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首页> 外文期刊>AIDS Research and Human Retroviruses >A naturally occurring single amino acid substitution in human TRIM5α linker region affects its anti-HIV type 1 activity and susceptibility to HIV type 1 infection
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A naturally occurring single amino acid substitution in human TRIM5α linker region affects its anti-HIV type 1 activity and susceptibility to HIV type 1 infection

机译：人类TRIM5α接头区域中天然存在的单个氨基酸取代会影响其抗HIV 1型活性和对HIV 1型感染的易感性

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摘要

TRIM5α is a factor contributing to intracellular defense mechanisms against retrovirus infection. Rhesus and cynomolgus monkey TRIM5αs potently restrict HIV-1, whereas human TRIM5α shows weak effects against HIV-1. We investigated the association between a single nucleotide polymorphism in the TRIM5α linker 2 region (rs11038628), which substituted aspartic acid (D) for glycine (G) at position 249, with susceptibility to HIV-1 infection in Japanese and Indian subjects. rs11038628 is rare in Europeans but common in Asians and Africans. Functional analyses were performed by multiple-round replication and single-round assays, and indicated that the G249D substitution attenuated anti-HIV-1 activity of human TRIM5α. A slight attenuation of anti-HIV-2 activity was also observed in TRIM5α with 249D. The predicted secondary structure of the linker region suggested that the 249D substitution extended the α-helix in the neighboring coiled-coil domain, suggesting that human TRIM5α with 249D may lose the flexibility required for optimal recognition of retroviral capsid protein. We further analyzed the frequency of G249D in Japanese (93 HIV-1-infected subjects and 279 controls) and Indians (227 HIV-1-infected subjects and 280 controls). The frequency of 249D was significantly higher among HIV-1-infected Indian subjects than in ethnicity-matched control subjects [odds ratio (OR)=1.52, p=0.026]. A similar weak tendency was observed in Japanese subjects, but it was not statistically significant (OR=1.19, p=0.302). In conclusion, G249D, a common variant of human TRIM5α in Asians and Africans, is associated with increased susceptibility to HIV-1 infection.
机译：TRIM5α是有助于抵抗逆转录病毒感染的细胞内防御机制的因素。恒河猴和食蟹猴TRIM5α有效地限制了HIV-1，而人类TRIM5α对HIV-1的作用较弱。我们调查了在TRIM5α接头2区（rs11038628）中的单核苷酸多态性与日本和印度受试者中HIV-1感染的易感性之间的关联，该区域将天冬氨酸（D）替换为249位的甘氨酸（G）。 rs11038628在欧洲人中很少见，但在亚洲人和非洲人中很常见。通过多轮复制和单轮分析进行功能分析，结果表明G249D取代减弱了人类TRIM5α的抗HIV-1活性。在带有249D的TRIM5α中也观察到抗HIV-2活性的轻微减弱。接头区域的预测二级结构表明249D取代扩展了相邻螺旋结构域中的α-螺旋，表明具有249D的人TRIM5α可能失去了逆转录病毒衣壳蛋白最佳识别所需的灵活性。我们进一步分析了日本人（93名感染HIV-1的受试者和279名对照）和印度人（227名感染HIV-1的受试者和280名对照）中G249D的频率。在受HIV-1感染的印度受试者中，249D的发生频率显着高于种族匹配的对照受试者[几率（OR）= 1.52，p = 0.026]。在日本受试者中观察到类似的弱趋势，但在统计学上不显着（OR = 1.19，p = 0.302）。总之，G249D是在亚洲人和非洲人中人类TRIM5α的常见变体，与HIV-1感染的易感性增加有关。

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