Schmökel Jan, Li Hui, Bailes Elizabeth, Schindler Michael, Silvestri Guido, Hahn Beatrice H, Apetrei Cristian, Kirchhoff Frank
Institute of Virology, University of Ulm, 89081 Ulm, Germany.
Retrovirology. 2009 Apr 9;6:36. doi: 10.1186/1742-4690-6-36.
SIVsmm is a simian immunodeficiency virus that persists efficiently without causing disease in naturally infected sooty mangabeys (SMs) but induces AIDS upon cross-species transmission to humans and macaques. Current phylogenetic data indicate that SIVsmm strains comprise a highly diverse group of viruses that can be subdivided into different lineages. Since only certain SIVsmm strains have successfully crossed the species barrier to humans and macaques, the question has been raised whether there are lineage specific differences in SIVsmm biology. In the present study we examined whether representatives of five different SIVsmm lineages show differences in the function of the accessory Nef protein, which plays an important role in viral persistence, transmission and pathogenesis.
We found that nef alleles from all SIVsmm lineages down-modulated CD4, MHC-I, CD28 and CD3 and up-regulated the invariant chain (Ii) associated with immature MHC-II molecules in human-derived cells. Moreover, they generally suppressed the responsiveness of virally infected T cells to activation, enhanced virion infectivity and promoted virus replication in human peripheral blood mononuclear cells. The functional activity of these nef alleles in the various assays varied substantially between different strains of SIVsmm but quantitative analyses did not reveal any significant lineage-specific differences in Nef function.
Nef alleles from different lineages of SIVsmm do not require adaptive changes to be functionally active in human cells. Strain rather than lineage-specific differences in Nef function may impact the virological and immunological feature of SIVsmm in SMs and possibly affected viral fitness and pathogenicity in human and macaque hosts.
猴免疫缺陷病毒（SIVsmm）是一种猿猴免疫缺陷病毒，在自然感染的黑猩猩中能高效持续存在且不引发疾病，但跨物种传播给人类和猕猴后会诱发艾滋病。当前的系统发育数据表明，SIVsmm毒株构成了一组高度多样化的病毒，可细分为不同的谱系。由于只有某些SIVsmm毒株成功跨越物种屏障传播给人类和猕猴，因此有人提出疑问，SIVsmm生物学特性是否存在谱系特异性差异。在本研究中，我们检测了五个不同SIVsmm谱系的代表毒株在辅助蛋白Nef功能上是否存在差异，Nef蛋白在病毒持续存在、传播及发病机制中发挥重要作用。
我们发现，来自所有SIVsmm谱系的nef等位基因在人源细胞中下调CD4、MHC-I、CD28和CD3，并上调与未成熟MHC-II分子相关的恒定链（Ii）。此外，它们通常会抑制病毒感染的T细胞对激活的反应性，增强病毒粒子的感染性，并促进病毒在人外周血单核细胞中的复制。这些nef等位基因在各种检测中的功能活性在不同的SIVsmm毒株之间有很大差异，但定量分析未发现Nef功能存在任何显著的谱系特异性差异。
来自不同SIVsmm谱系的nef等位基因在人细胞中发挥功能活性不需要适应性变化。Nef功能的毒株特异性而非谱系特异性差异可能会影响SIVsmm在黑猩猩中的病毒学和免疫学特征，并可能影响其在人类和猕猴宿主中的病毒适应性和致病性。
