1. Chapter 10 An Evolving Enemy Silvio Penta Silvio Penta Christie DiDonato Christie DiDonato Carl Tuoni Carl Tuoni Beth Miller Beth Miller

2. Question What is AZT and how does it stop HIV from reproducing and causing AIDS? In the early 1990s researchers began to find AZT -resistant strains of HIV in recently infected patients who have never been treated with AZT. How can this be? Explain What is AZT and how does it stop HIV from reproducing and causing AIDS? In the early 1990s researchers began to find AZT -resistant strains of HIV in recently infected patients who have never been treated with AZT. How can this be? Explain

3. Background Azidothymidine, or AZT, was the first antiretroviral drug approved for treatment of HIV. First synthesized in 1964 by the US National Institute of Health for treatment of cancer. It was found ineffective on cancer infected lab rats and was shelved. In 1985 it was reexamined as an AIDS treatment and was found to prolong the life of AIDs infected patients. Azidothymidine, or AZT, was the first antiretroviral drug approved for treatment of HIV. First synthesized in 1964 by the US National Institute of Health for treatment of cancer. It was found ineffective on cancer infected lab rats and was shelved. In 1985 it was reexamined as an AIDS treatment and was found to prolong the life of AIDs infected patients. http://www.chrisdellavedova.com/wp- content/uploads/2007/10/scientist.gif http://www.niaid.nih.gov/publications/hiv aids/23.htm

4. www.3dchem.com What is AZT? AZT is the foundation stone of the AIDS drug construction. AZT is the foundation stone of the AIDS drug construction. It was the first drug approved for the treatment of AIDS and the HIV infection in 1987. It was the first drug approved for the treatment of AIDS and the HIV infection in 1987. It is usually used in two or three drug “cocktails”, rather than alone. It is usually used in two or three drug “cocktails”, rather than alone. It is also the main drug used to prevent HIV transmission from mother to child. It is also the main drug used to prevent HIV transmission from mother to child. AZT works by interfering with cell division. AZT works by interfering with cell division. DNA is a chain of molecular beads (nucleotides) one being Thymidine, of which AZT is a defective analog. This can be threaded on the chain, but stops further growth through the addition of natural nucleotides. DNA is a chain of molecular beads (nucleotides) one being Thymidine, of which AZT is a defective analog. This can be threaded on the chain, but stops further growth through the addition of natural nucleotides. This mechanism stops the HIV from inserting itself into human DNA. This mechanism stops the HIV from inserting itself into human DNA.

5. www.aidsinfonet.org/factsheet_det ail.php?fsnumber=411 AZT AZT is one of the nucleoside reverse transcriptase inhibitors (NRTIs). These drugs work by disrupting an HIV protein or enzyme called reverse transcriptase, which is involved in the production of new viruses. These drugs block the reverse transcriptase enzyme. AZT is one of the nucleoside reverse transcriptase inhibitors (NRTIs). These drugs work by disrupting an HIV protein or enzyme called reverse transcriptase, which is involved in the production of new viruses. These drugs block the reverse transcriptase enzyme.

6. www.aras.ab/articles AZT continued… AZT does not destroy the HIV infection, but only delays the progression of the disease and the replication of the virus, even at high doses. AZT does not destroy the HIV infection, but only delays the progression of the disease and the replication of the virus, even at high doses. During prolonged AZT treatment, HIV has the ability to gain an increased resistance by mutation of the reverse transcriptase. During prolonged AZT treatment, HIV has the ability to gain an increased resistance by mutation of the reverse transcriptase.

7. AZT resistant strains in untreated patients? Mutations that result in drug-resistant variants can occur both prior to the administration of antiviral drugs as well as during therapy. Mutations that result in drug-resistant variants can occur both prior to the administration of antiviral drugs as well as during therapy. HIV is notorious for its’ ability to develop drug resistance in patients taking antivirals. Resistance in AZT is peculiar in that multiple amino acid changes and mutations build up over time, yielding a number of virus variants with a high-level drug resistance. HIV is notorious for its’ ability to develop drug resistance in patients taking antivirals. Resistance in AZT is peculiar in that multiple amino acid changes and mutations build up over time, yielding a number of virus variants with a high-level drug resistance.

8. AZT resistance HIV does not make perfect copies of itself. With billions of viruses being made every day, lots of small, random differences like mistakes can happen. The differences are called mutations. HIV does not make perfect copies of itself. With billions of viruses being made every day, lots of small, random differences like mistakes can happen. The differences are called mutations. Mutations that change the parts of the virus the drugs are meant to stop can keep the drugs from working. When the drug no longer works against HIV, it is called drug resistance. The virus with the mutation is resistant to the drug. Mutations that change the parts of the virus the drugs are meant to stop can keep the drugs from working. When the drug no longer works against HIV, it is called drug resistance. The virus with the mutation is resistant to the drug. www.atdn.org/simple/resistance.html www.atdn.org/simple/resistance.html

9. When AZT resistant strains of HIV are produced they keep multiplying while the non AZT resistant strains are killed off. Eventually there are only AZT resistant strains of HIV left in the body. When AZT resistant strains of HIV are produced they keep multiplying while the non AZT resistant strains are killed off. Eventually there are only AZT resistant strains of HIV left in the body. This strain of HIV will then spread like the normal virus. This strain of HIV will then spread like the normal virus. Drug-resistant viruses may be transmitted in primary infection via sexual or intravenous routes. Drug-resistant viruses may be transmitted in primary infection via sexual or intravenous routes.

10. http://aliveandwell Side Effects of AZT AZT has a dark side. Although the immediate results of the treatment in AIDS patients may be positive, over time they produce the same symptoms of AIDS itself! There are numerous debilitating or even fatal side effects. AZT has a dark side. Although the immediate results of the treatment in AIDS patients may be positive, over time they produce the same symptoms of AIDS itself! There are numerous debilitating or even fatal side effects. Severe anemia that without transfusions could be deadly. Severe anemia that without transfusions could be deadly. Damage to the blood, bone marrow, nerves and muscle is believed to arise from effects on the mitochondria, regulating organelles in every cell. Damage to the blood, bone marrow, nerves and muscle is believed to arise from effects on the mitochondria, regulating organelles in every cell.

11. The Links: http://www.abc.net.au/rn/talks/8.30/helthrpt/stories/s11490.htm http://www.abc.net.au/rn/talks/8.30/helthrpt/stories/s11490.htmhttp://www.abc.net.au/rn/talks/8.30/helthrpt/stories/s11490.htm http://www.aids.org/atn/a-191-06.html http://www.aids.org/atn/a-191-06.htmlhttp://www.aids.org/atn/a-191-06.html http://gateway.nlm.nih.gov/MeetingAbstracts/ma?f=10220348 5.html http://gateway.nlm.nih.gov/MeetingAbstracts/ma?f=10220348 5.html May There Be a Cure