We have reported the presence of a CD4+ subpopulation of Natural Killer cells (NK) in humans. These cells also express HIV coreceptors CCR5 or CXCR4 and are infectable by HIV-1. Infection is productive and persistent in vitro and in vivo. Infected people under therapy have evidence of viral DNA in their NK pool. In vitro experiments show that the NK compartment is important for virus propagation, since HIV-1 growth is significantly reduced in PBMC depleted of NK cells. This reduction was observed for both R5 and X4 molecular clones of HIV-1. In addition, evidence is presented demonstrating that infected NK cells are killed less efficiently by the virus as compared to T cells. This is reminiscent of macrophage infection, where the virus-infected cells survive for long periods of time. Therefore, few infected NK cells may contribute significantly to the infectious virus produced in vitro. These results further underscore the importance of NK infection for understanding pathogenic mechanisms leading to AIDS, as well as the various reservoirs and sanctuaries for HIV upon antiretroviral treatment.