BIV is a lentivirus which is structurally, antigenically and molecularly related to the Human Immunodeficiency Virus-1 (HIV-1), the causative agent of AIDS in man. The early reports associated BIV infection with persistent lymphocytosis, generalized lymphadenopathy and wasting disease. However, controlled studies to define the pathogenesis associated with BIV infection in cattle, are needed. Additionally, the effects of BIV in association with other bovine retroviruses have yet to be reported. Therefore, a study was undertaken to define the pathogenesis of BIV or BIV/BLV infection in calves. Holstein calves, including three BIV inoculated, two BIV/BLV inoculated and four sham inoculated controls were followed from 0-18 months post inoculation (P.I.). Clinical abnormalities in BIV animals were early periodic lymphocytosis and in BIV/BLV, sustained lymphocytosis, periodic fever and diarrhea in BIV calves, lymphadenopathy at 45-60 days P.I. in both BIV and BIV/BLV inoculated, lymphoid depletion at 8 months P.I. with immunocytochemical detection of virus, and depression of lymphocyte blastogenesis assays at multiple time points in both BIV and BIV/BLV inoculated. Additionally, increases in percent circulating CD4+ cells in BIV and BIV/BLV infected calves were observed at 7, 10 and 18 months by flow cytometry, however, increases in absolute numbers of CD4+ cells were present, only in BIV/BLV animals. Serum immunoglobulin G levels were elevated in BIV infected animals, only. In vivo responses to PPD delayed-type hypersensitivity were increased in both BIV and BIV/BLV infected. Histopathology at eighteen months revealed mild lymphoid hyperplasia in peripheral lymph nodes of BIV infected and marked hyperplasia in BIV/BLV infected, with immunocytochemical detection of virus antigen. In the brains of BIV and BIV/BLV infected animals there were scattered perivascular cuffs of inflammatory cells. Immunocytochemically BIV antigen was localized in the cortex and midbrain. The results of this study suggest that, BIV alone or in combination with BLV cause transient alterations in immune function as assayed by in vitro and in vivo methods, produces lesions in lymphoid tissues and the CNS. The clinical and pathologic features of BIV infection share similarities with other lentiviral infections of other domestic animals.