|MadSci Network: Immunology|
HIV Tat protein, is a cell permeable peptide. Doesn't it lead to an immune response? Even though Tat is found in the blood, Tat is not very immunogenic. Small soluble peptides (like Tat), that aren't converted into a lot of fragments that bind MHC (like Tat), tend not to elicit the production of antibodies. (MHC is the molecule needed to hold foreign molecules for the immune system.) Similarly, Tat doesn't trigger much of the other type of immune response, the cell mediated immune system. Despite initial optimism, Tat has not yet led to a good vaccine against AIDS. Tat is short for "transactivator", and Tat is a regulatory gene in HIV that accelerates production of more HIV virus. Tat is crucial to HIV and without Tat, HIV does not replicate. Tat is secreted early after infection and it is then taken up by neighboring cells. This way, Tat can activate HIV in cells that have been infected with an inactive HIV. It also modifies key cellular functions, and this may play a role in the ill effects of AIDS. Some say that extracellular Tat and the number of infected cells are too low to make transactivation important, and that extracellular Tat is the result of lysed cells. Still, about a third of infected people make antibodies to Tat. Krone, Med Virol. 26 p261 (1988). In the 1990s, it was noticed that people with antibodies to Tat tend to progress more slowly to AIDS. In 2000, Robert Gallo developed a vaccine for monkeys with Tat toxoid (Tat treated to eliminate its toxic cellular effects) that produced a good antibody response and reduced disease after a simian/HIV challenge. PNAS 97, p3535 (2000). Development of human vaccines got underway and by 2003 it was shown that the human Tat toxoid vaccine was safe (phase 1) and could elicit antibodies (phase 2). Phase 3 trails have started in Italy led by Gallo to test the Tat toxoid vaccine and another Tat trial led by Barbara Ensoli. A Tat vaccine that stimulated the cell mediated immune response in monkeys was not successful. Allen, J Virol. 76 p4108 (2002). A cell mediated immune system vaccine combining Tat and other proteins to make a larger target is being developed. Nkolola, Gene Therapy 11, p1068 (2004). I think "escape mutants" are preventing Tat vaccines and the immune response to Tat protein from stopping HIV. When HIV replicates it makes many mutants, or variants, of each protein. The immune system eliminates viruses and virus infected cells by making molecules that bind to foreign molecules. This triggers the elimination of the foreign material. But when the foreign molecules keep changing, it becomes impossible for the immune system to keep up with them. Tat is a small protein, with only a few epitopes, or "immunological handles". It is easy for Tat to mutate to avoid the immune system. Additionally, HIV causes a loss of CD4 T cells needed to produce an immune response, so it gets harder and harder for the body to fight the virus. Will there be an HIV vaccine? An HIV Vaccine will need to elicit a high level of antibodies, induce a strong cell mediated response, stimulate a potent mucosal immune response, and protect against the many different HIV clades. About animal trials, Larry Corey, who heads the government's HIV Vaccine Trials Network said, "No model (animal) system that we have is equivalent to humans..." However, it is clear that there has been much progress toward developing a vaccine. Mike Conrad.
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