We examined the cell-surface expression of chemokine and natural killer (NK) cell inhibitory receptors (iNKRs) on NK cells from individuals with human immunodeficiency virus (HIV) infection, chronic hepatitis C infection, and Wegener's granulomatosis (WG), an inflammatory, granulomatous vasculitis. The expression of CCR5 on NK cells was up-regulated in individuals with HIV viremia and in individuals with active WG, indicating that expression of this receptor is modulated by states of immune activation associated with viral infection and inflammatory or immune-mediated diseases. In contrast, iNKRs were shown to be up-regulated only on NK cells of individuals with HIV viremia, and they returned to a normal level when viremia was controlled with effective antiviral therapy. In individuals with HIV-1 viremia, there was a direct correlation between the level of expression of p58.1, p58.2, and CD94 receptors and plasma HIV viremia, suggesting that ongoing active HIV replication has an effect on the expression of such receptors on NK cells. These results suggest that immune activation leads to abnormal cell-surface expression of chemokine receptors on NK cells, whereas HIV-specific processes account for the up-regulation of iNKRs on NK cells; this may explain the NK cell-functional defects seen in HIV infection.