A Molecular View of HIV Therapy

During infection by HIV, three enzymes play essential roles in the life cycle of the virus: Reverse Transcriptase, Integrase, and Protease. The first enzyme, HIV Reverse Transcriptase copies the viral RNA genome by combining individual host nucleotides to build a complementary DNA strand. When Reverse Transcriptase finishes this strand, It will replace the original viral RNA with another DNA strand forming a DNA double helix. The second enzyme, HIV Integrase inserts the viral DNA into the cell’s DNA. The third enzyme, HIV Protease is needed at the last step of the viral life cycle to cut the HIV polyprotein into its individual functional parts. HIV enzymes are targets for drug therapy. Two types of drugs block Reverse Transcriptase. Drugs like AZT mimic the normal building blocks of DNA, but prematurely terminate the DNA chain. Drugs like nevirapine bind on the back side of Reverse Transcriptase, distorting the enzyme so that it can no longer perform its DNA building reaction. Raltegravir binds to two magnesium ions in Integrase that are essential for the DNA integration reaction. Drugs likes the Saquinavir mimic the proteins cut by HIV protease, blocking the maturation of the virus. Drug resistance is a major problem for HIV drug therapy. For instance, when patients are treated with drugs that block HIV Protease, most of the viruses are destroyed but rare mutant forms of the virus survive. These mutant viruses make a mutated form of the Protease. This Protease resists the binding of drugs, but can still cut the viral polyprotein. Over many generations the population of viruses builds up additional mutations that further resist the drug. The most effective current treatment method uses a combination of drugs that attack the different enzymes, so that some of the drugs will still be active even if one of the enzymes becomes resistant.

3 comments

  1. I am honestly surprised it took so long to figure out that combination therapy is the right way. It is because doctors do not think like engineers. At least most don't. I am so lucky to know a doctor who does. We speak for hours just for intellectual gain. It is wonderful to speak to one who really gets it. Now we have PeP and PreP. IMHO we should engineer body cells to make their own Truvada and other defenses. Meanwhile we got a ton of naysayers trying to convince us to fail. Get it: WE WON"T GIVEUP.

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