Two populations of IFN-alpha producing cells (IPC) were examined to determine whether they are coordinately dysregulated in human immunodeficiency virus (HIV) disease. IFN-alpha produced in response to herpes simplex virus (HSV) and Sendai virus (SV) was measured and the frequencies of the IPC were obtained by ELISpot assay. IPC that respond to HSV (natural IFN-alpha producing cells) and those responding to SV (predominantly monocytes) were present, on average, at 7.6 and 138 per 10(4) PBMC in healthy controls, respectively. More patients had a reduced IFN-alpha response to HSV than to SV, and individual patients did not show a decreased response to SV without a decreased response to HSV. Neither IPC function was correlated with CD4+ cell levels. We conclude that the defects in IFN-alpha production in these two cell populations arise independently, possibly due to differences in susceptibility to HIV infection or molecular regulation.