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. We previously demonstrated that replication-competent Ad-SIV recombinant prime/protein boost regimens elicit potent immunogenicity and strong, durable protection of rhesus macaques against SIVmac251. Additionally, native Tat vaccines have conferred strong protection against SHIV89.6P challenge of cynomolgus monkeys, while native, inactivated, or vectored Tat vaccines have failed to elicit similar protective efficacy in rhesus macaques. Here we asked if priming rhesus macaques with replicating Ad-HIVtat and boosting with Tat protein would elicit protection against SHIV89.6P. We also evaluated a tat/env regimen, adding an Ad-HIVenv recombinant and envelope protein boost to test whether envelope antibodies would augment acute phase protection. Further, expecting cellular immunity to enhance chronic viremia control, we tested a multigenic group: Ad-HIVtat, -HIVenv, -SIVgag and -SIVnef recombinants and Tat, Env, and Nef proteins. All regimens were immunogenic. A hierarchy was observed in ELISPOT responses (Env gt Gag gt Nef gt Tat) and antibody titers (Env gt Tat gt Nef gt Gag). Following intravenous SHIV89.6P challenge, all macaques became infected. Compared to controls, no protection was seen in the Tat-only group, confirming previous reports. However, the multigenic group blunted acute viremia approximately 1 log (p = 0.017), and both the multigenic and tat/env groups reduced chronic viremia by 3 and 4 logs respectively compared to controls (multigenic, p = 0.0003;tat/env, p lt 0.0001). The strikingly greater reduction in the tat/env compared to the multigenic group (p = 0.014) was correlated with Tat and Env binding antibodies. As pre-challenge anti-Env antibodies lacked SHIV89.6P neutralizing activity, other functional anti-Env and anti-Tat activities are under investigation, as is a possible synergy between Tat and Env immunogens. We are continuing to monitor the remaining animals to assess possible survival differences between the groups.
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