Functional analyses of natural killer cells in macaques infected with neurovirulent simian immunodeficiency virus

Clearance of HIV and SIV from the peripheral blood by the cellular immune system lessens the viral burden in infected individuals and may have an impact on virus infection of the CNS and the development of CNS lesions. However, the role of immune responses in preventing or limiting CNS infection has not been clearly defined. We investigated the role of natural killer cells in the outcome of SIV infection of macaques as a model for humans with AIDS and HIV encephalitis. in our study, six pig-tailed macaques were infected with the neurovirulent virus, SIV/17E-Fr, and the immunosuppressive virus, SIV/DeltaB670, in a model system that causes rapid progression to AIDS and a high frequency of CNS lesions. NK lytic activity in each macaque was monitored longitudinally. In addition, we enumerated NK cells and tested macaque PBMC for the ability to lyse SIV-infected target cells. We found that there was a significant inverse correlation (P=0.02) between the robustness of NK response and the development of CNS lesions. Animals lacking strong NK cell responses developed more severe CNS lesions than those with robust NK responses did. Furthermore, pre-infection levels of NK activity were predictive of CNS lesion severity. The macaque with the most robust pre-infection NK activity developed no CNS lesions. In these infected macaques, NK activity was shown to be directed against SIV-infected cells. We extended these in vivo findings to delineate precisely which cell type was mediating this SIV-directed lysis. We used both macaque and human cells to demonstrate that the population that mediated anti-SIV and anti-HIV cytolytic effects was NK cells. Furthermore, we showed that this anti-SIV and anti-HIV cytolytic effect was directed at the envelope protein and not gag proteins. Thus, NK cells have the capacity to recognize and lyse cells expressing SIV and HIV antigens. These data support a role for NK cells in the modulation of CNS disease.