Pathogenic simian/human immunodeficiency virus SHIV(KU) inoculated into immunized macaques caused infection, but virus burdens progressively declined with time.

Despite the pressing need for a vaccine against human immunodeficiency virus (HIV), evaluation of the efficacy of any vaccine candidate in human beings will require several years of observation. The reasons for this are that the incubation period and the clinical course of HIV-induced disease are both unpredictably variable and that the immunological correlates of protection against HIV infection and/or disease are not known (16). Evaluation of the concept that a vaccine against HIV could be developed despite the formidable biological properties of this virus has been greatly expedited using macaque models of HIV pathogenesis (5, 6, 8, 9, 22, 23). Use of the simian immunodeficiency virus (SIV) model has pioneered this field and demonstrated that deletion of accessory genes from genomes of pathogenic viruses greatly attenuated the virulence of the latter agents and that use of such viruses as live vaccines induced protection against disease caused by pathogenic strains of SIV (10–13, 31). The SIV/HIV (SHIV)-macaque model was created on the rationale that this virus is biologically closer to HIV than to SIV because it has the envelope of HIV type 1 (HIV-1) (17). Use of the SHIV-macaque system to model vaccine efficacy required the availability of a predictably pathogenic strain of SHIV that could serve as challenge. SHIVKU satisfied this condition because it not only causes both the loss of CD4+ T cells and AIDS but it is also pathogenic after inoculation on the vaginal mucosal surface, thus providing a model of sexually transmitted HIV. Following leads on vaccine development in the SIV system, we deleted the accessory gene vpu from a strain of nonpathogenic SHIV and used this virus as a vaccine to test the concept that an orally inoculated vaccine could induce protection against AIDS caused by vaginally inoculated pathogenic SHIVKU (10). In a previous report we had shown that orally inoculated vaccine virus, ΔvpuSHIVPPc (V-II), caused a transiently productive subclinical systemic infection in all of the macaques and that that this resulted in infection and establishment of vaccine virus DNA in the lymph nodes of the animals. Intravaginal challenge of the six immunized and four nonimmunized animals with SHIVKU resulted in infection in all 10 animals with this virus. However, whereas the nonimmunized animals rapidly developed productive infection followed by the onset of AIDS, the infection with SHIVKU in the six immunized animals was maintained at a minimally productive level that had no pathological effects. Nevertheless, DNA of challenge virus persisted in the lymph nodes of all six animals when examined at 18 weeks postchallenge (10). In this study we report on the nature of the persistent infection caused by the two viruses. All six immunized animals have remained healthy, and all developed and maintained strong antibody and cytotoxic-T-lymphocyte (CTL) responses against both viruses. DNA of the vaccine virus has persisted in lymph nodes of all six animals throughout the observation period. However, whereas the DNA of the challenge virus was also present in all six animals at 18 weeks postchallenge, concentrations of this DNA in the animals progressively decreased with time, and by 63 weeks postchallenge it had become undetectable in four of the six animals. This suggested that the immunization had not only prevented AIDS but also contributed to the gradual decline in the level of challenge virus.