Although lymphocytes expressing the CD4 surface receptor for HIV-1 have been identified as the principal target of the virus, the extent to which infection of other cell types of the immune system contributes to immunodeficiency is unknown. We investigated the cell types in peripheral blood infected with HIV and the relation of viral load in different subsets to disease progression.The study group consisted of 16 HIV-infected individuals, eight of whom had clinically defined AIDS with CD4 cell counts less than 200/microL blood. The main component subsets of peripheral blood mononuclear cells were purified by magnetic bead separation, and included CD4 and CD8 lymphocytes, B lymphocytes, monocytes, and dendritic cells. HIV proviral sequences within these separate populations were quantified by limiting-dilution nested polymerase chain reaction.HIV-1 proviral sequences were detected in T-helper cells, cytotoxic T cells, dendritic cells, and monocytes. CD4 T lymphocytes constituted the main reservoir of HIV in all but one of the symptom-free individuals studied (those with CD4 count > 200/microL). However, in all the individuals with CD4 counts of less than 200/microL, most infected cells within the peripheral blood mononuclear cell fraction were either dendritic cells or CD8 lymphocytes. Infection of CD8 cells accounted for between 66% and 97% of total proviral load in five of the eight AIDS patients. A strong inverse relation between total CD8 count and the frequency of CD8 T-lymphocyte infection was found.This study provides evidence for widespread infection of lymphocytes of the CD8 phenotype, indicating that HIV-1 has a broader tropism for different cell types in vivo than described for cultured virus. Infection of CD8 cells may contribute to the decline of this subset upon disease progression in HIV-infected individuals. Infection of CD8 cells may or may not occur by a non-CD4-dependent mechanism of virus entry.