Melamed Anat, Fitzgerald Tomas W, Wang Yuchuan, Ma Jian, Birney Ewan, Bangham Charles R M
Department of Infectious Diseases, Faculty of Medicine, Imperial College London, London, UK.
European Bioinformatics Institute (EMBL-EBI), Cambridge, UK.
Sci Adv. 2022 Apr 29;8(17):eabm6210. doi: 10.1126/sciadv.abm6210.
The human retroviruses HTLV-1 (human T cell leukemia virus type 1) and HIV-1 persist in vivo as a reservoir of latently infected T cell clones. It is poorly understood what determines which clones survive in the reservoir. We compared >160,000 HTLV-1 integration sites (>40,000 HIV-1 sites) from T cells isolated ex vivo from naturally infected individuals with >230,000 HTLV-1 integration sites (>65,000 HIV-1 sites) from in vitro infection to identify genomic features that determine selective clonal survival. Three statistically independent factors together explained >40% of the observed variance in HTLV-1 clonal survival in vivo: the radial intranuclear position of the provirus, its genomic distance from the centromere, and the intensity of local host genome transcription. The radial intranuclear position of the provirus and its distance from the centromere also explained ~7% of clonal persistence of HIV-1 in vivo. Selection for the intranuclear and intrachromosomal location of the provirus and host transcription intensity favors clonal persistence of human retroviruses in vivo.
人类逆转录病毒HTLV-1（人类T细胞白血病病毒1型）和HIV-1作为潜伏感染的T细胞克隆库在体内持续存在。目前对于决定哪些克隆能在库中存活的因素了解甚少。我们将从自然感染个体离体分离的T细胞中获得的超过160,000个HTLV-1整合位点（超过40,000个HIV-1位点）与体外感染获得的超过230,000个HTLV-1整合位点（超过65,000个HIV-1位点）进行比较，以确定决定选择性克隆存活的基因组特征。三个统计学上独立的因素共同解释了体内HTLV-1克隆存活中超过40%的观察到的变异：前病毒的核内径向位置、其与着丝粒的基因组距离以及局部宿主基因组转录强度。前病毒的核内径向位置及其与着丝粒的距离也解释了HIV-1在体内约7%的克隆持续性。对前病毒的核内和染色体内位置以及宿主转录强度的选择有利于人类逆转录病毒在体内的克隆持续性。
