Cloning and Analysis of Sooty Mangabey Alternative Coreceptors That Support Simian Immunodeficiency Virus SIVsmm Entry Independently of CCR5
Cloning and Analysis of Sooty Mangabey Alternative Coreceptors That Support Simian Immunodeficiency Virus SIVsmm Entry Independently of CCR5
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DOI：
10.1128/jvi.06415-11
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发表时间：
2012-01-01
影响因子：
5.4
通讯作者：
Collman, Ronald G.
中科院分区：
文献类型：
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作者：
Elliott, Sarah T. C.;Riddick, Nadeene E.;Collman, Ronald G.
感染猴免疫缺陷病毒SIVsmm的自然宿主白眉猴（SM）尽管有高病毒血症，但不会发展为AIDS。SM和其他自然宿主在CD4（+）T细胞上表达非常低水平的CCR5，我们最近发现SIVsmm感染和稳健的复制发生在遗传上缺乏CCR5的SM体内，表明使用了额外的进入途径。SIVsmm在体外使用几种人源的替代辅助受体，但SM源的哪些分子支持进入尚不清楚。我们从SM克隆了一组推定的辅助受体，并通过携带来自多种SIVsmm亚型的Env的假型，与smCD4一起检测其介导感染的能力。smCXCR6支持所有SIVsmm分离株的有效感染，其进入水平与smCCR5相当，而smGPR15使所有分离株以中等水平进入。smGPR1和smAPJ支持低和可变进入，而smCCR2b、smCCR3、smCCR4、smCCR8和smCXCR4不被大多数分离株使用。相比之下，来自罕见感染SM的SIVsmm具有严重的CD4（+）T细胞损失，先前报道已扩大使用人类辅助受体，包括CXCR 4，有效地使用smCXCR 4，smCXCR 6和smCCR 5，并且还表现出通过smCCR 3，smCCR 8，smGPR 1，smGPR 15和smAPJ的稳健进入。smCD 4的两个已知等位基因的进入相似。这些替代的辅助受体，特别是smCXCR6和smGPR15，可能支持在具有限制性CCR5表达的SM以及遗传上缺乏CCR5的SM中的病毒复制。确定这些分子在SM CD4（+）亚群上的表达可以描绘出能够支持SIVsmm复制而不损失CD4（+）T细胞的不同天然宿主靶细胞群。
Natural host sooty mangabeys (SM) infected with simian immunodeficiency virus SIVsmm do not develop AIDS despite high viremia. SM and other natural hosts express very low levels of CCR5 on CD4(+) T cells, and we recently showed that SIVsmm infection and robust replication occur in vivo in SM genetically lacking CCR5, indicating the use of additional entry pathways. SIVsmm uses several alternative coreceptors of human origin in vitro, but which molecules of SM origin support entry is unknown. We cloned a panel of putative coreceptors from SM and tested their ability to mediate infection, in conjunction with smCD4, by pseudotypes carrying Envs from multiple SIVsmm subtypes. smCXCR6 supported efficient infection by all SIVsmm isolates with entry levels comparable to those for smCCR5, and smGPR15 enabled entry by all isolates at modest levels. smGPR1 and smAPJ supported low and variable entry, whereas smCCR2b, smCCR3, smCCR4, smCCR8, and smCXCR4 were not used by most isolates. In contrast, SIVsmm from rare infected SM with profound CD4(+) T cell loss, previously reported to have expanded use of human coreceptors, including CXCR4, used smCXCR4, smCXCR6, and smCCR5 efficiently and also exhibited robust entry through smCCR3, smCCR8, smGPR1, smGPR15, and smAPJ. Entry was similar with both known alleles of smCD4. These alternative coreceptors, particularly smCXCR6 and smGPR15, may support virus replication in SM that have restricted CCR5 expression as well as SM genetically lacking CCR5. Defining expression of these molecules on SM CD4(+) subsets may delineate distinct natural host target cell populations capable of supporting SIVsmm replication without CD4(+) T cell loss.