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  HIV-1 TAT VACCINES: SCIENTIFIC BACKGROUND & RATIONALE

When compared to other viruses, HIV has a number of differences that makes it particularly difficult to fight
. Over the past 20 years, most of the efforts in HIV vaccine development have focused on using HIV's Envelope protein (gp120 or Env) in vaccines, in the attempt to induce anti-Env antibodies able to neutralise the infection of the cell by HIV. Theoretically, Env-specific antibodies would prevent entry of the virus into cells. If successful, the vaccine would provide sterilizing immunity, which protects the vaccinated person from becoming infected with HIV.

However, historically, results of Env-based vaccines in pre-clinical and clinical trials have been largely disappointing. In fact, an Env-based vaccine from Vaxgen failed to protect volunteers in phase III clinical trials. (Pitisuttithum P, Gilbert P, Gurwith M, Heyward W, Martin M, van Griensven F, Hu D, Tappero JW, Choopanya K; Bangkok Vaccine Evaluation Group - J Infect Dis. 2006 Dec 15;194(12):1661-71).
A more recent phase III trial based on clade B and C Env conducted in Thailand in cooperation with US Army has shown limited efficacy (Vaccari M, Poonam P, Franchini G. Expert Rev Vaccines, 2010 Sep;9(9):997-1005.

Env-based vaccine candidates are believed to have failed because the envelope proteins of the HIV virus mutate rapidly. Because of this characteristic, the immune system is not able to recognize and fight all the variants of the virus. This is similar to what happens with influenza (the flu) each year, but HIV mutates much faster than influenza.
More recently, other approaches have been developed aimed at inducing T-cell mediated responses against other HIV antigens. However also these approaches failed. An example of this is the recent trial from Merck, based on gag, pol and nef genes, that failed to protect volunteers. These last results come from an international study partly funded by the US National Institutes of Health (NIH).
Failures with vaccines using HIV envelope proteins have prompted scientists at the National AIDS Center of the Italian National Institute of Health (ISS) to pursue a radically different approach over the past 10 years. Researchers at ISS, led by Dr. Barbara Ensoli, have focused their efforts on tat, a key HIV regulatory gene and its protein product, Tat, as a vaccine candidate.
Regulatory genes, including tat, express proteins soon after infection and are essential for virus replication and pathogenesis. They are also more highly conserved among the different types of the HIV virus found worldwide than are other HIV genes. In addition, Tat is released by infected cells and instructs cells in close proximity to become more prone to infection. These features make the Tat protein a logical candidate for vaccine development.
The Italian scientists at ISS are pursuing a strategy aimed not only at preventing viral infection, but also at blocking virus replication and transmission, and blocking development of the AIDS syndrome in infected individuals. They believe that Tat may prove to be an excellent candidate for the development of both preventive and therapeutic vaccines against HIV-1.
 

 

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