Natural killer (NK) cells direct cytotoxicity against tumor or virally infected cells. NK cell-mediated cytotoxicity is stimulated by several activating receptors associated with the signaling adapter DNAX activation 12/killer cell-activating receptor-associated protein (DAP12). NKp44 is a natural cytotoxicity receptor that is is expressed on IL-2-activated human NK cells and may contribute to the increased efficiency of NK cells to mediate tumor cell lysis. NKp44 is composed of one Ig-like extracellular domain, a transmembrane segment, and a cytoplasmic domain. Prolactin up-regulates and cortisol down-regulates the surface expression of NKp44 at the transcriptional level. A cellular ligand for NKp44 (NKp44L) is expressed during HIV-1 infection and is correlated with the progression of CD4+ T cell depletion and an increase of viral load. This implicates NKp44 as a therapeutic agent that may aid in the progress towards a vaccine for HIV-1 infection.