Background:  Highly active antiretroviral therapy (HAART) of HIV-1-infected individuals has dramatically decreased the mortality and morbidity of chronic HIV-1 infection.  Toxicity, accessibility, and affordability of prolonged HAART treatment limits its use in both developed and developing countries.  In addition, while continuous HAART treatment does not eradicate HIV-1-infected cells, it does reduce the level of virus-specific immune response, presumably because of the decreased viral replication.  Therefore, when HAART is suspended in HIV-1 chronic infection because of toxic side effects or in the context of a coordinated effort to assess the effect of structured treatment interruption (STI), it is not surprising that sustained viral rebound occurs in most individuals. 

Methods: A cohort of rhesus macaques chronically infected with the highly pathogenic SIV251 was subjected to continuous antiretroviral therapy (ART) for 8 months.  Of these, a group of macaques was vaccinated with 2 highly attenuated poxvirus vector-based vaccines, 1 expressing the structural SIVmac Gag-Pol-Env protein (NYVAC-SIV-gpe) and the other expressing a novel chimeric fusion protein, generated from the Rev-Tat-Nef open reading frame (NYVAC-SIV-rtn).  Another group of macaques received the same vaccines in addition to daily low dose of IL-2 and an additional control group was mock vaccinated.  In each group, genetically characterized Mamu-A*01 positive macaques were included. 

Results: Vaccination resulted in a significant expansion of the Mamu-A*01 restricted CD8+ T cell response to the immunodominant Gag epitope measured by tetramer staining as well as other virus specific responses measured as IFN- production following in vitro stimulation with peptide pools encompassing almost entirely the SIVmac proteins.  IL-2 significantly expanded further the response to the immunodominant Gag epitope.  Following ART suspension, viral rebound was contained significantly better in vaccinated macaques than in the control macaques.  Containment of viral rebound correlated with the early expansion of virus specific CD8+ T-cell response, which occurred earlier and was of greater magnitude in vaccinated macaques in comparison with control macaques. 

Conclusions: The data provide the proof of concept that therapeutic vaccination ameliorates the virological outcome following ART suspension in an animal model that best predicts HIV-1 infection of humans.  These data support testing this and other vaccine modalities able to elicit/expand virus specific CD8+ T-cell responses in HIV-1-infected individuals.