Within-host HIV dynamics: the emergence of drug resistance

Level 1 module

Basic problem

Infection with human immunodeficiency virus type 1 (HIV-1) is still incurable, but potent drugs are now available that are able to suppress the replication of the virus and maintain the treated individuals in a disease free condition. Anti-HIV drugs act by inhibiting specific enzymes of the virus. A major problem in the treatment of HIV is the emergence of drug resistance: one or more mutations in the targeted enzymes of the virus can change the enzymes such that the drugs can no longer bind to them, and their effect is therefore lost. Understanding how and why drug resistance develops is crucial for the control of the epidemic.

General approach

We will model the within-host dynamics of HIV with simple sets of differential equations that implement both wild type and drug resistant viruses. Using this model system, we will show what factors inhibit or facilitate the emergence of drug resistance, which provides lessons for the optimal treatment strategy.

What can be learned

Concepts:

• Mutation-selection equilibrium
• Drug resistance

Methods:

• Numerical simulation of ordinary differential equations
  

Starting point
Download reader and R script describing the equations for the basic model of within-host HIV dynamics. Extend the model to incorporate wild type and resistant virus, and observe the emergence of resistance under therapy.

Interesting questions that you can investigate

• How does the efficacy of the drugs affect the time to the emergence of resistance?
• What are the conditions for the emergence of drug resistance?
• Resistance mutations can exist in a mutation-selection equilibrium even before treatment: how does this affect the emergence of resistance under therapy?
• What is the advantage of administering a combination of different drugs?
  

Advanced questions:

• Implement and follow the concentration of the drug(s). Try to devise an optimal treatment strategy (number and dose of pills per day).
• Inhibitors of the reverse transcriptase block new infections; inhibitors of the viral protease make newly produced virus particles non-infectious. Model these specific effects explicitly.
• Model the effect of a drug sanctuary on long-term treatment.
• Model compensatory mutations.

Glossary

• Protease: one of the main targets of anti-HIV drugs, this viral enzyme is essential for the maturation of virus particles. Inhibition of the protease renders newly produced virus particles noninfectious.
• Resistance mutations: primary resistance mutations decrease the sensitivity of the viral enzyme to the drug, but often impair the enzymatic function. Secondary (compensatory) mutations do not affect drug sensitivity, but restore enzymatic function when present in an enzyme that contains primary mutations, as well.
• Reverse transcriptase (RT): the other major target of drugs, this enzyme is essential in the life cycle of the virus. Inhibition of the RT blocks the infection of new target cells.
• Wild type (WT): the basic variant (genotype) of the virus, which is dominant in the absence of drug treatment. WT can be defined over the whole length of the genome, or at a single locus or amino acid position.

Literature & Weblinks

• See the related module: Within-host HIV dynamics: the estimation of parameters.

• Bonhoeffer S, Nowak MA. Pre-existence and emergence of drug resistance in HIV-1 infection. Proc. R. Soc. Lond. B, 264: 631-637. (1997)

• Bonhoeffer S, May RM, Shaw GM, Nowak MA. Virus dynamics and drug therapy. Proc Natl Acad Sci U S A, 94:6971-6. (1997)
  

• Ribeiro RM, Bonhoeffer S. Production of resistant HIV mutants during antiretroviral therapy. Proc Natl Acad Sci U S A, 97:7681-6. (2000)