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HIV-1 TAT VACCINES: PRE-CLINICAL STUDIES |
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 To test the hypothesis that Tat may be an optimal candidate for an HIV vaccine, a complex multidisciplinary approach was deployed, encompassing multiple milestones, to address national and international regulations. Activities included: production of the candidate vaccine; evaluation of its safety, immunogenicity and efficacy in preclinical models; dossier preparation and submission; and approval for use in human clinical trials. |
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| In addition, a parallel set of activities was deployed to define the role of Tat and the Tat immune response in natural HIV infection, to identify correlates of protection, and to validate tests to monitor vaccinees. Finally, Capacity building activities were undertaken in key developing countries to prepare sites for the conduction of clinical trials. |
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| As part of the required set of pre-clinical studies , the Tat vaccine candidate was tested in different animal models, including mice, rabbits and cynomolgus (Macaque) monkeys. |
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| The preclinical studies demonstrated that: |
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- Vaccination with a biologically active Tat protein or tat DNA is safe, and it elicits a broad and specific immune response. Most importantly, it induces in monkeys a long-term protection against infection with a highly pathogenic virus (simian/human immunodeficiency virus, SHIV). This virus is known to cause AIDS and death in the monkeys used in these studies.
- biologically-active Tat protein induced cellular immune responses from Th-1 and CD8+ CTLs, as well as high titers of anti-Tat antibodies. It also blocked primary infection of cynomolgus monkeys (macaques) with SHIV 89.6P. This was indicated by maintenance of the CD4+ T cell counts, undetectable viremia, and lack of disease onset post-infection.
Protection was long-lasting. No signs of virus replication were found either in peripheral blood mononuclear cells and/or lymph nodes of the protected animals during the 2 years of follow-up.
- No residual virus was detected in resting cells of any of the protected macaques either in the plasma and/or lymph nodes after two boosts with tetanus toxoid, a stimulus known to activate virus replication. Long-term protection correlated with the presence of high and stable humoral and cellular responses against Tat.
- Finally, a pilot study conducted in SHIV-infected macaques indicated that vaccination with either tat DNA or Tat protein is safe in monkeys with AIDS.
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