Protection of Macaca nemestrina from disease following pathogenic simian immunodeficiency virus (SIV) challenge: Utilization of SIV nucleocapsid mutant DNA vaccines with and without an SIV protein boost

Molecular clones were constructed that express nucleocapsid (NC) deletion m utant simian immunodeficiency viruses (SIVs) that are replication defective but capable of completing virtually all of the steps of a single viral inf ection cycle. These steps include production of particles that are viral RN A deficient yet contain a full complement of processed viral proteins. The mutant particles are ultrastructurally indistinguishable from wild-type vir us. Similar to a live attenuated vaccine, this approach should allow immuno logical presentation of a full range of viral epitopes, without the safety risks of replicating virus. A total of 11 Macaca nemestrina macaques were i noculated with NC mutant SIV expressing DNA, intramuscularly (i.m.) in one study and i.m. and subcutaneously in another study. Six control animals rec eived vector DNA lacking SIV sequences. Only modest and inconsistent humora l responses and no cellular immune responses were observed prior to challen ge. Following intravenous challenge with 20 animal infectious doses of the pathogenic SIV(Mne) in a long-term study, all control animals became infect ed and three of four animals developed progressive SIV disease leading to d eath. All 11 NC mutant SIV DNA-immunized animals became infected following challenge but typically showed decreased initial peak plasma SIV RNA levels compared to those of control animals (P = 0.0007). In the long-term study, most of the immunized animals had low or undetectable postacute levels of plasma SIV RNA, and no CD4(+) T-cell depletion or clinical evidence of prog ressive disease, over more than 2 years of observation. Although a subset o f immunized and control animals were boosted with SIV(Mne) proteins, no app arent protective benefit was observed. Immunization of macaques with DNA th at codes for replication-defective but structurally complete virions appear s to protect from or at least delay the onset of AIDS after infection with a pathogenic immunodeficiency virus. With further optimization, this may be a promising approach for vaccine development.