesha A. Motala: University of KwaZulu-Natal
James I. Mullins: University of Washington
Kireem Nam: Northwestern University
Niels Obel: Copenhagen University Hospital, Rigshospitalet
Fraser Pirie: University of KwaZulu-Natal
Francis A. Plummer: University of Manitoba
Guido Poli: San Raffaele Scientific Institute
Matthew A. Price: International AIDS Vaccine Initiative
Andri Rauch: Bern University Hospital, University of Bern
Ioannis Theodorou: Hôpital Robert Debré Paris
Alexandra Trkola: University of Zurich
Bruce D. Walker: MIT and Harvard
Cheryl A. Winkler: National Cancer Institute
Jean-François Zagury: EA7528, Conservatoire National des Arts et Métiers, HESAM Université
Stephen B. Montgomery: Stanford University School of Medicine
Angela Ciuffi: Lausanne University Hospital and University of Lausanne
Judd F. Hultquist: Northwestern University
Steven M. Wolinsky: Northwestern University
Gordon Dougan: Wellcome Trust Sanger Institute
Andrew M. L. Lever: University of Cambridge
Deepti Gurdasani: Queen Mary University of London
Harriet Groom: University of Cambridge
Manjinder S. Sandhu: Imperial College London
Jacques Fellay: École Polytechnique Fédérale de Lausanne

Nature, 2023, vol. 620, issue 7976, 1025-1030

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41586-023-06370-4

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