The mechanisms of resistance to AIDS development in HIV-1-infected chimpanzees have remained elusive. Unique among chimpanzees naturally or experimentally infected with HIV, several animals of the Yerkes cohort have progressed to clinical AIDS with selection of isolates showing increased pathogenicity for chimpanzees. We compared progressors vs. nonprogressors among the HIV-infected chimpanzees that made up this cohort, eight of which have been infected with HIV-1 for over 14 years. The additional two progressors were infected de novo with chimpanzee-pathogenic HIV, rapidly leading to a progressor status. Nonprogressors were characterized by normal CD4(+) T cell counts and the absence of detectable viremia. In contrast, progressor chimpanzees had relatively high plasma viral loads associated with a dramatic loss of CD4(+) T cells. The analysis of immune responses showed a similar amplitude and breadth of ELISPOT T cell responses in both groups. HIV-specific proliferative responses were, however, absent in the progressor animals, which also exhibited increased levels of immune activation characterized by elevated levels of the circulating chemokines IP-10 and MCP-1. Of interest was the conservation of potent NK cell activity in all animals, potentially contributing to the extended symptom-free survival of progressor animals. Modest anti-HIV antibody titers were detectable in the nonprogressor group, but these antibodies exhibited good neutralizing activity. In progressors, however, two sets of data were noted: in animals that gradually selected for pathogenic isolates, or that were superinfected, very high neutralizing antibody titers were observed, although none to the pathogenic HIV. In contrast, two animals infected de novo with chimpanzee pathogenic HIV failed to mount an extensive humoral response and both failed to develop neutralizing antibodies to the virus. Taken together, pathogenic HIV infection in chimpanzees is associated with rapid loss of CD4(+) T cells and proliferative responses as well as higher levels of immune activation.