Bottom of the Ninth: With Two Down And Integrase On Deck, AIDS Research Team Hopes For a Hit--Or Will It Be 'Three Up, Three Down?'
Third and Final Enzymatic Target
The HIV genome encodes for three enzymes that are necessary for infection and replication. These enzymes are reverse transcriptase, protease and integrase. While the reverse transcriptase and protease activities have been extensively studied, the process of HIV DNA integration is less well understood. Once the HIV RNA genome is transcribed into double stranded pro-viral DNA by reverse transcriptase, the DNA is inserted into the host's DNA by a large integration complex consisting of several copies of HIV integrase and other cellular proteins. HIV integrase is absolutely necessary for viral infectivity and replication and is responsible for trimming the pro-viral DNA, cutting the host DNA and inserting the pro-viral DNA into the host genome. Host enzymes are then used to ligate the inserted DNA into the nascent strands. Only upon insertion can the pro-viral DNA be use to create viral RNA and proteins for assembling daughter viruses.
Blocking integrase is widely considered a viable target for potential anti-HIV drugs, since recombinant (genetically altered) HIV virions that lack the integrase gene are incapable of infecting and killing cells. As integrase is responsible for carrying out several distinct enzymatic steps involved in DNA integration, blocking any one of these steps would likely interfere with DNA integration and, as a result, HIV infection. Since recent studies indicate that infected cells turn over (die) at a rapid rate which is matched by (and eventually exceeds) the rate of new infection, reducing the rate of infection could maintain a state of homeostasis that could result in a stabilized immune defense condition.
Integrase is also an attractive target because, like reverse transcriptase, no integrase activity is normally present in human cells. And this fact could reduce the side effects of integrase inhibitors used to treat HIV infection. There are, however, potential problems with an anti-integrase strategy. Integration only needs to happen once for a cell to become infected. Once a cell is infected, an integrase inhibitor would not help the infected cell or reduce its production of new virions. Nucleoside based reverse transcriptase inhibitors (AZT, ddI, ddC, d4T, 3TC) can act at anytime reverse transcriptase is used to add a particular nucleotide to the growing pro-viral DNA strand, which amounts to many thousand times. If reverse transcriptase accepts the nucleoside analogue at any one of these times, the incomplete DNA is not a viable for integration and infection. Integrase inhibitors, on the other hand, have only one chance to inhibit the enzyme and once this opportunity is lost the inhibitor becomes ineffective for that cell.
Another potential pitfall of integrase inhibitors, which is shared by the present group of protease and reverse transcriptase inhibitors, is that resistant mutants are likely to arise. There is no reason to believe that inhibition of integrase will not force the emergence of 'escape mutants' that will re-expand. It is, however, possible that in order to escape inhibition, the resistant virus would have to mutate to such an extent that the resultant mutant virus would not be wholly viable, allowing the immune system to keep the infection under control, as some scientists have proposed.
A recent conference sponsored by the National Institutes of Health (NIH) focused exclusively on HIV integrase. The meeting, the first of its kind, brought together a variety of scientists studying every aspect of the integrase enzyme. Much of the research presented focused on how the enzyme achieves its vital task, and possible approaches towards blocking integration of the HIV genome. Scientists from the NIH reported the three-dimensional structure of the active site of HIV integrase and thereby provided a frame work from which chemists can model possible integrase inhibitors. Similar studies of the HIV protease provided the means to rapidly produce several of the protease inhibitors that are currently in clinical trials at sites around the world. Several companies presented lead compounds derived from in vitro integrase assays. Several of the identified compounds have high activity and exhibit encouraging in vitro anti-HIV activity. At the present time however, these compounds can only be considered test compounds and not true drugs, given their toxicological and absorption profiles. These lead compounds, however, could rapidly be turned into viable clinical entities by chemical alterations and modeling, and such studies are under way.
One of the most encouraging aspects of the meeting was the wide interest that pharmaceuticals companies and scientists have demonstrated in exploring the HIV integrase enzyme as a possible therapeutic target. Most of the large companies, and a sizable number of smaller bio-tech and mid-size firms, were represented at the meeting. It is plausible that the successful control of HIV infection may arise from the combination of several, less-than-optimal drugs that have different modes of action. As integrase represents the third and final HIV native enzyme protein encoded in the HIV genome, exploring it as a therapeutic target should be, and has become, a major research priority.
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This article was provided by Treatment Action Group. It is a part of the publication TAGline.