Xu X N, Screaton G R, Gotch F M, Dong T, Tan R, Almond N, Walker B, Stebbings R, Kent K, Nagata S, Stott J E, McMichael A J
Molecular Immunology, Institute of Molecular Medicine, John Radcliffe Hospital, Oxford OX3 9DU, United Kingdom.
J Exp Med. 1997 Jul 7;186(1):7-16. doi: 10.1084/jem.186.1.7.
Inoculation of macaques with live attenuated SIV strains has been shown to protect against subsequent challenge with wild-type SIV. The protective mechanism(s) remain obscure. To study the effect in more detail, we have investigated the role of virus-specific CTL responses in macaques infected with an attenuated SIV strain (pC8), which has a four-amino acid deletion in the nef gene, as compared with the wild-type SIVmac32H clone (pJ5). Cynomolgus macaques infected with pC8 were protected against subsequent challenge with pJ5 and did not develop any AIDS-like symptoms in the 12 months after infection. The pC8-induced protection was associated with high levels of virus-specific CTL responses to a variety of viral antigens. In contrast, pJ5-infected macaques had little, if any, detectable CTL response to the viral proteins after three months. The latter group of macaques also showed increased Fas expression and apoptotic cell death in both the CD4(+) and CD8(+) populations. In vitro, pJ5 but not pC8 leads to an increase in FasL expression on infected cells. Thus the expression of FasL may protect infected cells from CTL attack, killing viral-specific CTLs in the process, and providing a route for escaping the immune response, leading to the increased pathogenicity of pJ5. pC8, on the other hand does not induce FasL expression, allowing the development of a protective CTL response. Furthermore, interruption of the Fas-FasL interaction allows the regeneration of viral-specific CTL responses in pJ5-infected animals. This observation suggests an additional therapeutic approach to the treatment of AIDS.
已证明用减毒活SIV毒株接种猕猴可保护其免受野生型SIV的后续攻击。其保护机制仍不清楚。为了更详细地研究这种效应，我们调查了病毒特异性CTL反应在感染减毒SIV毒株（pC8）的猕猴中的作用，该毒株在nef基因中有四个氨基酸缺失，与野生型SIVmac32H克隆（pJ5）相比。感染pC8的食蟹猴在感染后的12个月内免受pJ5的后续攻击，并且未出现任何类似艾滋病的症状。pC8诱导的保护作用与对多种病毒抗原的高水平病毒特异性CTL反应相关。相比之下，感染pJ5的猕猴在三个月后对病毒蛋白几乎没有（如果有的话）可检测到的CTL反应。后一组猕猴在CD4(+)和CD8(+)群体中还表现出Fas表达增加和凋亡细胞死亡。在体外，pJ5而非pC8导致感染细胞上FasL表达增加。因此，FasL的表达可能保护感染细胞免受CTL攻击，在此过程中杀死病毒特异性CTL，并提供逃避免疫反应的途径，导致pJ5的致病性增加。另一方面，pC8不诱导FasL表达，从而允许产生保护性CTL反应。此外，Fas-FasL相互作用的中断可使感染pJ5的动物体内病毒特异性CTL反应再生。这一观察结果提示了一种治疗艾滋病的额外治疗方法。
