Russell Rebecca A, Smith Jessica, Barr Rebekah, Bhattacharyya Darshana, Pathak Vinay K
Viral Mutation Section, HIV Drug Resistance Program, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, Maryland 21702, USA.
J Virol. 2009 Feb;83(4):1992-2003. doi: 10.1128/JVI.01621-08. Epub 2008 Nov 26.
Human APOBEC3G (A3G) and APOBEC3F (A3F) inhibit the replication of Vif-deficient human immunodeficiency virus type 1 (HIV-1). HIV-1 Vif overcomes these host restriction factors by binding to them and inducing their degradation. Thus, the Vif-A3G and Vif-A3F interactions are attractive targets for antiviral drug development, as inhibiting these interactions could allow the host defense mechanism to control HIV-1 replication. Recently, it has been reported that amino acids 105 to 156 of A3G are involved in the interaction with Vif; however, to date, the region of A3F involved in Vif binding has not been identified. Using our previously reported Vif mutants that are capable of binding to only A3G (3G binder) or only A3F (3F binder), in conjunction with a series of A3G-A3F chimeras, we have now mapped the APOBEC3-Vif interaction domains. We found that the A3G domain that interacts with the Vif YRHHY region is located between amino acids 126 and 132 of A3G, which is consistent with the conclusions reported in previous studies. The A3F domain that interacts with the Vif DRMR region did not occur in the homologous domain but instead was located between amino acids 283 and 300 of A3F. These studies are the first to identify the A3F domain that interacts with the Vif DRMR region and show that distinct domains of A3G and A3F interact with different Vif regions. Pharmacological inhibition of either or both of these Vif-A3 interactions should prevent the degradation of the APOBEC3 proteins and could be used as a therapy against HIV-1.
人类载脂蛋白B mRNA编辑酶催化多肽样蛋白3G（APOBEC3G，A3G）和载脂蛋白B mRNA编辑酶催化多肽样蛋白3F（APOBEC3F，A3F）可抑制缺乏病毒感染性因子（Vif）的1型人类免疫缺陷病毒（HIV-1）的复制。HIV-1 Vif通过与这些宿主限制因子结合并诱导其降解来克服它们的作用。因此，Vif-A3G和Vif-A3F相互作用是抗病毒药物开发的有吸引力的靶点，因为抑制这些相互作用可以使宿主防御机制控制HIV-1复制。最近，有报道称A3G的105至156位氨基酸参与与Vif的相互作用；然而，迄今为止，尚未确定A3F中参与Vif结合的区域。利用我们先前报道的仅能与A3G结合的Vif突变体（3G结合剂）或仅能与A3F结合的Vif突变体（3F结合剂），结合一系列A3G-A3F嵌合体，我们现已绘制出APOBEC3-Vif相互作用结构域。我们发现，与Vif YRHHY区域相互作用的A3G结构域位于A3G的126至132位氨基酸之间，这与先前研究报道的结论一致。与Vif DRMR区域相互作用的A3F结构域并非出现在同源结构域中，而是位于A3F的283至300位氨基酸之间。这些研究首次确定了与Vif DRMR区域相互作用的A3F结构域，并表明A3G和A3F的不同结构域与Vif的不同区域相互作用。对这些Vif-A3相互作用中的一个或两个进行药理学抑制应可防止APOBEC3蛋白的降解，并可作为抗HIV-1的一种治疗方法。
