This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The immunogenicity and protective capacity of recombinant, replication-defective herpes simplex virus (HSV) vector with or without DNA priming were examined in rhesus monkeys. Three rhesus monkeys were inoculated with a mixture of replication-defective HSV vectors expressing Gag, Env, and a Tat-Rev-Nef fusion protein of simian immunodeficiency virus (SIV) at weeks 0, 4, 12 and 20. Three other rhesus monkeys were inoculated with a mixture of recombinant DNAs expressing Gag, Env and a Pol-Tat-Nef-Vif fusion protein at weeks 0 and 4 and boosted with the same mixture of HSV vectors at weeks 12 and 20. Anti-SIV antibody responses and neutralizing activity in all six vaccinated monkeys were weak. Cellular responses to SIV were detected in all six monkeys and were significantly higher in the DNA-primed animals following recombinant HSV boosting when measured by IFN-gamma ELISPOT, CM9 Gag tetramer staining, and intracellular cytokine staining. IFN- gamma ELISPOT numbers to Gag and Env exceeded 1000 per 10 to the 6th PBMC and CM9 Gag tetramer staining exceeded 0.8 percent of all CD8+ T lymphocytes in PBMC in the DNA-primed animals after recombinant HSV boosting. Both CD4+ and CD8+ T lymphocyte responses to SIV were induced in the vaccinated monkeys. All six vaccinated monkeys were challenged intravenously at 26 weeks with wild-type, cloned, homologous SIV239. All six vaccinated monkeys became infected with SIV following the challenge. However, the six vaccinated monkeys had significantly lower viral loads than control monkeys following the challenge; at 12 weeks post challenge, there was a 1.6 log difference in mean viral load between control and vaccinated monkeys. Two of the HSV-HSV-HSV-HSV vaccinated monkeys and one DNA-DNA-HSV-HSV vaccinated monkey continue to maintain low viral loads at 24 weeks post challenge. These partially-protected monkeys tended to have higher neutralizing activity on the day of challenge, higher anti-Rev ELISPOT activity on the day of challenge, and a more rapid ELISPOT response to Tat following challenge. These findings support continued study of recombinant herpesviruses as a potentially promising vaccine approach for AIDS.
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