Africa-specific human genetic variation near CHD1L associates with HIV-1 load
作者：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
Nature：2023/08/02
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.
HIV-1仍然是一种；全球卫生危机1，强调需要确定新的治疗目标。在这里，考虑到非洲不成比例的HIV-1负担和显著的人类基因组多样性2，我们评估了3879名参与HIV3基因组学国际合作的HIV-1非洲祖先控制设定点病毒载量的遗传决定因素。我们在1号染色体上发现了一个以前未描述的关联信号，其中峰值变体与每毫升约0.3 log10个转化拷贝相关，每个次要等位基因拷贝的病毒载量较低，并且对非洲裔人群具有特异性。最相关的变体是基因间变体，位于长基因间非编码RNA（LINC00624）和编码基因CHD1L之间，CHD1L编码一种参与DNA修复的解旋酶4。iPS中的感染检测；细胞衍生的巨噬细胞和其他永生化细胞系在CHD1L敲除和CHD1L基因敲除细胞中显示HIV-1复制增加。我们从群体遗传学研究中提供的证据表明，CHD1L附近的非洲特异性遗传变异与HIV在体内的复制有关。尽管实验研究表明，CHD1L能够在体外限制某些细胞类型的HIV感染，但还需要进一步的研究来了解我们观察到的潜在机制，包括CHD1L对HIV在体内传播的任何潜在间接影响，这些影响是我们基于细胞的分析无法概括的。
由人类免疫缺陷病毒（HIV）引发的获得性免疫缺陷综合征（AIDS），至今仍是一项重大的健康危机。在全球范围内有近4000万HIV感染者，没有疫苗也没有治愈方法。不少科学家想从人类基因组中找到与HIV感染进程有关的线索。最近，一项发表于《自然》杂志的研究在非洲血统的人群中发现，CHD1L基因的一种突变型，可以限制一个白细胞亚群中的HIV复制。
