AIDS RESEARCH AND HUMAN RETROVIRUSES Volume 22, Number 3, 2006, pp. 289–293 © Mary Ann Liebert, Inc. Sequence Note Phenotypic Drug Resistance Patterns in Subtype A HIV-1 Clones with Nonnucleoside Reverse Transcriptase Resistance Mutations SUSAN H. ESHLEMAN, 1 DANA JONES, 1 JUSTIN GALOVICH, 2,3 ELLEN E. PAXINOS, 2 CHRISTOS J. PETROPOULOS, 2 J. BROOKS JACKSON, 1 and NEIL PARKIN 2 ABSTRACT We analyzed the nonnucleoside reverse transcriptase (RT) inhibitor (NNRTI) susceptibility of 29 subtype A HIV-1 clones isolated from 10 Ugandan women after single-dose nevirapine (NVP) administration. Six clones had no NNRTI resistance-associated mutations (“wild type”), eight had K103N, nine had Y181C, five had G190A, and one had Y181S. Three clones displayed unexpected phenotypic drug susceptibility/resistance based on their RT genotypes. One wild-type clone had reduced susceptibility to NVP, delavirdine (DLV), and efavirenz (EFV), one clone with K103N was susceptible to all three NNRTIs, and one clone with G190A had extreme hy- persusceptibility to DLV. Three unusual HIV-1 RT amino acid substitutions may have contributed to the un- expected phenotypes of the clones: I31T, N136S, and N265D. These polymorphisms were rarely detected among 47,900 HIV-1 genotypes from clinical samples of predominantly United States origin. Further studies are needed to define the genetic correlates of antiretroviral drug resistance in nonsubtype B HIV-1. 289 T HREE NONNUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS (NNRTIs) are currently licensed in the United States: nevi- rapine (NVP), delavirdine (DLV), and efavirenz (EFV). Use of these drugs for HIV-1 treatment may be associated with selec- tion of HIV-1 strains with NNRTI resistance. NNRTI resistance is also seen in many women and infants following exposure to a single dose of NVP for prevention of HIV-1 mother-to-child transmission (pMTCT). 1 Mutations associated with NNRTI resistance have been iden- tified primarily in HIV-1 subtype B, the most prevalent sub- type in the United States. Antiretroviral-naive individuals with nonsubtype B HIV-1 infection frequently have polymorphisms at amino acid positions associated with HIV-1 drug resis- tance. 2,3 Further, subtype-specific differences in the viral back- bone may influence the rate of drug resistance following anti- retroviral drug exposure, 4,5 as well as the type of mutations selected under drug pressure. 6–8 It is becoming increasingly im- portant to characterize antiretroviral drug resistance mutations in other subtypes, since the prevalence of non-subtype B HIV-1 is increasing in some countries where antiretroviral drugs are widely used, and since the availability of antiretroviral drugs for prevention and treatment of HIV-1 infection is increasing in resource-limited settings where non-B subtypes are endemic. We analyzed HIV-1 from 10 Ugandan women, 7 days after the administration of single-dose NVP for pMTCT. All women were antiretroviral drug naive prior to NVP administration. Hu- man experimentation guidelines of the U.S. Department of Health and Human Services and those of the authors’ institu- tions were followed in the conduct of this research. The Vi- roSeq HIV-1 genotyping system (Celera Diagnostics, Alameda, CA) was used to identify NVP resistance mutations and to de- termine the HIV-1 subtype in the pol region. 9 We considered any of the following mutations as associated with resistance to at least one of the NNRTI drugs: A98G, L100I, K101E, K103N, 1 Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205. 2 Monogram Biosciences, South San Francisco, California 94080. 3 Present address: School of Medicine, St. George’s University, Grenada, West Indies. 6099_10_p289-293 3/7/06 9:30 AM Page 289