Possible Footprints of APOBEC3F and/or Other APOBEC3 Deaminases, but Not APOBEC3G, on HIV-1 from Patients with Acute/Early and Chronic Infections
Possible Footprints of APOBEC3F and/or Other APOBEC3 Deaminases, but Not APOBEC3G, on HIV-1 from Patients with Acute/Early and Chronic Infections
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DOI：
10.1128/jvi.01460-14
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发表时间：
2014-11-01
影响因子：
5.4
通讯作者：
Iversen，Astrid K. N.
中科院分区：
文献类型：
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作者：
Armitage，Andrew E.;Deforche，Koen;Iversen，Astrid K. N.
载脂蛋白B mRNA编辑酶催化多肽样3（APOBEC 3）先天性细胞胞苷脱氨酶家族的成员，特别是APOBEC 3F和APOBEC 3G，可导致HIV-1正链DNA中广泛和致命的G至A突变（称为超突变）。目前还不清楚APOBEC 3诱导的体内突变是否总是致命的，或者可以在亚致死水平发生，从而增加HIV-1的多样化和病毒对宿主的适应。病毒辅助蛋白Vif通过与APOBEC 3结合并促进蛋白酶体降解来抵消APOBEC 3活性;然而，这种相互作用的效率各不相同，因为在HIV-1患者DNA中观察到一系列高突变频率。因此，我们通过确定G-to-A突变是否发生在这些脱氨酶有利或不利的基序中，检查了来自约3,000名慢性感染患者的纵向HIV-1 RNA polsequences中APOBEC 3G和APOBEC 3F活性的“足迹”。G-to-A突变在APOBEC 3G不利的情况下比在APOBEC 3G有利的情况下更频繁。相比之下，APOBEC 3F不利背景中的突变相对罕见，而有利于APOBEC 3F（可能还有其他脱氨酶）的背景中的突变比平均G到A突变多发生16%。这些结果得到了来自急性/早期感染的>500个HIV-1 env序列的分析的支持。重要的是，我们的研究结果表明，APOBEC 3G诱导的诱变对HIV-1是致命的，而APOBEC 3F和/或其他脱氨酶引起的诱变可能导致亚致死突变，这可能有助于病毒的多样化。因此，Vif特异性细胞毒性T淋巴细胞（CTL）反应和操纵Vif与APOBEC 3之间相互作用的药物可能会产生有益或有害的临床效果，具体取决于它们如何影响Vif与APOBEC 3家族各个成员的结合。
Members of the apolipoprotein B mRNA-editing enzyme-catalytic polypeptide-like-3 (APOBEC3) innate cellular cytidine deaminase family, particularly APOBEC3F and APOBEC3G, can cause extensive and lethal G-to-A mutations in HIV-1 plus-strand DNA (termed hypermutation). It is unclear if APOBEC3-induced mutationsin vivoare always lethal or can occur at sublethal levels that increase HIV-1 diversification and viral adaptation to the host. The viral accessory protein Vif counteracts APOBEC3 activity by binding to APOBEC3 and promoting proteasome degradation; however, the efficiency of this interaction varies, since a range of hypermutation frequencies are observed in HIV-1 patient DNA. Therefore, we examined “footprints” of APOBEC3G and APOBEC3F activity in longitudinal HIV-1 RNApolsequences from approximately 3,000 chronically infected patients by determining whether G-to-A mutations occurred in motifs that were favored or disfavored by these deaminases. G-to-A mutations were more frequent in APOBEC3G-disfavored than in APOBEC3G-favored contexts. In contrast, mutations in APOBEC3F-disfavored contexts were relatively rare, whereas mutations in contexts favoring APOBEC3F (and possibly other deaminases) occurred 16% more often than average G-to-A mutations. These results were supported by analyses of >500 HIV-1envsequences from acute/early infection.IMPORTANCECollectively, our results suggest that APOBEC3G-induced mutagenesis is lethal to HIV-1, whereas mutagenesis caused by APOBEC3F and/or other deaminases may result in sublethal mutations that might facilitate viral diversification. Therefore, Vif-specific cytotoxic T lymphocyte (CTL) responses and drugs that manipulate the interplay between Vif and APOBEC3 may have beneficial or detrimental clinical effects depending on how they affect the binding of Vif to various members of the APOBEC3 family.