Department of Biochemistry, Molecular Biology and Biophysics, Institute for Molecular Virology, Center for Genome Engineering, University of Minnesota, Minneapolis, MN 55455, USA.
J Virol. 2011 Nov;85(21):11220-34. doi: 10.1128/JVI.05238-11. Epub 2011 Aug 10.
Successful intracellular pathogens must evade or neutralize the innate immune defenses of their host cells and render the cellular environment permissive for replication. For example, to replicate efficiently in CD4(+) T lymphocytes, human immunodeficiency virus type 1 (HIV-1) encodes a protein called viral infectivity factor (Vif) that promotes pathogenesis by triggering the degradation of the retrovirus restriction factor APOBEC3G. Other APOBEC3 proteins have been implicated in HIV-1 restriction, but the relevant repertoire remains ambiguous. Here we present the first comprehensive analysis of the complete, seven-member human and rhesus APOBEC3 families in HIV-1 restriction. In addition to APOBEC3G, we find that three other human APOBEC3 proteins, APOBEC3D, APOBEC3F, and APOBEC3H, are all potent HIV-1 restriction factors. These four proteins are expressed in CD4(+) T lymphocytes, are packaged into and restrict Vif-deficient HIV-1 when stably expressed in T cells, mutate proviral DNA, and are counteracted by HIV-1 Vif. Furthermore, APOBEC3D, APOBEC3F, APOBEC3G, and APOBEC3H of the rhesus macaque also are packaged into and restrict Vif-deficient HIV-1 when stably expressed in T cells, and they are all neutralized by the simian immunodeficiency virus Vif protein. On the other hand, neither human nor rhesus APOBEC3A, APOBEC3B, nor APOBEC3C had a significant impact on HIV-1 replication. These data strongly implicate a combination of four APOBEC3 proteins--APOBEC3D, APOBEC3F, APOBEC3G, and APOBEC3H--in HIV-1 restriction.
成功的细胞内病原体必须逃避或中和宿主细胞的固有免疫防御，并使细胞环境有利于复制。例如，为了在 CD4(+)T 淋巴细胞中高效复制，人类免疫缺陷病毒 1 (HIV-1) 编码一种称为病毒感染性因子 (Vif) 的蛋白，通过触发逆转录病毒限制因子 APOBEC3G 的降解来促进发病机制。其他 APOBEC3 蛋白已被牵连到 HIV-1 的限制中，但相关的作用谱仍不清楚。在这里，我们首次对 HIV-1 限制中完整的、七个成员的人类和恒河猴 APOBEC3 家族进行了全面分析。除了 APOBEC3G 之外，我们还发现另外三种人类 APOBEC3 蛋白，APOBEC3D、APOBEC3F 和 APOBEC3H，都是强大的 HIV-1 限制因子。这四种蛋白在 CD4(+)T 淋巴细胞中表达，在 T 细胞中稳定表达时被包装并限制 Vif 缺陷的 HIV-1，突变前病毒 DNA，并被 HIV-1 Vif 拮抗。此外，恒河猴的 APOBEC3D、APOBEC3F、APOBEC3G 和 APOBEC3H 也被包装到 Vif 缺陷的 HIV-1 中，并在 T 细胞中稳定表达，它们都被猿猴免疫缺陷病毒 Vif 蛋白中和。另一方面，人类和恒河猴的 APOBEC3A、APOBEC3B 或 APOBEC3C 都没有对 HIV-1 复制产生重大影响。这些数据强烈暗示了一组四种 APOBEC3 蛋白（APOBEC3D、APOBEC3F、APOBEC3G 和 APOBEC3H）在 HIV-1 限制中的作用。
