Adaptation of HIV-1/HIV-2 Chimeras with Defects in Genome Packaging and Viral Replication.
Adaptation of HIV-1/HIV-2 Chimeras with Defects in Genome Packaging and Viral Replication.
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频繁的重组是逆转录病毒复制的标志。在极少数情况下，远缘逆转录病毒之间发生重组，产生新的病毒，可能会显着影响病毒进化和公共卫生。由于来自两种亲本病毒的蛋白质和/或核酸之间的相互作用受损，这些重组体最初可能具有实质性的复制缺陷。然而，考虑到逆转录病毒的高突变率，这些重组体可能能够进化出这些病毒元件的改善的相容性。为了验证这一假设，我们研究了两种远亲人类病原体HIV-1和HIV-2之间嵌合体的适应性。我们构建了基于HIV-1的嵌合体，其含有HIV-2核衣壳（NC）结构域的Gag或HIV-2 NC的两个锌指，这对于特异性识别病毒RNA至关重要。这些嵌合体在T细胞中的RNA基因组包装和复制动力学方面表现出显著缺陷。然而，在一些实验中，嵌合病毒在再传代时以更快的动力学复制，表明病毒适应已经发生。序列分析显示，获得一个单一的氨基酸取代，S18 L，在第一个锌指的HIV-2 NC。这种取代，这代表了从一个保守的HIV-2残基的一个保守的HIV-1残基在这个位置的开关，部分拯救RNA包装和复制动力学。进一步的分析显示，HIV-2 NC中的两个取代W10 F和S18 L的组合几乎完全恢复了RNA包装和复制动力学。我们的研究表明，远缘逆转录病毒的嵌合体可以通过获得一个单一的替代来适应并显着增强其复制。
Frequent recombination is a hallmark of retrovirus replication. In rare cases, recombination occurs between distantly related retroviruses, generating novel viruses that may significantly impact viral evolution and public health. These recombinants may initially have substantial replication defects due to impaired interactions between proteins and/or nucleic acids from the two parental viruses. However, given the high mutation rates of retroviruses, these recombinants may be able to evolve improved compatibility of these viral elements. To test this hypothesis, we examined the adaptation of chimeras between two distantly related human pathogens: HIV-1 and HIV-2. We constructed HIV-1-based chimeras containing the HIV-2 nucleocapsid (NC) domain of Gag or the two zinc fingers of HIV-2 NC, which are critical for specific recognition of viral RNA. These chimeras exhibited significant defects in RNA genome packaging and replication kinetics in T cells. However, in some experiments, the chimeric viruses replicated with faster kinetics when repassaged, indicating that viral adaptation had occurred. Sequence analysis revealed the acquisition of a single amino acid substitution, S18L, in the first zinc finger of HIV-2 NC. This substitution, which represents a switch from a conserved HIV-2 residue to a conserved HIV-1 residue at this position, partially rescued RNA packaging and replication kinetics. Further analysis revealed that the combination of two substitutions in HIV-2 NC, W10F and S18L, almost completely restored RNA packaging and replication kinetics. Our study demonstrates that chimeras of distantly related retroviruses can adapt and significantly enhance their replication by acquiring a single substitution.
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影响因子：
5.4
作者：
Dilley, Kari A.;Nikolaitchik, Olga A.;Hu, Wei-Shau
通讯作者：
Hu, Wei-Shau
DOI：
10.1146/annurev-virology-092917-043448
发表时间：
2018-01-01
期刊：
ANNUAL REVIEW OF VIROLOGY, VOL 5
影响因子：
--
作者：
Bieniasz, Paul;Telesnitsky, Alice
通讯作者：
Telesnitsky, Alice
影响因子：
5.4
作者：
DUPRAZ, P;SPAHR, PF
通讯作者：
SPAHR, PF
影响因子：
5.4
作者：
Ariën, KK;Abraha, A;Arts, EJ
通讯作者：
Arts, EJ
影响因子：
5.4
作者：
Galli, Andrea;Kearney, Mary;Hu, Wei-Shau
通讯作者：
Hu, Wei-Shau