Recent evidence suggests that the innate immune response plays an important role in controlling the initial infection and spread of HIV. Natural killer (NK) cells and dendritic cells (DCs) both function as first defenders against assault by invading pathogens and are likely involved in immune surveillance against HIV infection. Previously, we and others have shown that specific NK cell subsets and their associated inhibitory and activating receptors exhibit abnormal phenotype and function in HIV-infected individuals. In the present study, we are investigating whether these abnormalities affect the bidirectional interaction between NK cells and DCs during the initial stages of HIV infection. A growing number of in vitro studies have shown that NK cells and DCs communicate and interact with one another during both the innate and adaptive immune responses. An inflammatory insult such as that initiated by virus infection at mucosal surfaces results in the release of a common set of chemokines that mediate the rapid recruitment of NK and DC cells. The bidirectional crosstalk between NK cells and DCs at these inflammatory sites mostly occurs through cell-cell interactions and leads to activation of both cell types. Early during activation and following antigen uptake, immature DCs (iDCs) undergo maturation and secrete various cytokines such as IL-12, that amplify NK cell activation. Activated NK cells release important antiviral cytokines (IFN-gamma TNF-alpha, GM-CSF) leading to reciprocal activation and maturation of iDCs. Mature DCs (mDCs) can then migrate to regional lymph nodes and acquire further effector functions such as priming T cells. As iDCs mature, more NK cells are recruited and activated, and the population of NK cells eventually overtakes that of iDCs. Activated NK cells also acquire the ability to directly kill iDCs. While mDCs are resistant to NK-mediated lysis, iDCS that do not achieve an appropriate level of maturation are lysed by NK cells. Thus, lysis of iDCs might represent a survival mechanism aimed at both reducing the DC-triggered immune response, and selecting DCs that are highly efficient in presenting antigen and stimulating the adaptive immune response. Despite their normal phenotype, mDCs derived from HIV-1 infected viremic individuals have altered biology and function. During active HIV-1 replication, mDCs show a decreased production of several cytokines and chemokines, and an impaired ability to prime T-cells despite maintaining the ability to process antigen. In particular, a significant decrease in IL-12 production by mDCs likely leads to lower levels of NK cell activation, which in turn, leads to secretion of significantly lower amounts of IFN-gamma, TNF-alpha, and GM-CSF;cytokines that are critical for DC maturation. Under physiologic conditions, the killing of iDCs requires NKp30, an activating NK cell receptor, and a sub-population of NK cells that are NKG2Apos and KIRsneg, denoting inhibitory NK cell receptors that bind non-classical HLA-E and classical HLA A/B/C, respectively. In chronically HIV-1 infected viremic patients, NK cells demonstrate a decreased expression of NKp30 and either conserved or increased cell surface expression of KIRs. In contrast, NKG2A expression is significantly decreased in NK cells. Moreover, in NK cells from HIV-1 viremic individuals, expansion of an unusual subset of CD56neg/CD16pos (CD56neg) cells has been observed. Such expansion is rare in uninfected donors and in aviremic individuals who have received antiretroviral therapy (ART) for 2 years or longer. The cell surface expression of NKp30 and NKG2A receptors is either negative or very low on CD56neg NK subpopulations, whereas KIRs are highly expressed. These NK cell receptor phenotypic changes lead to a defect in activated NK cell killing of iDCs. Subsequently, iDCs undergoing HIV-driven aberrant maturation are still able to migrate to lymph nodes, due to the conserved or increase expression of the chemokine, CCR7. Once they arrive in the secondary lymphoid compartments, however, mDCs are unable to prime T cells for an effective adaptive immune response. Finally, the decreased production of beta_chemokines by NK cells and decreased secretion of IL-10 by mDCs in HIV-1 infected viremic individuals could enhance the viral replication of HIV-1 and further spread the infection to several target cells and tissues.