TRIM5alpha Modulates Immunodeficiency Virus Control in Rhesus Monkeys.
TRIM5alpha Modulates Immunodeficiency Virus Control in Rhesus Monkeys.
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DOI：
10.1371/journal.ppat.1000738
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发表时间：
2010-01-22
期刊：
影响因子：
6.7
通讯作者：
Letvin NL
中科院分区：
文献类型：
--
作者：
Lim SY;Rogers T;Chan T;Whitney JB;Kim J;Sodroski J;Letvin NL
某些哺乳动物谱系的细胞质TRIM 5 α蛋白有效识别特定逆转录病毒的传入衣壳，并以物种特异性方式有效限制感染。成功的逆转录病毒已经进化出衣壳，其被天然宿主的TRIM 5 α蛋白识别的效率较低。为了解决TRIM 5 α是否有助于易感宿主物种中逆转录病毒感染的结果，我们研究了恒河猴中TRIM 5多态性对猿猴免疫缺陷病毒（SIV）感染过程的影响。全长TRIM 5 α cDNA来自79只远系交配猴中的每一只并测序。研究了特定TRIM 5等位基因的表达与体外SIV感染细胞的容许性和体内SIV感染的临床后遗症之间的关联。TRIM 5 α B30.2（SPRY）结构域的自然变异影响SIVmac衣壳结合效率和猴细胞对SIVmac感染的体外易感性。我们还显示了SIVmac与TRIM 5的不同等位基因形式的相互作用在体内的重要性，证明了特定的等位基因与SIVmac感染的恒河猴中设定点病毒载量的中位对数差异高达1.3。此外，TRIM 5的这些等位基因形式与受感染猴子的中央记忆（CM）CD 4 + T细胞的丧失程度和进展为AIDS的速度相关。这些发现表明TRIM 5 α在限制灵长类宿主中免疫缺陷病毒感染的复制中起着重要作用。细胞质TRIM 5 α以物种特异性方式限制多种逆转录病毒的复制。在本研究中，我们表明TRIM 5 α不仅仅是逆转录病毒的种属屏障。我们表明，自然发生的B30.2（SPRY）多态性影响逆转录病毒感染。这些观察结果证明了SIV/B30.2（SPRY）在体内相互作用的重要性。这些发现是第一次证明这种病原体/宿主蛋白质在体内相互作用的重要性。重要的是，HIV感染者临床病程的显著变化长期以来一直困扰着生物医学界。大量的研究人员投入了相当大的努力，以确定基因决定的因素可能有助于遏制艾滋病毒的复制，推理的有效控制艾滋病毒传播的决定因素的理解将提供药物和疫苗开发的重要目标。我们在本研究中证明B30.2（SPRY）多态性对艾滋病病毒感染的临床结果有显著影响，突出了TRIM 5 α在控制艾滋病病毒感染方面的非凡重要性。
The cytoplasmic TRIM5α proteins of certain mammalian lineages efficiently recognize the incoming capsids of particular retroviruses and potently restrict infection in a species-specific manner. Successful retroviruses have evolved capsids that are less efficiently recognized by the TRIM5α proteins of the natural hosts. To address whether TRIM5α contributes to the outcome of retroviral infection in a susceptible host species, we investigated the impact of TRIM5 polymorphisms in rhesus monkeys on the course of a simian immunodeficiency virus (SIV) infection. Full-length TRIM5α cDNAs were derived from each of 79 outbred monkeys and sequenced. Associations were explored between the expression of particular TRIM5 alleles and both the permissiveness of cells to SIV infection in vitro and clinical sequelae of SIV infection in vivo. Natural variation in the TRIM5α B30.2(SPRY) domain influenced the efficiency of SIVmac capsid binding and the in vitro susceptibility of cells from the monkeys to SIVmac infection. We also show the importance in vivo of the interaction of SIVmac with different allelic forms of TRIM5, demonstrating that particular alleles are associated with as much as 1.3 median log difference in set-point viral loads in SIVmac-infected rhesus monkeys. Moreover, these allelic forms of TRIM5 were associated with the extent of loss of central memory (CM) CD4+ T cells and the rate of progression to AIDS in the infected monkeys. These findings demonstrate a central role for TRIM5α in limiting the replication of an immunodeficiency virus infection in a primate host. The cytoplasmic TRIM5α restricts the replication of a broad range of retroviruses in a species-specific manner. In the present study we show that TRIM5α is more than a species barrier for retroviruses. We show that naturally occurring B30.2(SPRY) polymorphisms affect retrovirus infection. These observations demonstrate the importance of SIV/B30.2(SPRY) interactions in vivo. These findings are the first demonstration of the importance of such a pathogen/host protein interaction in vivo. Importantly, the striking variability in the clinical course of HIV-infected individuals has long puzzled the biomedical community. A large number of investigators have devoted considerable effort to determine what genetically determined factors might contribute to the containment of HIV replication, reasoning that an understanding of the determinants of effective control of HIV spread will provide important targets for both drug and vaccine development. Our demonstration in the present study that B30.2(SPRY) polymorphisms have a dramatic effect on the clinical outcome of an AIDS virus infection highlight the extraordinary importance of TRIM5α on the control of an AIDS virus infection.
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影响因子：
5.4
作者：
Pal, R;Venzon, D;Franchini, G
通讯作者：
Franchini, G
影响因子：
5.4
作者：
Li, Xing;Sodroski, Joseph
通讯作者：
Sodroski, Joseph
影响因子：
30.8
作者：
Martin, MP;Gao, XJ;Carrington, M
通讯作者：
Carrington, M
DOI：
10.1073/pnas.0403364101
发表时间：
2004-08-10
影响因子：
11.1
作者：
Perron, MJ;Stremlau, M;Sodroski, J
通讯作者：
Sodroski, J
影响因子：
5.4
作者：
Perron, Michel J.;Stremlau, Matthew;Sodroski, Joseph
通讯作者：
Sodroski, Joseph