The role of cell mediated immune mechanisms in the progression of disease in HIV-1 infection is poorly understood. Prospective studies to elucidate such mechanisms and their progressive impairment can be best addressed in the nonhuman primate model of AIDS, due to its close evolutionary relationship to man. In addition, the model provided by experimentally infected macaques susceptible to disease and the naturally infected but disease resistant sooty mangabey offers an ideal platform for comparative analyses. A total of 9 macaques and 3 mangabeys were immunized with keyhole limpet hemocyanin (KLH), tetanus toxoid (TT) and the highly attenuated influenza virus strain A/PR8 prior to challenge with SIVmac251 (6 out of the 9 macaques). Immune responses not only to SIV but also to KLH, TT and influenza were followed throughout the course of infection in order to identify the onset of critical immune dysfunctions following SIV infection. Data accumulated so far, suggest that a rapid loss of antigen specific IFNK response is observed in all infected animals accompanied with a gradual increase in IL-6 response as the monkeys reach the clinically symptomatic stage. Humoral responses established prior to SIV infection did not seem to be affected when compared to uninfected control animals. However, the kinetic of cell mediated response to influenza appeared to correlate with the length of time between infection with SIV and development of AIDS, suggesting a preponderant role for these mechanisms at controlling the primary acute infection.