This study set out to characterize the unique features of natural lentivirus infection in chimpanzees over time. The virologic and serologic characteristics of this infection were followed longitudinally in a naturally infected chimpanzee together with a small cohort of experimentally HIV-1-infected chimpanzees. The subsequent isolates from the naturally infected chimpanzee were all non-syncytium forming (NSI) versus syncytium forming in the experimentally infected animals. In contrast to HIV-1-infected chimpanzees virus load was higher and plasma viremia occurred but in a cyclic pattern. Serologic follow-up suggested the development of neutralizing antibodies with subsequent escape of new isolates. Interestingly, the sequence of the principal neutralizing (V3 loop) domain (of HIV-1) remained constant over time. Antibodies to peptides from the V3 loop were type specific. The occurrence of persistent, fluctuating plasma viremia and NSI-type virus variants of this natural lentivirus infection are unique characteristics not previously reported in experimentally infected chimpanzees.