The 4th and 112th Residues of Viral Capsid Cooperatively Modulate Capsid-CPSF6 Interactions of HIV-1
The 4th and 112th Residues of Viral Capsid Cooperatively Modulate Capsid-CPSF6 Interactions of HIV-1
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病毒衣壳的第4个和第112个残基协同调节HIV-1的衣壳-CPSF6相互作用
DOI：
10.1089/aid.2019.0250
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发表时间：
2020
影响因子：
1.5
通讯作者：
Shioda Tatsuo
中科院分区：
文献类型：
--
作者：
Saito Akatsuki;Sultana Tahmina;Ode Hirotaka;Nohata Kyotaro;Samune Yoshihiro;Nakayama Emi E.;Iwatani Yasumasa;Shioda Tatsuo
HIV-1衣壳（CA）与切割和多聚腺苷酸化特异性因子6（CPSF 6）的结合被假设为在体内病毒复制中提供显著的适应性优势，解释了为什么CA-CPSF 6相互作用在灵长类慢病毒中是严格保守的。最近，我们在干扰素（IFN）-β-超敏感CA突变体RGDA/Q112 D（H87 R，A88 G，P90 D，P93 A和Q112 D）病毒在IFN-β处理的细胞中增殖后，在CA中鉴定出Q4 R突变。Q4 R取代通过影响病毒的几种性质，包括对粘病毒抗性蛋白B（Mx B）的敏感性、逆转录动力学和脱壳起始，赋予了对RGDA/Q112 D病毒的显著IFN-β抗性。值得注意的是，Q4 R取代恢复了RGDA/Q112 D病毒的CPSF 6相互作用。为了更好地理解Q4 R取代如何调节CA-CPSF 6相互作用，我们产生了一系列在第4和第112个残基处具有取代的CA突变体。与RGDA/Q112 D背景中的作用相反，Q4 R取代减少了在其他野生型病毒中的CA-CPSF 6相互作用。我们的遗传和结构分析显示，虽然Q4 R或Q112 D取代损害了CA-CPSF 6相互作用，但这些取代的组合恢复了这种相互作用。这些结果表明，HIV-1 CA中的第4位和第112位残基协同调节CA-CPSF 6相互作用，进一步突出了灵长类慢病毒CA中巨大的可塑性水平，这是HIV-1感染个体抗逆转录病毒治疗的障碍之一。
Binding of HIV-1 capsid (CA) to cleavage and polyadenylation specificity factor 6 (CPSF6) is hypothesized to provide a significant fitness advantage toin vivoviral replication, explaining why CA-CPSF6 interactions are strictly conserved in primate lentiviruses. We recently identified a Q4R mutation in CA after propagation of an interferon (IFN)-β-hypersensitive CA mutant, RGDA/Q112D (H87R, A88G, P90D, P93A and Q112D) virus, in IFN-β-treated cells. The Q4R substitution conferred significant IFN-β resistance to the RGDA/Q112D virus by affecting several properties of the virus, including the sensitivity to myxovirus resistance protein B (MxB), the kinetics of reverse transcription, and the initiation of uncoating. Notably, the Q4R substitution restored the CPSF6 interaction of the RGDA/Q112D virus. To better understand how the Q4R substitution modulated the CA-CPSF6 interaction, we generated a series of CA mutants harboring substitutions at the 4th and 112th residues. In contrast to the effect in the RGDA/Q112D background, the Q4R substitution diminished CA-CPSF6 interaction in an otherwise wild-type virus. Our genetic and structural analyses revealed that while either the Q4R or Q112D substitution impaired CA-CPSF6 interaction, the combination of these substitutions restored this interaction. These results suggest that the 4th and 112th residues in HIV-1 CA cooperatively modulate CA-CPSF6 interactions, further highlighting the tremendous levels of plasticity in primate lentivirus CA, which is one of the barriers to antiretroviral therapy in HIV-1-infected individuals.