A Replication-Competent Adenovirus-Human Immunodeficiency Virus (Ad-HIV)tatand Ad-HIVenvPriming/Tat and Envelope Protein Boosting Regimen Elicits Enhanced Protective Efficacy against Simian/Human Immunodeficiency Virus SHIV_89.6PChallenge in Rhesus Macaques

Abstract

We previously demonstrated that replication-competent adenovirus (Ad)-simian immunodeficiency virus (SIV) recombinant prime/protein boost regimens elicit potent immunogenicity and strong, durable protection of rhesus macaques against SIV mac251 . Additionally, native Tat vaccines have conferred strong protection against simian/human immunodeficiency virus SHIV 89.6P 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-human immunodeficiency virus (HIV) tat and boosting with the Tat protein would elicit protection against SHIV 89.6P . We also evaluated a Tat/Env regimen, adding an Ad-HIV env 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-HIV tat, -HIV env, -SIV gag, and -SIV nef recombinants and Tat, Env, and Nef proteins. All regimens were immunogenic. A hierarchy was observed in enzyme-linked immunospot responses (with the strongest response for Env, followed by Gag, followed by Nef, followed by Tat) and antibody titers (with the highest titer for Env, followed by Tat, followed by Nef, followed by Gag). Following intravenous SHIV 89.6P challenge, all macaques became infected. Compared to controls, no protection was seen in the Tat-only group, confirming previous reports for rhesus macaques. However, the multigenic group blunted acute viremia by 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 < 0.0001). The strikingly greater reduction in the Tat/Env group than in the multigenic group (P ‫؍‬ 0.014) was correlated with Tat and Env binding antibodies. Since prechallenge anti-Env antibodies lacked SHIV 89.6P -neutralizing activity, other functional anti-Env and anti-Tat activities are under investigation, as is a possible synergy between the Tat and Env immunogens.

Comparative study of Tat vaccine regimens in Mauritian cynomolgus and Indian rhesus macaques: Influence of Mauritian MHC haplotypes on susceptibility/resistance to SHIV89.6P infection

“…When corrected for multiple comparisons in a multi-arm vaccine study, this protection was no longer statistically significant [44]. In the cynomolgus model, however, MHC class IB haplotypes were seen to influence the course of SHIV 89.6P infection.…”

“…Immunizations with Tat plus Rev and Tat plus other nonstructural HIV gene products have shown protection against SIV [45,46]. A potential synergy between Tat and Env leading to enhanced protective efficacy in rhesus macaques against SHIV 89.6P was recently reported [44]. Prospective studies using Tat-based vaccine strategies are being conducted in non-human primates typed to control for host susceptibility/resistance factors.…”

“…The significantly higher peak Tat-specific T cell proliferative responses seen in vaccinated macaques with the resistant haplotypes prior to challenge suggest cellular immunity should be further explored as a possible mechanism for the observed resistance. Results of the haplotype analysis and vaccine evaluations, together with reports showing that vaccines targeting Tat in combination with other viral proteins elicit good protective efficacy in non-human primates [44][45][46], suggest that HIV Tat vaccines might be best exploited in combination with other viral antigens.…”

Differential CD4+versus CD8+T-Cell Responses Elicited by Different Poxvirus-Based Human Immunodeficiency Virus Type 1 Vaccine Candidates Provide Comparable Efficacies in Primates

“…However, vaccine-induced T-cell and humoral immune responses were not sufficient to protect animals from SHIV 89.6p infection, but immunized animals that became infected were protected from disease progression for more than a year (66 weeks), while the majority of control animals developed evidence of AIDS-like disease. Others also have previously shown vaccine-induced control of the SHIV 89.6P load and protection from disease progression (3,8,19,21,24). It is possible that protection is relatively easy to induce in the challenge model used (25).…”

HIV-1 Tat-Based Vaccines: An Overview and Perspectives in the Field of HIV/AIDS Vaccine Development

“…Also, a replication-defective adenovirus (Ad)-type 5 (Ad5)-HIV tat vaccine (86 aa) failed to protect rhesus macaques against homologous SHIV 89.6P challenge administered intravenously [180]. Finally, other studies in rhesus macaques showed that priming with a replication-competent Ad5-HIV tat vector and boosting with the Tat protein (86 aa) did not protect against intravenous challenge with homologous SHIV 89.6P [181]. Although the reasons for these conflicting results are not known, it is likely that the different outcomes of infection may reflect species differences with regard to immunogenicity or host resistance factors; difference in vaccine characteristics; immunization protocol; timing and route of administration; delivery systems; and/or type, dose, and route of administration of the challenge virus.…”