Conserved Molecular Signatures in gp120 Are Associated with the Genetic Bottleneck during Simian Immunodeficiency Virus (SIV), SIV-Human Immunodeficiency Virus (SHIV), and HIV Type 1 (HIV-1) Transmission
Conserved Molecular Signatures in gp120 Are Associated with the Genetic Bottleneck during Simian Immunodeficiency Virus (SIV), SIV-Human Immunodeficiency Virus (SHIV), and HIV Type 1 (HIV-1) Transmission
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DOI：
10.1128/jvi.03235-14
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发表时间：
2015-04-01
影响因子：
5.4
通讯作者：
Spouge, John L.
中科院分区：
文献类型：
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作者：
Gonzalez, Mileidy W.;DeVico, Anthony L.;Spouge, John L.
人类免疫缺陷病毒（HIV）的传播通常是由单一传播/创始者（T/F）变体感染引起的。T/F变异是从供体库中随机均匀选择的，还是基于有利于传播的有利性状选择的？在传播过程中寻找选择的证据特别令人感兴趣，因为这将表明病毒的表型和/或遗传特性可能被用作潜在的疫苗靶点或免疫疗法。在这里，我们系统地评估了猴免疫缺陷病毒/猴艾滋病病毒（SIV/SHIV）股票和T/F变异体的Env蛋白之间的差异，以寻找“签名”的传播位点。我们还调查了HIV在SIV/SHIV签名位点的残基偏好。gp 120的4个位点表现出显著的选择性，另外2个位点表现出类似的趋势。因此，这6个位点明确区分了T/F病毒与贮备液中的大多数流行变异体。SIV/SHIV的选择可以在接种疫苗和未接种疫苗的受试者中合理推断，感染由阴道、直肠和静脉内传播途径引起，而与病毒剂量无关。在SIV和SHIV T/F变异体中选择的证据是强有力的和丰富的，在HIV中的证据是提示性的，尽管与用于分析的合适数据的可用性相称。其中两个特征残基在我们检测的SIV、SHIV和HIV变体中是完全保守的。5个特征残基映射到gp 120的C1区域，1个映射到信号肽。我们的数据提出的可能性，C1，而管理gp 120和gp 41之间的关联，调制传输效率，复制健身，和/或宿主细胞嗜性在病毒细胞的附着和entry.IMPORTANCEThe本研究发现重大证据的SIV/SHIV T/F病毒的gp 120分子的选择。这些数据提供了辅助证据，表明在艾滋病毒中选择了相同的位点。我们的研究结果表明，签名残基参与增加感染病毒的传播性;因此，它们是开发疫苗或其他保护措施的潜在目标。最近的一项研究确定了相同的T/F特征基序，但将其解释为中和抗性的影响。在这里，我们表明，T/F基序具有更广泛的功能意义超出中和敏感性，因为它是存在于非免疫受试者。此外，在动物试验中流行的疫苗方案可能增加了变异的传播，否则传播适应度低。我们的观察结果可能解释了为什么许多动物疫苗试验没有忠实地预测人类疫苗试验的结果，并建议需要相应地重新审视目前的疫苗设计实践。
Human immunodeficiency virus (HIV) transmission typically results from infection by a single transmitted/founder (T/F) variant. Are T/F variants chosen uniformly at random from the donor pool, or are they selected based on advantageous traits facilitating transmission? Finding evidence for selection during transmission is of particular interest, because it would indicate that phenotypic and/or genetic properties of the viruses might be harnessed as potential vaccine targets or immunotherapies. Here, we systematically evaluated the differences between the Env proteins of simian immunodeficiency virus/simian HIV (SIV/SHIV) stock and T/F variants in search of "signature" sites of transmission. We also surveyed residue preferences in HIV at the SIV/SHIV signature sites. Four sites of gp120 showed significant selection, and an additional two sites showed a similar trend. Therefore, the six sites clearly differentiate T/F viruses from the majority of circulating variants in the stocks. The selection of SIV/SHIV could be inferred reasonably across both vaccinated and unvaccinated subjects, with infections resulting from vaginal, rectal, and intravenous routes of transmission and regardless of viral dosage. The evidence for selection in SIV and SHIV T/F variants is strong and plentiful, and in HIV the evidence is suggestive though commensurate with the availability of suitable data for analysis. Two of the signature residues are completely conserved across the SIV, SHIV, and HIV variants we examined. Five of the signature residues map to the C1 region of gp120 and one to the signal peptide. Our data raise the possibility that C1, while governing the association between gp120 and gp41, modulates transmission efficiency, replicative fitness, and/or host cell tropism at the level of virus-cell attachment and entry.IMPORTANCEThe present study finds significant evidence of selection on gp120 molecules of SIV/SHIV T/F viruses. The data provide ancillary evidence suggesting the same sites are under selection in HIV. Our findings suggest that the signature residues are involved in increasing the transmissibility of infecting viruses; therefore, they are potential targets for developing a vaccine or other protective measures. A recent study identified the same T/F signature motif but interpreted it as an effect of neutralization resistance. Here, we show that the T/F motif has broader functional significance beyond neutralization sensitivity, because it is present in nonimmune subjects. Also, a vaccine regimen popular in animal trials might have increased the transmission of variants with otherwise low transmission fitness. Our observations might explain why many animal vaccine trials have not faithfully predicted outcomes in human vaccine trials and suggest that current practices in vaccine design need to be reexamined accordingly.