Africa-specific human genetic variation near CHD1L associates with HIV-1 load.
Sathya Moorthy M,
De Luca A,
Africa-specific human genetic variation near CHD1L associates with HIV-1 load. Nature. 2023;620(7976):1025-30.
JGM, Humans, Cell Line, DNA Helicases, DNA-Binding Proteins, Genetic Variation, HIV Infections, HIV-1, Viral Load, Africa, Chromosomes, Human, Pair 1, Alleles, RNA, Long Noncoding, Virus Replication
This research was supported by the Cambridge NIHR BRC Cell Phenotyping Hub; Funding EPFL School of Life Sciences; Medical Research Council UK grant MR/N02043/X; National Institute for Health Research, UK (Cambridge Biomedical Research Centre), Cambridge Clinical Academic Reserve; Swiss National Science Foundation (SNF 310030L_197721); Sanger core grant (WT206194); and H3ABioNet, supported by the National Institutes of Health Common Fund under grant number U24HG006941. The National Institutes of Health grants and contracts supporting this work are U01 HL146240, U01 HL146201, U01 HL146208, U01 HL146333, P30 AI117943, R01 AI165236 and U54 AI170792. This study was supported in part by the Italian Ministry of University PRIN project 2017TYTWZ3 and by the Italian Ministry of health RF-2019- 12369226 to G.P. J.M.M. received a personal 80:20 research grant from Institut d’Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), Barcelona, Spain, during 2017–2023. This study has been financed in part within the framework of the SHCS, supported by the Swiss National Science Foundation (grant no. 201369), by SHCS project no. 841 and by the SHCS research foundation. The data are gathered by the Five Swiss University Hospitals, two Cantonal Hospitals, 15 affiliated hospitals and 36 private physicians (listed at http://www.shcs.ch/180- health-care-providers). This project has been funded in part with federal funds from the Frederick National Laboratory for Cancer Research, under contract no. 75N91019D00024 and by the Intramural Research Program of the NIH, Frederick National Lab, Center for Cancer Research. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does the mention of trade names, commercial products or organizations imply endorsement by the US Government. This work was supported in part by IAVI funded by the United States Agency for International Development (USAID). The full list of IAVI donors is available at http://www.iavi.org. The contents of this manuscript are the responsibility of the authors and do not necessarily reflect the views of USAID or the US Government. J.F.H. received an award from the Gilead Sciences Research Scholars Program in HIV. H.G.’s fellowship is from Sidney Sussex College, Cambridge. S.F. is supported by the Wellcome Trust (grant no. 220740/Z/20/Z)
HIV-1 remains a global health crisis, 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.