Recent Advances in the Development of HIV-1 Tat-Based Vaccines

Antonella      Caputo; Riccardo      Gavioli; Barbara      Ensoli

doi:10.2174/1570162043350986

Abstract

Over the last two decades most of the efforts in HIV vaccine development have been based on the use of the HIV Env with the goal to induce sterilizing immunity. However, as a result of Env variability disappointing results have been obtained in preclinical and phase III clinical trials. Although the objective of a preventive immunity still remains a priority, secondary endpoints (e.g. block of virus replication and disease onset) are being considered at the present as more achievable end-points in HIV vaccine development. This is based on accumulating evidence indicating that low viral load correlates with maintenance of immune functions and slow progression to disease, and that cell-mediated immunity plays a major protective role in the absence of sterilizing immunity. The promising results obtained in non-human primates with a vaccine based on a native Tat protein (B-clade), which is an early regulatory protein key for HIV replication and AIDS pathogenesis, highlights the importance of targeting the virus very early after infection. In particular, the immune response against Tat appears to modify the virus-host interactions at the very beginning of infection, thus containing the depletion of critical immune cells and the progression of infection. Moreover, since Tat targets and induces maturation of dendritic cells, has immunomodulatory activities and drives Th-1 and CTL responses, immunization with Tat may drive or increase these immune responses also against other HIV antigens to support an effective, long-lasting and hopefully even sterilizing antiviral immunity. Finally, Tat B-clade is similarly recognized by sera from individuals infected by different virus clades (A, B, C, D) supporting the concept of a cross-clade vaccine. Therefore, the Tat-vaccine should contain virus replication protecting from disease progression (non-sterilizing immunity) or even favoring an abortive infection. Although only a phase III clinical trial will establish the efficacy of this vaccine strategy, the Tat-vaccine has recently entered preventive and therapeutic phase I clinical testing in Italy to establish safety (primary-endpoint) and immunogenicity (secondary end-point) and phase II studies are being prepared.

Keywords: hiv-1 tat, hiv vaccine, rodents, non-human primates, humans, anti-tat immune responses, clinical trials

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