| There is an urgent need for a vaccine for AIDS worldwide, particularly in developing countries where vaccination may prove the only affordable and feasible option given limited resources and infrastructure. A vaccine for AIDS may not have to provide full-protection. Therapeutic vaccines that improve the clinical course of infection by reducing viral load, prolonging the asymptomatic phase and reducing transmission may suffice initially. Identification of factors associated with stable long-term non-progression or fast-progression to AIDS in HIV-1 infection may aid vaccine development as promising vaccine targets and useful immunological markers. In the GRIV cohort of HIV-1 seropositive slow/non-progressors, higher levels of T-cell receptor excision circles (TREC) and antibodies to the HIV-1 regulatory protein Tat are associated with and predictive of maintenance of stable non-progression status. Based on the association of antibodies to Tat with stable non-progression status, vaccination with IIIB and 89.6P Tat and inactivated Tat toxoids was evaluated in the SHIV89.6P model of HIV-1 infection. The humoral and cellular immune responses to Tat in vaccinated rhesus macaques prior to intravenous SHIV89.6P viral challenge were impressive. However, protection was not observed following viral challenge and there was no significant association between immune responses to Tat and attenuated disease course, although a trend was observed toward higher numbers of macaques with cellular immune responses to Tat among animals that controlled infection to some degree. Evaluation of TREC in the SHIV89.6P model revealed a significant reduction in TREC at endpoint that was associated with reduced percentages of CD4+ T-cells and higher serum viral loads. Higher levels of TREC were present in animals that controlled infection. A separate analysis of TREC in the SIVmac251 model of HIV-1 infection in the context of highly active anti-retroviral therapy (HAART) revealed higher levels of TREC in animals that received hydroxyurea continuously, and an inverse association with markers of immune activation and proliferation. In summary, Tat may be a suitable component of a multi-subunit vaccine for AIDS given its immunogenicity. TREC appears to be a potential surrogate marker for predicting clinical stability, and may be useful for monitoring the response to therapeutics, including vaccines. |
