Alexander Louis, Illyinskii Petr O, Lang Sabine M, Means Robert E, Lifson Jeffrey, Mansfield Keith, Desrosiers Ronald C
Department of Epidemiology and Public Health, Yale University School of Medicine, New Haven, Connecticut, USA.
J Virol. 2003 Jun;77(12):6823-35. doi: 10.1128/jvi.77.12.6823-6835.2003.
Most rhesus macaques infected with simian immunodeficiency virus SIVmac239 with nef deleted (either Delta nef or Delta nef Delta vpr Delta US [Delta 3]) control viral replication and do not progress to AIDS. Some monkeys, however, develop moderate viral load set points and progress to AIDS. When simian immunodeficiency viruses (SIVs) recovered from two such animals (one Delta nef and the other Delta 3) were serially passaged in rhesus monkeys, the SIVs derived from both lineages were found to consistently induce moderate viral loads and disease progression. Analysis of viral sequences in the serially passaged derivatives revealed interesting changes in three regions: (i) an unusually high number of predicted amino acid changes (12 to 14) in the cytoplasmic domain of gp41, most of which were in regions that are usually conserved; these changes were observed in both lineages; (ii) an extreme shortening of nef sequences in the region of overlap with U3; these changes were observed in both lineages; and (iii) duplication of the NF-kappa B binding site in one lineage only. Neither the polymorphic gp41 changes alone nor the U3 deletion alone appeared to be responsible for increased replicative capacity because recombinant SIVmac239 Delta nef, engineered to contain either of these changes, induced moderate viral loads in only one of six monkeys. However, five of six monkeys infected with recombinant SIVmac239 Delta nef containing both TM and U3 changes did develop persisting moderate viral loads. These genetic changes did not increase lymphoid cell-activating properties in the monkey interleukin-2-dependent T-cell line 221, but the gp41 changes did increase the fusogenic activity of the SIV envelope two- to threefold. These results delineate sequence changes in SIV that can compensate for the loss of the nef gene to partially restore replicative and pathogenic potential in rhesus monkeys.
大多数感染了缺失nef基因的猿猴免疫缺陷病毒SIVmac239（Delta nef或Delta nef Delta vpr Delta US [Delta 3]）的恒河猴能够控制病毒复制，不会发展成艾滋病。然而，一些猴子会出现中等水平的病毒载量设定点并发展成艾滋病。当从两只这样的动物（一只Delta nef和另一只Delta 3）中分离出的猿猴免疫缺陷病毒（SIV）在恒河猴中连续传代时，发现来自两个谱系的SIV都能持续诱导中等水平的病毒载量和疾病进展。对连续传代衍生物中的病毒序列分析揭示了三个区域有趣的变化：（i）gp41胞质结构域中预测的氨基酸变化数量异常高（12至14个），其中大多数位于通常保守的区域；两个谱系中均观察到这些变化；（ii）nef序列与U3重叠区域极度缩短；两个谱系中均观察到这些变化；（iii）仅在一个谱系中出现NF-κB结合位点的重复。单独的多态性gp41变化或单独的U3缺失似乎都不是复制能力增加的原因，因为经过基因工程改造以包含这些变化之一的重组SIVmac239 Delta nef，在六只猴子中只有一只诱导出中等水平的病毒载量。然而，感染了同时包含TM和U3变化的重组SIVmac239 Delta nef的六只猴子中有五只确实出现了持续的中等水平病毒载量。这些基因变化并未增加猴白细胞介素-2依赖的T细胞系221中的淋巴细胞激活特性，但gp41变化确实使SIV包膜的融合活性提高了两到三倍。这些结果描绘了SIV中的序列变化，这些变化可以补偿nef基因的缺失，以部分恢复恒河猴中的复制和致病潜力。
