An in vivo model for HIV resistance development

Area of Science:

• Virology
• Pharmacology
• Animal Models

Background:

• Antiretroviral therapy for HIV-1 rapidly selects for drug-resistant strains.
• Developing reliable animal models is essential for studying the emergence and reversal of drug resistance.
• A hybrid simian-human immunodeficiency virus (SHIV) with HIV-1 reverse transcriptase (RT) was previously established.

Purpose of the Study:

• To evaluate a monkey model using RT-SHIV for studying drug resistance development.
• To investigate the emergence of nevirapine resistance in cynomolgus monkeys infected with RT-SHIV.
• To assess the impact of nevirapine dosage and therapy interruptions on resistance mutations.

Main Methods:

• Cynomolgus monkeys infected with RT-SHIV were treated with nevirapine.
• Drug administration mimicked clinical nevirapine monotherapy duration (2-3 weeks).
• Selection of drug-resistant mutations and monitoring of viral populations were performed.

Main Results:

• Nevirapine treatment selected for RT mutations Y181C and K103N, mirroring HIV-1 resistance mutations.
• Mutant and wild-type viruses coexisted, allowing monitoring of resistance dynamics.
• Low-dose nevirapine was not more effective in inducing mutations than a virus-inhibiting dose.
• Structured therapy interruptions were feasible within the model.

Conclusions:

• The RT-SHIV monkey model provides a viable in vivo system for studying HIV-1 drug resistance.
• This model can be used to assess the effects of various therapies on resistance development.
• Understanding resistance dynamics is critical for optimizing HIV-1 treatment strategies.