Normally I don’t post things that could potentially be considered related to my job, but I figure a “fresh” look at potential HIV therapeutics is far enough away that I am not that concerned.
The first is a drug that increases the fidelity of the HIV reverse transcriptase. This sounds totally stupid, but one of the key mechanisms of viral survival is an error prone replication. One of the reasons that combination therapies fail is the virus mutates and the population becomes resistant. This drug would slow the mutation rate, and prolong the efficacy of these therapies. Obviously you can’t use this drug in combination with drugs that interfere with reverse transcription, (no AZT or what ever they are using now days) but it could stabilize the viral population, and slow the creation of multi-drug resistant strains.
The second treatment would be for individuals at risk or just recently exposed. Basically you would use lipid vesicles with gp120 as the targeting mechanism and RNA molecules that would target the HIV RNAs to Dicer as the payload. (The gp120 thing might not work so regular fusion vesicles could work as well, but you'd the lose the cellular targeting.) I’m guessing here but in cells that were not infected already it could serve as a molecular trap, so that when they became infected the HIV RNA would be destroyed, and be unable to integrate. In cells that were already infected it could suppress the translation of viral proteins and possibly the creation of viral genomes.
The next two suggestions are that people focus on the viral proteins Rev and Nef as drug/treatment targets, since both of these proteins are required for successful HIV infections and since they interact with the host they can mutate very much and still be functional. The treatment could be either small molecule or suppressive RNA. I would suggest suppressive RNA since small molecules that could suppress these proteins might also have activities against host proteins as well.
It could be useful to interfere with Vif, but it might be more useful to instead up-regulate Vif’s target APOBEC3G. Interestingly if a drug that could suppress Cullin5 E3 ubiquitin ligase (Vif hijacks this protein to degrade the APOBEC3G) was available it would not only serve as a very effective HIV therapeutic but it could also treat autoimmune diseases as well.
The best way I see to deal with Tat is using engineered antibodies, that bind important (conserved) but not normally highly immunogenic epitopes. This kind of treatment could damage the spleen and kidneys of AIDS patients so they will likely need some kind of secondary therapy “blood cleansing” to remove the Tat/Ab complex from the blood. I would suggest a secondary antibody that recognizes an epitope in the primary antibody that is created by binding Tat. The antibody can be bound to a substrate, and the patient’s blood passed over it. If their blood has to be outside their body anyways; why not deplete it for gp120? This would just inactivate any virus particles in the blood and reduce the chance that infected cells will produce functional virus for a couple days.
Unfortunately even if it was possible to totally suppress an HIV infection, we would just have a new problem, blood cancers. HIV integrates into the host genome, which is why it is so hard to get rid of. Now days, the infected cells and sometimes the host die before this becomes too much of a problem. Once people start living a long time with a chronic HIV infection, some of the cells will have an HIV integration event that alters the expression of an important gene. This event can be the start of some fairly nasty T-cell leukemia’s. However, I suggest we worry about this problem once HIV is no longer the killer it is.
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