Primary sooty mangabey simian immunodeficiency virus and human immunodeficiency virus type 2 nef alleles modulate cell surface expression of various human receptors and enhance viral infectivity and replication
Primary sooty mangabey simian immunodeficiency virus and human immunodeficiency virus type 2 nef alleles modulate cell surface expression of various human receptors and enhance viral infectivity and replication
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DOI：
10.1128/jvi.79.16.10547-10560.2005
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发表时间：
2005-08-01
影响因子：
5.4
通讯作者：
Kirchhoff, F
中科院分区：
文献类型：
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作者：
Münch, J;Schindler, M;Kirchhoff, F
致病性猴免疫缺陷病毒（SIV）mac 239克隆的nef基因已得到很好的表征。然而，很少有人知道nef等位基因的功能来自自然SIVsm感染的白眉猴（Cercocebus atys）和人类免疫缺陷病毒2型（HIV-2）感染的个人。为了解决这个问题，我们证明，与SIVmac 239 nef类似，初级SIVsm和HIV-2 nef等位基因下调人CD 4、CD 28、CD 3和I类或11类主要组织相容性复合体的细胞表面表达（分别为MHC-I或MHC-II）分子，上调与未成熟MHC-II相关的不变链（Ii）的表面表达，抑制早期T细胞活化事件，并增强病毒粒子的感染性。两者也刺激病毒复制，尽管HIV-2 nef等位基因在该测定中的活性低于STVsm nef等位基因。突变分析表明，SIV或HIV-2 Nef的C近端环中基于双亮氨酸的分选基序对于其对CD 4、CD 28和Ii的作用至关重要，但对于下调CD 3、MHC-I和MHC-II的作用则不重要。SIV和HIV-2 Nef的C末端是MHC-I下调所唯一需要的，进一步证明了类似的功能是由来自不同灵长类慢病毒组的Nef蛋白中的不同结构域介导的。我们的研究结果表明，没有八个Nef功能的调查已经获得了新的跨物种传播后，SIVsm从自然感染的白眉猴到人类或猕猴。值得注意的是，HIV-2和SIVsm nef等位基因有效地下调CD 3和C28表面表达，并且比HIV-1 nef等位基因更有效地抑制T细胞活化。Nef功能的这些差异可能导致在HIV-2感染的人类个体中观察到的免疫激活水平相对较低。
The nef gene of the pathogenic simian immunodeficiency virus (SIV) mac239 clone has been well characterized. Little is known, however, about the function of nef alleles derived from naturally SIVsm-infected sooty mangabeys (Cercocebus atys) and from human immunodeficiency virus type 2 (HIV-2) -infected individuals. Addressing this, we demonstrate that, similarly to the SIVmac239 nef, primary SIVsm and HIV-2 nef alleles down-modulate cell surface expression of human CD4, CD28, CD3, and class I or 11 major histocompatibility complex (MHC-I or MHC-II, respectively) molecules, up-regulate surface expression of the invariant chain (Ii) associated with immature MHC-II, inhibit early T-cell activation events, and enhance virion infectivity. Both also stimulate viral replication, although HIV-2 nef alleles were less active in this assay than STVsm nef alleles. Mutational analysis showed that a dileucine-based sorting motif in the C-proximal loop of SIV or HIV-2 Nef is critical for its effects on CD4, CD28, and Ii but dispensable for down-regulation of CD3, MHC-I, and MHC-II. The C terminus of SIV and HIV-2 Nef was exclusively required for down-modulation of MHC-I, further demonstrating that analogous functions are mediated by different domains in Nef proteins derived from different groups of primate lentiviruses. Our results demonstrate that none of the eight Nef functions investigated had been newly acquired after cross-species transmission of SIVsm from naturally infected mangabeys to humans or macaques. Notably, HIV-2 and SIVsm nef allelles efficiently down-modulate CD3 and C28 surface expression and inhibit T-cell activation more efficiently than HIV-1 nef allelles. These differences in Nef function might contribute to the relatively low levels of immune activation observed in HIV-2-infected human individuals.