Combined vaccine modalities for HIV-1 immune therapy in Long-Term Slow-Progressor Rhesus Macaques subjected to ART.

De Giuli Morghen C., Zanotto C., Elli V., Paganini M., Basavecchia V., Neri M. and Radaelli A. Depts. of Medical Pharmacology and Pharmacological Sciences, University of Milan, Milan (Italy).

Background: The broadening of the CD8+ T-cell response is considered to be necessary in both therapeutic and preventive vaccine inasmuch as it may reduce the risk of the immune escape that occurs during viral rebound. We therefore designed immunization regimens to directly compare, in SIVmac251-infected Mamu-A*01-positive Rhesus macaques, the relative immunogenicity of a DNA/poxvirus to a poxvirus/poxvirus immunization. Material and Methods: Two groups of SIV-infected ART-treated Rhesus macaques were immunized with SIVgag/pol-expressing fowlpox vectors to assess their ability to restore the immune response by the ability to induce/expand Mamu-A*01-restricted SIV-specific CD8+ and CD4+ T-helper cells, to produce cytokines and the effector function of virus-specific CD8+ T-cells, and to assess in parallel the durability of the virus-specific immune responses generated by two immunization regimens. Results: The macaques we studied were long-term non-progressors that naturally contained viremia, but were nevertheless treated with a combination of antiviral drugs to assess more carefully the effect of vaccination in the context of ART. The combination of a DNA expressing the gag and pol genes (DNA-SIV-gp) of SIVmac239 followed by a recombinant fowlpox expressing the same SIVmac genes (FP-SIV-gp) was significantly more immunogenic than two immunizations of FP-SIV-gp in SIVmac251-infected macaques treated with ART. The DNA/FP combination significantly expanded and broadened Gag-specific T-cell responses measured by tetramer staining, ELISPOT, and intracellular cytokine staining and measurement of ex vivo cytolytic function. Importantly, the combination of these vaccine modalities also induced a large expansion of Gag-specific CD8- (CD4+) T-cells able to produce TNF-α in most macaques.  Hopefully, this vaccine combination may be useful in the clinical management of HIV-1-infected individuals. Conclusion: These results suggest that a therapeutic immunization can be a useful approach to restore the cell-mediated immunity in SIV-infected animals.