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Journal of Virology, May 2003, p. 5685-5693, Vol. 77, No. 10
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.10.5685-5693.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

A Novel Genetic Pathway of Human Immunodeficiency Virus Type 1 Resistance to Stavudine Mediated by the K65R Mutation

J. Gerardo García-Lerma,1* Hamish MacInnes,1 Diane Bennett,2 Patrick Reid,1 Soumya Nidtha,1 Hillard Weinstock,2,{dagger} Jonathan E. Kaplan,1,2 and Walid Heneine1

HIV and Retrovirology Branch, Division of AIDS, STD, and TB Laboratory Research, National Center for Infectious Diseases,1 Prevention Services Research Branch, Division of HIV/AIDS Prevention, National Center for HIV, STD, and TB Prevention, Centers for Disease Control and Prevention, Atlanta, Georgia2

Received 18 November 2002/ Accepted 28 February 2003

Stavudine (d4T) and zidovudine (AZT) are thymidine analogs widely used in the treatment of human immunodeficiency virus type 1 (HIV-1)-infected persons. Resistance to d4T is not fully understood, although the selection of AZT resistance mutations in patients treated with d4T suggests that both drugs have similar pathways of resistance. Through the analysis of genotypic changes in nine recombinant viruses cultured with d4T, we identified a new pathway for d4T resistance mediated by K65R, a mutation not selected by AZT. Passaged viruses were derived from treatment-naïve persons or HIV-1HXB2 and had wild-type reverse transcriptase (RT) or T215C/D mutations. K65R was selected in seven viruses and was associated with a high level of enzymatic resistance to d4T-triphosphate (median, 16-fold; range, 5- to 48-fold). The role of K65R in d4T resistance was confirmed in site-directed mutants generated in three different RT backgrounds. Phenotypic assays based on recombinant single-cycle replication or a whole-virus multiple replication cycle were unable to detect d4T resistance in d4T-selected mutants with K65R but detected cross-resistance to other nucleoside RT inhibitors. Four of the six viruses that had 215C/D mutations at baseline acquired the 215Y mutation alone or in association with K65R. Mutants having K65R and T215Y replicated less efficiently than viruses that had T215Y only, suggesting that selection of T215Y in patients treated with d4T may be favored. Our results demonstrate that K65R plays a role in d4T resistance and indicate that resistance pathways for d4T and AZT may not be identical. Biochemical analysis and improved replication assays are both required for a full phenotypic characterization of resistance to d4T. These findings highlight the complexity of the genetic pathways of d4T resistance and its phenotypic expression.

* Corresponding author. Mailing address: HIV and Retrovirology Branch, Centers for Disease Control and Prevention, 1600 Clifton Rd. NE, MS G-19, Atlanta, GA 30333. Phone: (404) 639-4987. Fax: (404) 639-1174. E-mail: GGarcia-lerma{at}cdc.gov.

{dagger} Present address: Epidemiology and Surveillance Branch, Division of STD Prevention, National Center for HIV, STD, and TB Prevention, Centers for Disease Control and Prevention, Atlanta, GA 30333.

Journal of Virology, May 2003, p. 5685-5693, Vol. 77, No. 10
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.10.5685-5693.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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