Interferon-alpha (IFN-alpha) generation by peripheral blood mononuclear cells (PBMC) responding in vitro to HSV was first found to be deficient in patients with severe ulcerative herpes simplex virus (HSV) infections early in the AIDS epidemic. Such deficits were soon found to be associated with all opportunistic infections (OI). Further studies during the natural history of HIV infection indicated that OI did not occur so long as IFN generation remained relatively intact. OI occurred only when both IFN-alpha generation and CD4 T cell counts were sufficiently depressed. The IFN-alpha response to HSV was innate, not adaptive. Evidence that the IFN-alpha response to HSV was derived from a rare and previously undefined cell type prompted studies eventually revealing that the IFN-producing cells were identical to the" enigmatic plasmacytoid T cells" described by Lennert in lymphoid tissues in 1958. The normal functions of these cells appear to be diverse, but one such function involves initiation of the Th-1 pathway in response to certain microbial antigens. The IFN-producing cells are now known as plasmacytoid dendritic cells (pDCs), because they differentiate following appropriate stimulation, into type-2 dendritic cells. During therapy for HIV infection, pDCs recover somewhat more rapidly than CD4 T cells to levels associated with resistance to OI, and their renewed response appears closely associated with clinically apparent immune reconstitution. Increased pDCs have been associated with nonprogressor status. In HIV infection and in certain other clinical states, PBMC IFN-alpha generation and pDCs numbers correlate closely, suggesting that numerical depletion of circulating pDCs is an important component of the immune deficiency of AIDS. Losses of pDCs during HIV progression and repletion during antiretroviral therapy could be involved in both the progressive loss and reconstitution of the Th-1 pathway.