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

• Published in: Nature (London) Vol. 620; no. 7976; pp. 1025 - 1030
• Main Authors: McLaren, Paul J., Porreca, Immacolata, Iaconis, Gennaro, Mok, Hoi Ping, Mukhopadhyay, Subhankar, Karakoc, Emre, Cristinelli, Sara, Pomilla, Cristina, Bartha, István, Thorball, Christian W., Tough, Riley H., Angelino, Paolo, Kiar, Cher S., Carstensen, Tommy, Fatumo, Segun, Porter, Tarryn, Jarvis, Isobel, Skarnes, William C., Bassett, Andrew, DeGorter, Marianne K., Sathya Moorthy, Mohana Prasad, Tuff, Jeffrey F., Kim, Eun-Young, Walter, Miriam, Simons, Lacy M., Bashirova, Arman, Buchbinder, Susan, Carrington, Mary, Cossarizza, Andrea, De Luca, Andrea, Goedert, James J., Goldstein, David B., Haas, David W., Herbeck, Joshua T., Johnson, Eric O., Kaleebu, Pontiano, Kilembe, William, Kirk, Gregory D., Kootstra, Neeltje A., Kral, Alex H., Lambotte, Olivier, Luo, Ma, Mallal, Simon, Martinez-Picado, Javier, Meyer, Laurence, Miro, José M., Moodley, Pravi, Motala, Ayesha A., Mullins, James I., Nam, Kireem, Obel, Niels, Pirie, Fraser, Plummer, Francis A., Poli, Guido, Price, Matthew A., Rauch, Andri, Theodorou, Ioannis, Trkola, Alexandra, Walker, Bruce D., Winkler, Cheryl A., Zagury, Jean-François, Montgomery, Stephen B., Ciuffi, Angela, Hultquist, Judd F., Wolinsky, Steven M., Dougan, Gordon, Lever, Andrew M. L., Gurdasani, Deepti, Groom, Harriet, Sandhu, Manjinder S., Fellay, Jacques
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 31.08.2023; Nature Publishing Group
• Subjects: 45; 45/43; 631/208/205/2138; 631/250/248; 692/308/2056; 692/699/255/1901; Africa; Alleles; Cell Line; Cell lines; Chromosome 1; Chromosomes; Chromosomes, Human, Pair 1 - genetics; Collaboration; DNA helicase; DNA Helicases - genetics; DNA Helicases - metabolism; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Drug resistance; Drug therapy; Genes; Genetic diversity; Genetic Variation; Genomes; Genomics; Global health; Hematology; HIV; HIV Infections - genetics; HIV-1 - growth & development; HIV-1 - physiology; Human immunodeficiency virus; Humanities and Social Sciences; Humans; In vivo methods and tests; Infections; International cooperation; Life Sciences; Macrophages; multidisciplinary; Population genetics; Population studies; Public health; Regression analysis; Replication; RNA, Long Noncoding - genetics; Science; Science (multidisciplinary); Target recognition; Viral Load - genetics; Virus Replication; Africa
• ISSN: 0028-0836; 1476-4687; 1476-4687
• DOI: 10.1038/s41586-023-06370-4

HIV-1 remains a global health crisis 1 , highlighting the need to identify new targets for therapies. Here, given the disproportionate HIV-1 burden and marked human genome diversity in Africa 2 , 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 HIV 3 . We identify a previously undescribed association signal on chromosome 1 where the peak variant associates with an approximately 0.3 log 10 -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 repair 4 . 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. Africa-specific genetic variation on chromosome 1 near CHD1L is associated with HIV replication in vivo.