Natural Killer (NK) cells, important components of the innate, or non-adaptive, immune response, exert a prompt cytolytic response against neoplastic cells or virus-infected cells. In HIV infection, NK cells may play a primary role in the first line of defense against the initial replication and dissemination of the virus. However, recent studies have shown that HIV-infected individuals have altered NK cell phenotypes and functions that might negatively influence the course and severity of the disease. The primary objective of this study is to understand the functional defects in NK cells during the course of HIV infection and to attempt to delineate, using non-human primates as a model, the phenotypic nature of NK cells in HIV pathogenesis. Development of a nonhuman primate model to investigate the role of NK cells in the immunopathogenesis of HIV-1 infection has been limited by the lack of appropriate phenotypic markers. In humans, the CD56 and CD16 surface molecules are the primary markers used to phenotype NK subpopulations. The majority of NK cells are CD56dim/CD16+ (approximately 85%-90%), whereas a minority (approximately 10%-15%) are CD56bright/CD16dim/-. Previous studies suggest that NK cells in non-human primates cannot be defined by CD56 expression, because monocytes, rather than lymphocytes, express CD56. Therefore, CD56 is not an appropriate surface antigen for the identification of NK cells in most simian species. Similarly, CD16 alone cannot be used as a marker of simian NK cells because monocytes also express this antigen. We demonstrate for the first time that two anti-human monoclonal antibodies (mAbs), derived from the activating NK receptor, NKp80 and the inhibitory NK receptor, NKG2D, recognize similar receptors on rhesus and pig-tailed macaque NK cells within the lymphocyte compartment of peripheral blood mononuclear cells (PBMCs). Unlike other lymphocytes, NK cells lack specific antigen receptors and, instead, have the ability to use ubiquitous cell-surface molecules to communicate via a pattern of receptors specific for MHC-1 molecules and their targets. In general, binding of inhibitory NK receptors sends a negative signal to NK cells thus avoiding lysis of the target cell. If target cells have down-regulated or altered MHC-1 expression, as often observed during initial viral infection, activating NK receptors send a positive signal to lyse the infected cell. We have shown that human NK receptor mAbs for Nkp80 and NKG2D, alone or in combination with anti-CD16 mAb, can positively identify the entire NK cell population in both macaque species. In addition, both cellular and molecular analyses of these two human NK receptors delineated their conserved function and phenotype in simian models when compared to human models. In redirected cytolytic experiments, mAb mediated- the ligation of NKp80-induced NK cell cytotoxicity, whereas NKG2A inhibited the lysis of target cells by NK cells from macaques. Furthermore, we amplified the simian NKG2A and NKp80 cDNA products, and the two sequences demonstrated 98% nucleotide homology with the human version. This high similarity in cDNA sequences between humans and non-human primates was also reflected in the encoded NKG2A and NKp80 proteins, whose functional sites were highly conserved in simians.