1. Africa-specific human genetic variation near CHD1L associates with HIV-1 load.
- Author
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McLaren PJ, Porreca I, Iaconis G, Mok HP, Mukhopadhyay S, Karakoc E, Cristinelli S, Pomilla C, Bartha I, Thorball CW, Tough RH, Angelino P, Kiar CS, Carstensen T, Fatumo S, Porter T, Jarvis I, Skarnes WC, Bassett A, DeGorter MK, Sathya Moorthy MP, Tuff JF, Kim EY, Walter M, Simons LM, Bashirova A, Buchbinder S, Carrington M, Cossarizza A, De Luca A, Goedert JJ, Goldstein DB, Haas DW, Herbeck JT, Johnson EO, Kaleebu P, Kilembe W, Kirk GD, Kootstra NA, Kral AH, Lambotte O, Luo M, Mallal S, Martinez-Picado J, Meyer L, Miro JM, Moodley P, Motala AA, Mullins JI, Nam K, Obel N, Pirie F, Plummer FA, Poli G, Price MA, Rauch A, Theodorou I, Trkola A, Walker BD, Winkler CA, Zagury JF, Montgomery SB, Ciuffi A, Hultquist JF, Wolinsky SM, Dougan G, Lever AML, Gurdasani D, Groom H, Sandhu MS, and Fellay J
- Subjects
- Humans, Cell Line, Africa, Chromosomes, Human, Pair 1 genetics, Alleles, RNA, Long Noncoding genetics, Virus Replication, DNA Helicases genetics, DNA Helicases metabolism, DNA-Binding Proteins genetics, DNA-Binding Proteins metabolism, Genetic Variation, HIV Infections genetics, HIV-1 growth & development, HIV-1 physiology, Viral Load genetics
- Abstract
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 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., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)- Published
- 2023
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