Abracadabra:
Magic Johnson and Anti-HIV Treatments

The good news is that HAART has successfully treated HIV-positive patients, giving them extended lifespans, allowing the immune system to regain control, and decreasing virus loads.  The bad news is that HIV is a smart virus; HIV has developed mechanisms to overcome the blocks imposed by drug treatments.

Through a microevolutionary process, HIV variants that are resistant to the intended inhibition are able to replicate and produce more virus.  Over time, in the presence of a drug such as AZT, random mutations may develop and be selected for that allow these variants to be resistant to the effects of AZT.  These drug resistant variants have greater fitness and can replicate in a person even in the presence of a drug.  Specifically, mutations in reverse transcriptase (RT) develop in the presence of AZT.  These variants allow HIV to continue to replicate in human T cells.  HIV variants may only contain a single amino acid change in the protein sequence to render an anti-HIV drug ineffective.

For many years, doctors emphasized the necessity for strict compliance with prescribed HAART treatment regimens.  Recently, a controversial new therapy called structured treatment interruption (STI) has been suggested to HIV-positive patients by their physicians.  STI refers to the practice of alternating time spent on antiretroviral drugs with time spent off drugs, and each cycle may last anywhere from several days to months.  However, it is not recommended for all HIV-positive patients.  The theory behind STI is that the alternating periods of HAART treatment with regulated withdrawals of drug therapy may serve as a means of inducing immune system control of HIV.

Questions

1. How are natural selection and microevolution illustrated in this scenario?  Identify the genetic basis for HIV evolutionary change, the selective pressure, and the resulting adaptation.  What happens to mutants that are able to escape detection by the immune system?
2. Describe how mutations could lead to drug resistance in the RT enzyme.  Include physical, molecular, and biochemical reasons.
3. Define compliance.  Draw a curve of what the virus load profile would look like if a patient is not compliant.  Label the X-axis with time and the Y-axis with virus load.
4. Why is STI considered a scientifically controversial strategy?  Suggest three biological reasons why STI could be advantageous.  Predict what will happen to the virus over time if patients are then allowed to resume their HAART therapy after STI.  Propose situations in which the STI approach may not be recommended or effective in some HIV-positive people.  How would a physician be able to tell if STI is working?
5. Predict what will happen to infection rates over time if drug resistant forms of HIV are allowed to spread through the population.  What conditions might slow the spread of drug resistant strains?

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