MadSci Network: Immunology

Re: Hiv Tat protein, a cell permeable peptide.doesnt it lead to immune response

Date: Thu Feb 24 22:33:45 2005
Posted By: Mike Conrad,
Area of science: Immunology
ID: 1103030677.Im

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

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

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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