Effects of Virus Burden and Chemokine Expression on Immunity to SHIV in Nonhuman Primates

HIV-1 vaccine candidates are designed to elicit Type 1 immune responses, including cytotoxic T cells and neutralizing antibodies. The type of immune response is influenced by many factors, including the levels of antigen expression and production of cytokines or chemokines; we designed a nonhuman primate study to evaluate the influence of these factors on protective immunity. Recombinant SHIV were engineered to express macrophage inflammatory protein-1 alpha (MIP-1α), regulated upon activation, normal T-cell expressed and secreted (RANTES), or Lymphotactin (Ltn) in place of nef in SHIV 89.6 (SHIV 89.6-MIP-1α , SHIV 89.6-RANTES , SHIV 89.6-Ltn ). The parental virus SHIV 89.6 was included because it replicates to higher titer while still not causing disease. Control groups included animals that received a recombinant SHIV with a truncated chemokine construct (SHIV 89.6-dLtn ) and unvaccinated macaques. After pathogenic challenge with SHIV 89.6pd , animals from groups that received recombinant ( nef -deleted) viruses had peak viremia levels three orders of magnitude lower than unvaccinated controls and increased survival times. Animals that received the original SHIV 89.6 ( nef +) were highly resistant to both intrarectal and intravenous challenge with SHIV 89.6PD , and showed no signs of disease. There were no differences in survival times comparing unvaccinated and SHIV 89.6-dLtn (control) groups, indicating that nef deleted viruses did not provide durable protection in this model. Strongest protection was seen in animals with the highest replicating virus (SHIV 89.6 ), and the lower effect on survival after SHIV 89.6 nef -deleted vaccination, likely reflects differences in replication capacity. The protective effect of nef -deleted virus was partly restored by expressing Type 1 chemokines to augment viral immunity.