Department of Microbiology and Immunology, College of Medicine, University of Saskatchewan Saskatoon, SK, Canada.
Front Microbiol. 2014 Aug 26;5:450. doi: 10.3389/fmicb.2014.00450. eCollection 2014.
The APOBEC3 restriction factors are a family of deoxycytidine deaminases that are able to suppress replication of viruses with a single-stranded DNA intermediate by inducing mutagenesis and functional inactivation of the virus. Of the seven human APOBEC3 enzymes, only APOBEC3-D, -F, -G, and -H appear relevant to restriction of HIV-1 in CD4+ T cells and will be the focus of this review. The restriction of HIV-1 occurs most potently in the absence of HIV-1 Vif that induces polyubiquitination and degradation of APOBEC3 enzymes through the proteasome pathway. To restrict HIV-1, APOBEC3 enzymes must be encapsidated into budding virions. Upon infection of the target cell during reverse transcription of the HIV-1 RNA into (-)DNA, APOBEC3 enzymes deaminate cytosines to form uracils in single-stranded (-)DNA regions. Upon replication of the (-)DNA to (+)DNA, the HIV-1 reverse transcriptase incorporates adenines opposite to the uracils thereby inducing C/G to T/A mutations that can functionally inactivate HIV-1. APOBEC3G is the most studied APOBEC3 enzyme and it is known that Vif attempts to thwart APOBEC3 function not only by inducing its proteasomal degradation but also by several degradation-independent mechanisms, such as inhibiting APOBEC3G virion encapsidation, mRNA translation, and for those APOBEC3G molecules that still become virion encapsidated, Vif can inhibit APOBEC3G mutagenic activity. Although most Vif variants can induce efficient degradation of APOBEC3-D, -F, and -G, there appears to be differential sensitivity to Vif-mediated degradation for APOBEC3H. This review examines APOBEC3-mediated HIV restriction mechanisms, how Vif acts as a substrate receptor for a Cullin5 ubiquitin ligase complex to induce degradation of APOBEC3s, and the determinants and functional consequences of the APOBEC3 and Vif interaction from a biological and biochemical perspective.
APOBEC3 限制因子是一类脱氨酶，能够通过诱导病毒突变和功能失活来抑制具有单链 DNA 中间体的病毒的复制。在人类的 7 种 APOBEC3 酶中，只有 APOBEC3-D、-F、-G 和 -H 似乎与 CD4+T 细胞中 HIV-1 的限制有关，因此将成为本综述的重点。在没有 HIV-1 Vif 的情况下，APOBEC3 酶的限制作用最强，Vif 通过蛋白酶体途径诱导 APOBEC3 酶的多泛素化和降解。为了限制 HIV-1，APOBEC3 酶必须被包裹在出芽的病毒粒子中。在 HIV-1 RNA 逆转录为(-)DNA 期间，当感染靶细胞时，APOBEC3 酶会将胞嘧啶脱氨形成单链(-)DNA 区域中的尿嘧啶。在(-)DNA 复制为(+)DNA 时，HIV-1 逆转录酶会将腺嘌呤掺入到与尿嘧啶相对的位置，从而诱导 C/G 突变为 T/A，这可能会使 HIV-1 功能失活。APOBEC3G 是研究最多的 APOBEC3 酶，已知 Vif 不仅通过诱导其蛋白酶体降解，还通过几种非降解依赖的机制来阻止 APOBEC3 功能，例如抑制 APOBEC3G 病毒粒子包裹、mRNA 翻译，对于那些仍然被包裹在病毒粒子中的 APOBEC3G 分子，Vif 可以抑制 APOBEC3G 的突变活性。虽然大多数 Vif 变体可以诱导 APOBEC3-D、-F 和 -G 的有效降解，但对于 APOBEC3H，似乎对 Vif 介导的降解有不同的敏感性。本综述从生物学和生物化学的角度检查了 APOBEC3 介导的 HIV 限制机制、Vif 如何作为 Cullin5 泛素连接酶复合物的底物受体诱导 APOBEC3 降解以及 APOBEC3 和 Vif 相互作用的决定因素和功能后果。
