Authors

Brief Overview:

How does Antiretroviral Therapy Affect HIV Mutation?

AIDS is a disease that struck fear in the hearts on many Americans in the early 1980s because not much was known about the disease. However, as scientific research has uncovered the structure of the virus, the mechanism by which the virus replicates inside the host cell, and the structure of the viral proteins needed for replication, new drugs have been developed to inhibit viral replication and help lengthen the lives of people infected with HIV. As with most treatments for infectious diseases, resistant strains of HIV have evolved rendering some of the treatments less effective.

You are a physician who works with people who are infected with HIV. In addition, you have agreed to allow undergraduate students to shadow you in your work. You want your students to learn as much as possible about the work that you do. On the first day that several undergraduate student have come to see your work, a patient comes to you with a CD4 cell count around 350 cells/�l of blood, which indicates that he/she might want to consider taking anti-retroviral drugs. Before giving your patient a particular regimen of drugs, you want to know if your patient has any strains of HIV that might be resistant to some of the available anti-retroviral drugs. You draw a sample of your patient’s blood and send it out for analysis. You ask the lab to determine nucleotide and amino acid sequence for HIV-1 protease and reverse transcriptase to determine which anti-retroviral drugs might be effective and which drugs might be ineffective.

After the patient leaves, the students bombard you with a list of the following questions.

• How do you determine if a patient needs to be treated?
• Why are you analyzing the patient's blood before giving him/her a set of drugs?
• What will the results of these tests on the patient's blood tell you?
• How do the drugs work?
• How does HIV become resistant to the drugs?
• Can a person be infected with multiple strains of HIV?
  

• First you ask the students what they understand about AIDS.
• Next you ask the students what more they need to understand about AIDS to answer their own questions.
• Then, you provide them with resources and exercises.

Within the activities you will find some suggestions on these topics.

Resources and References:

Web links

Basic information on DNA
http://nobelprize.org/chemistry/educational/dna/intro.html
http://gslc.genetics.utah.edu/units/basics/
http://www.ornl.gov/sci/techresources/Human_Genome/posters/chromosome/

Bioinformatics resources –Project Bedrock
http://hivdb.stanford.edu/ Stanford HIV Database
http://www.bioquest.org/bedrock/other_resources.php

Animation on enzyme action
http://www.lewport.wnyric.org/jwanamaker/animations/Enzyme%20activity.html

Animation on enzymes kinetics
http://www.wellesley.edu/Biology/Concepts/Html/vmaxfrommme.html

General information on structure of HIV protease
http://molvis.sdsc.edu/protexpl/morfdoc.htm

Power point presentation on HIV protease function, structure and drug design
http://www.biotechnology.uwc.ac.za/teaching/BIO343/Notes/BIO343_Section5.pdf

Video on HIV protease (available for purchase)
http://jchemed.chem.wisc.edu/JCESoft/Programs/Videotape/HIV/

Inhibitors of HIV Protease: An Introduction to Carbonyl Chemistry
http://www.chem.wisc.edu/~newtrad/CurrRef/AIDStopic/AIDStext/AIDStoc.html

Protease Inhibitors
http://www.thebody.com/treat/protinh.html

HIV Structural Database and Chem-BLAST
http://xpdb.nist.gov/hivsdb/hivsdb.html

Basic information on enzymes
http://www.rcsb.org/pdb/molecules/pdb6_1.html
http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/E/Enzymes.html

Articles

HIV-1 Protease
Molecular modeling of the HIV-1 protease and its substrate binding site.
Science. 1989 Feb 17;243(4893):928-31. PMID: 2537531

Human Immunodeficiency Virus Type 1 Protease Cleavage Site Mutations Associated with Protease Inhibitor Cross-Resistance Selected by Indinavir, Ritonavir, and/or Saquinavir.
Brumme ZL, Harrigan PR. J Virol. 2001 Jan; 75(2): 589-594. PMCID: 113954

Computational study of protein specificity: The molecular basis of HIV-1 protease drug resistance. Wang W, Kollman PA. Proc Natl Acad Sci U S A. 2001 Dec 18; 98(26): 14937-14942. PMCID: 64962

High Degree of Interlaboratory Reproducibility of Human Immunodeficiency Virus Type 1 Protease and Reverse Transcriptase Sequencing of Plasma Samples from Heavily Treated Patients. Shafer RW, Hertogs K, Zolopa AR, Warford A, Bloor S, Betts BJ, Merigan TC, Harrigan R, Larder BA. J Clin Microbiol. 2001 Apr; 39(4): 1522-1529. PMCID: 87964

A genetic screen for the isolation and characterization of site-specific proteases.
Sices HJ, Kristie TM. Proc Natl Acad Sci U S A. 1998 Mar 17; 95(6): 2828-2833.
PMCID: 19654

Coevolutionary analysis of resistance-evading peptidomimetic inhibitors of HIV-1 protease.
Rosin CD, Belew RK, Morris GM, Olson AJ, Goodsell DS. Proc Natl Acad Sci U S A. 1999 Feb 16; 96(4): 1369-1374. PMCID: 15469