afflict a person with AIDS. Early research suggested that AZT might delay the onset of disease in infected but healthy individuals, but more recent studies have hinted that it may offer no advantage to asymptomatic people.
Although AZT is currently one of the best treatments available, it has many drawbacks. First, it is somewhat toxic. It also suppresses immune activity and causes some tissue damage. In addition, the virus seems to become resistant to AZT at an alarmingly quick rate—sometimes after only 1 year. For that reason physicians are now investigating the use of AZT in combination with or alternating with ddI and ddC, since all three drugs act in essentially the same way but have different sets of toxicities. These three drugs are the only ones approved so far by the Food and Drug Administration for use in treating AIDS.
The ability of reverse transcriptase to mutate in such a way as to become resistant to AZT has inspired a new strategy for drug intervention. In laboratory studies, researchers exposed the virus to three different drugs targeted against reverse transcriptase, with the hope that the enzyme would become resistant to all three at the same time. These alterations would require the enzyme to change so much that it could no longer perform its DNA-synthesizing function. In theory, the virus would successfully resist the drugs but would become ineffectual in the process. This approach has produced disappointing laboratory results, and no one yet knows whether it will be effective or safe for humans, but it is an interesting example of how knowledge of the viral life cycle can lead to new and creative strategies for cutting that cycle short. In this case that means cleverly turning a viral defensive strategy against the virus itself.
Another good target for therapeutic interventions is the integrase that incorporates viral DNA into the host chromosomes, but nothing has yet been developed that can do that. There is now a great deal of interest in agents that can inhibit gene activation by the Tat protein. While nothing truly promising has yet emerged, the hope is that when a Tat inhibitor is developed it will have the potential to block as much as 80 percent of HIV gene expression and possibly that much viral replication. If genes are expressed in the nucleus, however, a good target for drugs would be the Rev protein, which may help escort messenger RNA out of the nucleus and into the cytoplasm to be translated into protein. No Rev blockers have yet been developed.
Once messenger RNA is in the cytoplasm its access to the protein-synthesizing machinery might be obstructed by the use of so-called antisense DNA. In this technology, strands of DNA can be manufactured