Meissner Eric G, Duus Karen M, Gao Feng, Yu Xiao-Fang, Su Lishan
Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC 27599, USA.
Virology. 2004 Oct 10;328(1):74-88. doi: 10.1016/j.virol.2004.07.019.
Loss of T cell homeostasis usually precedes the onset of AIDS. We hypothesized that rapid progressors may be transmitted with HIV-1 that is particularly able to perturb T cell homeostasis. To this end, we have tested two transmitted, syncytium-inducing (SI) viral isolates from a rapid progressor in two thymus models. One of the isolates (R3A) exhibited markedly rapid kinetics of replication and thymocyte depletion. These phenotypes mapped to the envelope, as a recombinant NL4-3 virus encoding the R3A envelope had similar phenotypes, even in the absence of nef. Notably, the viruses with high pathogenic activity in the thymus (R3A and NL4-R3A) did not show enhanced replication or cytopathicity in PHA-stimulated PBMCs. Furthermore, NL4-R3A did not enhance replication of the coinfected NL4-3 virus in the thymus, suggesting an intrinsic advantage of the R3A envelope. The R3A envelope showed higher entry activity in infecting human T cells and in depleting CD4+ thymocytes when expressed in trans. These data suggest that SI viruses with unique envelope functions which can overcome barriers to transmission may hasten disease progression by perturbing T cell homeostasis.
T细胞稳态的丧失通常先于艾滋病的发病。我们推测，快速进展者可能感染了特别能够扰乱T细胞稳态的HIV-1。为此，我们在两种胸腺模型中测试了来自一名快速进展者的两种传播性合胞体诱导（SI）病毒分离株。其中一种分离株（R3A）表现出明显快速的复制动力学和胸腺细胞耗竭。这些表型定位于包膜，因为编码R3A包膜的重组NL4-3病毒具有相似的表型，即使在没有nef的情况下也是如此。值得注意的是，在胸腺中具有高致病活性的病毒（R3A和NL4-R3A）在PHA刺激的外周血单核细胞（PBMC）中并未显示出增强的复制或细胞病变效应。此外，NL4-R3A并未增强共感染的NL4-3病毒在胸腺中的复制，这表明R3A包膜具有内在优势。当R3A包膜通过反式表达时，在感染人T细胞和耗竭CD4+胸腺细胞方面表现出更高的进入活性。这些数据表明，具有独特包膜功能、能够克服传播障碍的SI病毒可能通过扰乱T细胞稳态加速疾病进展。
