The gag proteins of SIV include the p8 nucleocapsid protein, which contains two cysteine arrays that are involved in viral RNA packaging and in a post-penetration step. Mutations in these arrays render the virus non-infectious. A deletion mutant (M14) of a molecular clone of SIVMne CL8 has been constructed that has a four amino acid deletion in the second cysteine array. This study is designed to test the efficacy of DNA immunizations in the SIV macaque model by immunizing macaques with DNA from the noninfectious viral construct, M14, as a potential AIDS vaccine. Five animals received mutant virus DNA and four controls were injected with vector plasmid DNA lacking the SIV construct. By SIV ELISA, antibody was detected after DNA immunizations, indicating that the mutant proviral DNA was expressed. None of the DNA-inoculated animals showed any signs of a productive SIV infection, indicating that the DNA construct is safe and does not lead to an established infection. Upon challenge, all four control animals became infected. Plasma virus was readily detected by QC-PCR assays at high levels (105 106 genome equivalents/ml) and virus was readily isolated from all four of these control animals. Of the five DNA-immunized animals, no virus was detected in one animal by either virus isolation or QC-PCR. Three of the animals became infected but the virus levels were less than in controls as determined by virus isolation and plasma RNA assays. Virus loads in one immunized animal were indistinguishable from those in control animals. One control animal and one immunized animal developed clinical AIDS and were euthanized in December 1997. The remaining animals are being monitored monthly.