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.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD042965-04
Application #
6895173
Study Section
AIDS and Related Research 8 (AARR)
Program Officer
Mofenson, Lynne M
Project Start
2002-07-01
Project End
2007-06-30
Budget Start
2005-07-01
Budget End
2007-06-30
Support Year
4
Fiscal Year
2005
Total Cost
$257,513
Indirect Cost
Name
Johns Hopkins University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Flys, Tamara S; McConnell, Michelle S; Matovu, Flavia et al. (2008) Nevirapine resistance in women and infants after first versus repeated use of single-dose nevirapine for prevention of HIV-1 vertical transmission. J Infect Dis 198:465-9
Huang, Wei; Eshleman, Susan H; Toma, Jonathan et al. (2007) Coreceptor tropism in human immunodeficiency virus type 1 subtype D: high prevalence of CXCR4 tropism and heterogeneous composition of viral populations. J Virol 81:7885-93
Flys, Tamara S; Mwatha, Anthony; Guay, Laura A et al. (2007) Detection of K103N in Ugandan women after repeated exposure to single dose nevirapine. AIDS 21:2077-82
Church, Jessica D; Hudelson, Sarah E; Guay, Laura A et al. (2007) HIV type 1 variants with nevirapine resistance mutations are rarely detected in antiretroviral drug-naive African women with subtypes A, C, and D. AIDS Res Hum Retroviruses 23:764-8
Eshleman, Susan H; Hudelson, Sarah E; Bruce, Robert et al. (2007) Analysis of HIV type 1 gp41 sequences in diverse HIV type 1 strains. AIDS Res Hum Retroviruses 23:1593-8
Flys, Tamara S; Donnell, Deborah; Mwatha, Anthony et al. (2007) Persistence of K103N-containing HIV-1 variants after single-dose nevirapine for prevention of HIV-1 mother-to-child transmission. J Infect Dis 195:711-5
Eshleman, Susan H; Hoover, Donald R; Hudelson, Sarah E et al. (2006) Development of nevirapine resistance in infants is reduced by use of infant-only single-dose nevirapine plus zidovudine postexposure prophylaxis for the prevention of mother-to-child transmission of HIV-1. J Infect Dis 193:479-81
Eshleman, Susan H; Jones, Dana; Galovich, Justin et al. (2006) Phenotypic drug resistance patterns in subtype A HIV-1 clones with nonnucleoside reverse transcriptase resistance mutations. AIDS Res Hum Retroviruses 22:289-93
Church, Jessica D; Jones, Dana; Flys, Tamara et al. (2006) Sensitivity of the ViroSeq HIV-1 genotyping system for detection of the K103N resistance mutation in HIV-1 subtypes A, C, and D. J Mol Diagn 8:430-2; quiz 527
Flys, Tamara S; Chen, Shu; Jones, Dana C et al. (2006) Quantitative analysis of HIV-1 variants with the K103N resistance mutation after single-dose nevirapine in women with HIV-1 subtypes A, C, and D. J Acquir Immune Defic Syndr 42:610-3

Showing the most recent 10 out of 22 publications