AIDS TREATMENT NEWS Issue #187, November 19, 1993
Dave Gilden

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.

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