Tat Inhibitor Approach Still Alive

A small Canadian company, Allelix Biopharmaceuticals, is
embarking on initial human safety trials of a new kind of
compound that inhibits the action of HIV's "tat" gene. A
single-dose test of human tolerance of the substance will
take place in Canada this fall.

HIV's tat, or transactivator, gene regulates the replication
of the virus within the cells where it has taken up
residence. The tat protein produced according to the gene's
instructions binds onto a sequence known as the TAR, or
transactivator response element, located at the end of the
HIV genetic chain. There, the tat protein helps assemble new
copies of HIV.

This transcription process is the reverse of the original
infection step, in which the RNA form of HIV genes is
converted into DNA, which integrates into the cell's genetic
machinery in the nucleus. Nucleoside analog drugs like AZT,
ddI and ddC interfere with that preliminary step.

The tat protein-TAR complex speeds up the rate of viral
reproduction by about a thousand times. If it is not present,
the transcription process frequently stops short, and few
functional HIV particles are produced.

The pharmaceutical company Hoffmann-La Roche was the leader
in tat inhibitor development until it abandoned the program
as a failure. Roche had used a laboratory screening process
to select a potential tat inhibitor from its private stock of
chemicals. The company's choice was an off-the-shelf
benzodiazepine derivative related to Roche's well-known
tranquilizer Valium. The compound ultimately failed to show
any benefits in humans, as Roche revealed during the
International Conference on AIDS last June. Company
researchers then tried increasing the dosage, but that just
produced more side effects. Roche announced August 2 that it
would not continue work on tat inhibitors.

In contrast, Allelix is following a "rational" drug design
strategy. "Our company focuses on regulatory genes," Martin
Sumner-Smith, Ph.D., Allelix's research director told AIDS
TREATMENT NEWS. "We studied the interaction between tat and
TAR and found the specific part of TAR that tat binds to.
Then we developed a peptide [short protein fragment] that
blocks that binding site."

A fundamental reason Roche cited for giving up on the whole
tat concept was new speculation, brought to a head at the
last International AIDS Conference by Flossie Wong-Staal, of
the University of California San Diego, that tat was not
essential to HIV replication. Other substances produced by
the host cells themselves also help establish the proper
conditions for replication. Dr. Sumner-Smith rejects this
analysis of the failure of the Roche project. "The Roche drug
didn't really target the tat protein, but a cellular factor
that bound to the TAR site along with tat. Tat remains an
important target for inhibiting HIV."

Gary Nolan, Ph.D., who has studied the HIV transcription
process extensively at Stanford University, agreed that tat
was essential for complete virus replication. He did worry,
though, that HIV could develop resistance to an effective tat
inhibitor if this compound was administered alone. "You have
to be ready for even supposedly invariant regions of the
virus to mutate," he said. "Theoretically you might need to
attack HIV in three ways to stop it -- well, we've already
lost our ability to employ nucleoside analogs as one of those
ways by using them as single agents and creating a pool of
resistant virus."

Dr. Sumner-Smith said he doesn't expect his company's product
to be a cure for AIDS by itself. "It's pretty clear HIV will
need a cocktail of drugs that act synergistically," he
concluded.

One idea that is attracting increasing interest is a
multidrug regimen that includes both a tat inhibitor and a
chemical to block or limit normal cell substances that HIV
also needs to induce replication. One such substance is a
molecule known as NF-kappa B, which usually serves to switch
on T-helper cell genes as part of the natural immune
response. NF-kappa B is overactive in HIV-infected T-helper
cells.

Glutathione, a major cellular antioxidant, may help prevent
overactivation of NF-kappa B. Glutathione levels are low in
HIV-infected cells for reasons that are not entirely clear,
and supplementing the diet with n-acetylcysteine (NAC), an
amino acid precursor to glutathione, has been suggested as a
means of replenishing those levels. Other dietary
antioxidants, including vitamin E and beta-carotene, also may
have a role in treatment of HIV disease. Although
antioxidants have become popular in the AIDS community,
questions remain as to their effectiveness and appropriate
dosage. This is also true of drugs such as pentoxifylline
that have been found to have an NF-kappa B inhibiting effect.