Zhang Hui, Yang Bin, Pomerantz Roger J, Zhang Chune, Arunachalam Shyamala C, Gao Ling
The Dorrance H. Hamilton Laboratories, Center for Human Virology and Biodefense, Division of Infectious Diseases and Environmental Medicine, Department of Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
Nature. 2003 Jul 3;424(6944):94-8. doi: 10.1038/nature01707. Epub 2003 May 28.
High mutation frequency during reverse transcription has a principal role in the genetic variation of primate lentiviral populations. It is the main driving force for the generation of drug resistance and the escape from immune surveillance. G to A hypermutation is one of the characteristics of primate lentiviruses, as well as other retroviruses, during replication in vivo and in cell culture. The molecular mechanisms of this process, however, remain to be clarified. Here, we demonstrate that CEM15 (also known as apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like 3G; APOBEC3G), an endogenous inhibitor of human immunodeficiency virus type 1 (HIV-1) replication, is a cytidine deaminase and is able to induce G to A hypermutation in newly synthesized viral DNA. This effect can be counteracted by the HIV-1 virion infectivity factor (Vif). It seems that this viral DNA mutator is a viral defence mechanism in host cells that may induce either lethal hypermutation or instability of the incoming nascent viral reverse transcripts, which could account for the Vif-defective phenotype. Importantly, the accumulation of CEM15-mediated non-lethal hypermutation in the replicating viral genome could potently contribute to the genetic variation of primate lentiviral populations.
逆转录过程中的高突变频率在灵长类慢病毒群体的遗传变异中起主要作用。它是产生耐药性和逃避免疫监视的主要驱动力。G到A的超突变是灵长类慢病毒以及其他逆转录病毒在体内和细胞培养中复制时的特征之一。然而，这一过程的分子机制仍有待阐明。在此，我们证明CEM15（也称为载脂蛋白B mRNA编辑酶，催化多肽样3G；APOBEC3G），一种人类免疫缺陷病毒1型（HIV-1）复制的内源性抑制剂，是一种胞苷脱氨酶，能够在新合成的病毒DNA中诱导G到A的超突变。这种效应可被HIV-1病毒体感染性因子（Vif）抵消。看来这种病毒DNA诱变剂是宿主细胞中的一种病毒防御机制，可能诱导致命的超突变或进入的新生病毒逆转录产物的不稳定性，这可以解释Vif缺陷表型。重要的是，CEM15介导的非致命性超突变在复制的病毒基因组中的积累可能有力地促进灵长类慢病毒群体的遗传变异。
