Foamy virus bet proteins function as novel inhibitors of the APOBEC3 family of innate antiretroviral defense factors
Foamy virus bet proteins function as novel inhibitors of the APOBEC3 family of innate antiretroviral defense factors
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DOI：
10.1128/jvi.79.14.8724-8731.2005
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发表时间：
2005-07-01
影响因子：
5.4
通讯作者：
Cullen, BR
中科院分区：
文献类型：
--
作者：
Russell, RA;Wiegand, HL;Cullen, BR
泡沫病毒是一个复杂的逆转录病毒家族，在广泛的非人灵长类动物中建立常见的生产性感染。相比之下，人类似乎不允许泡沫病毒复制，尽管人畜共患感染确实发生。在这里，我们分析了灵长类动物和小鼠APOBEC 3G蛋白抑制灵长类泡沫病毒（PFV）病毒粒子在其存在下产生的感染性的能力。我们证明了几种APOBEC 3蛋白可以有效地抑制基于PFV的病毒载体的感染性。这种抑制作用与抑制性APOBEC 3蛋白包装到PFV病毒粒子中有关，这是由于PFV Gag/APOBEC 3的特异性相互作用，并导致PFV逆转录物的G至A超突变。虽然灵长类动物APOBEC 3蛋白对PFV病毒粒子感染性的抑制在很大程度上通过PFV Bet蛋白（一种先前功能不确定的细胞质辅助蛋白）的共表达而缓解，但Bet未能缓解小鼠APOBEC 3引起的抑制。PFV Bet与共表达细胞中的人APOBEC 3蛋白结合，但不与小鼠APOBEC 3蛋白结合，这种结合与其掺入PFV病毒体的特异性抑制相关。值得注意的是，PFV Bet和源自非洲绿色猴泡沫病毒的第二种Bet蛋白拯救了在非洲绿色猴APOBEC 3G存在下产生的Vif缺陷型人类免疫缺陷病毒1型（HIV-1）病毒粒子的感染性，并阻断了该宿主因子掺入HIV-1病毒粒子。然而，泡沫病毒Bet蛋白都没有降低病毒粒子生产细胞中APOBEC 3蛋白的表达水平。虽然这些数据确定泡沫病毒Bet蛋白是HIV-1 Vif辅助蛋白的功能性直系同源物，但它们也表明Vif和Bet通过不同的机制阻断APOBEC 3蛋白的功能。
Foamy viruses are a family of complex retroviruses that establish common, productive infections in a wide range of nonhuman primates. In contrast, humans appear nonpermissive for foamy virus replication, although zoonotic infections do occur. Here we have analyzed the ability of primate and mouse APOBEC3G proteins to inhibit the infectivity of primate foamy virus (PFV) virions produced in their presence. We demonstrate that several APOBEC3 proteins can potently inhibit the infectivity of a PFV-based viral vector. This inhibition correlated with the packaging of inhibitory APOBEC3 proteins into PFV virions, due to a specific PFV Gag/APOBEC3 interaction, and resulted in the G to A hypermutation of PFV reverse transcripts. While inhibition of PFV virion infectivity by primate APOBEC3 proteins was largely relieved by coexpression of the PFV Bet protein, a cytoplasmic auxiliary protein of previously uncertain function, Bet failed to relieve inhibition caused by murine APOBEC3. PFV Bet bound to human, but not mouse, APOBEC3 proteins in coexpressing cells, and this binding correlated with the specific inhibition of their incorporation into PFV virions. Of note, both PFV Bet and a second Bet protein, derived from an African green monkey foamy virus, rescued the infectivity of Vif-deficient human immunodeficiency virus type 1 (HIV-1) virions produced in the presence of African green monkey APOBEC3G and blocked the incorporation of this host factor into HIV-1 virion particles. However, neither foamy virus Bet protein reduced APOBEC3 protein expression levels in virion producer cells. While these data identify the foamy virus Bet protein as a functional ortholog of the HIV-1 Vif auxiliary protein, they also indicate that Vif and Bet block APOBEC3 protein function by distinct mechanisms.