Development of a safe, efficacious vaccine is needed to prevent further spread of the AIDS pandemic. Intravenous (i.v.) inoculation of SIVmac239delta3, a live-attenuated mutant of simian immunodeficiency virus(SIV) deleted in nef, vpr, and NRE, protected approximately 50% of adult macaques from challenge with wild-type SIV. In contrast, oral inoculation of neonatal macaques with SIVmac239delta3 resulted in high virus loads and lethal AIDS. In the present study, we observed that a mother/infant pair inoculated intra-amniotically with SIVmac239delta3 became culture positive several months after virus exposure and eventually developed high virus loads and immune dysfunction. As such, initial evaluation of animals exposed to this live-attenuated prototype vaccine by intra-amniotic inoculation suggested that the host/virus interaction favored the host; however, after long-term follow-up, both the adult and neonate developed a high virus load and immune dysfunction. In another experimental series, neonatal macaques exposed i.v. to SIVmac239delta3 also developed high virus loads and AIDS. Finally, i.v. inoculation of virus into a cohort of adult macaques resulted in a latent period, but after prolonged observation, resurgence of viremia and alteration of T-cell subsets developed. These results indicate that this live-attenuated vaccine prototype retains its full pathogenic potential for neonates and adults in the absence of nef, vpr, and NRE. Therefore, vaccines based upon similar prototypes are dangerous and should not be used to protect humans from AIDS.