Resistance to antiretroviral drugs can limit the efficacy of regimens for prevention and treatment of HIV-I infection. A wealth of studies have analyzed HIV-1 drug resistance in subtype B, the most common HIV-1 subtype in the U.S. However, remarkably little is known about drug resistance in other subtypes, even though non-B subtypes account for the overwhelming majority of HIV-1 infections worldwide. Research on drug resistance in non-subtype B HIV-1 is becoming increasingly important for two reasons: (1) the prevalence of non-subtype B is increasing in the U.S. and other countries where antiretroviral drugs are widely used, and (2) the availability and use of antiretroviral drugs is growing in countries where non-subtype B HIV-1 is prevalent. This proposal will test the hypothesis that resistance of HIV-1 to antiretroviral drugs is influenced by HIV-I subtype. These experiments will be performed in the context of the Ugandan HIVNET 012 trial, which demonstrated that single dose nevirapine (NVP) prophylaxis can prevent HIV-1 mother-to-child transmission. That regimen is now being implemented in resource-poor countries around the world. We found that NVP resistance (NVPR) arose in 24% of women in HIVNET 012 6-8 weeks after NVP administration. Furthermore, we found that the rate of NVPR 6-8 weeks after NVP is significantly higher in women with subtype D than A (35/98=36% vs. 24/149=16%, respectively, p=0.0004). Emergence of NVPR in this setting could limit the efficacy of NVP prophylaxis in future pregnancies, and could limit treatment options for women and infants. NVPR could also spread in the population, decreasing the efficacy of NVP prophylaxis over time. In this proposal, we will further define the virologic factors that influence emergence and fading of NVPR following NVP prophylaxis in women with subtype A and D infection.
The Specific Aims of this proposal are:
Aim 1 : Compare HIV-1 sequences from women in HIVNET 012 before and after single dose NVP to define the genetic correlates of NVPR in subtype A and D.
Aim 2 : Compare the emergence and fading of NVPR in women in HIVNET 012 with subtype A vs. D.
Aim 3 : Compare the antiretroviral drug susceptibility of subtype A and D HIV-1 variants in the presence and absence of NVPR mutations.
Aim 4 : Compare the fitness of subtype A vs. D HIV-I variants in the presence and absence of NVPR mutations. Information gained from this proposal will enhance our understanding of the impact of HIV-I subtype on antiretroviral drug resistance, and will help optimize antiretmviral regimens for prevention and treatment of HIV-1 infection.
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