"HIV is an urgent global health problem and a safe and effective vaccine is desperately required. Although many studies have shown that the innate immune system, and in particular, natural killer (NK) cells play a central role in determining the quality of the host immune response to HIV -1, the full host beneficial potential of the anti-HIV-1 NK-mediated activity can not be realized in vivo, as NK cells function becomes compromised in a majority of HIV-1 infected individuals. Several previous experience with HIV-1 infected patients, indicate the significant changes in the redistribution of NK cell subset in the peripheral circulation towards the dysfunctional subpopulation of NK cell. It is likely that the redistribution of NK cell towards this aberrant population may contribute to the observed lack of NK cell function over the course of HIV-1 infection. However, changes in NK cell subset distributions and in effector functions in different anatomical sites and tissues, in healthy donors and in HIV-1 patients, at different stages of HIV-1 infection have been poorly characterized and require further investigation. Given that NK cell are found in female reproductive and in gastrointestinal tracts and that these mucosal layers can play critical roles in the course of HIV-1 infection: as the site of the HIV-1 invasion, as the mother-to-child transmission site, and as the reservoir and important source of virus in HIV-1 infected patients, we propose a multidisciplinary “translational research” project that will exploit: (i) the correlation between tissue-specific distribution of NK cell subpopulation(s) and different stages of HIV-1 infection, (ii) the source of functional and molecular dysfunctions of tissue-specific NK cell subpopulation(s) and their relevance in HIV-1 pathogenesis, (iii) the strategies that virus utilize in local undergoing infections in order to avoid killing by NK cells."