Recent evidence suggests a much higher prevalence of human immunodeficiency virus type 1 (HIV-1) recombinants than previously anticipated. These recombinants arise from secondary HIV infections in individuals already infected with the virus. It remains unclear why some individuals acquire secondary HIV-1 infections and others do not. To address this question, a study was undertaken of a small cohort of chimpanzees with well-defined HIV-1 infection. After exposure to an infectious dose of heterologous primary isolate, 4 of 8 HIV-1 seropositive chimpanzees resisted secondary infection, whereas 2 naive controls became readily infected. Only animals who were immunologically boosted were protected. Protection from heterologous secondary exposure appeared to be related to the repertoire of the cytolytic CD8(+) T cell responses to HIV-1. Data suggested that immunologic boosting by HIV-1 antigens or exposure to subinfectious doses of virus may be important events in sustaining sufficient immunity to prevent secondary infections from occurring.