1st International Workshop on HIV Drug Resistance & Treatment Strategies 25-28 June 1997, St. Petersburg, Florida, USA

NOVEL MECHANISM OF DRUG RESISTANCE DUE TO Lys103Asn MUTATION SUGGESTED BY CRYSTAL STRUCTURES OF UNLIGANDED AND INHIBITOR-BOUND Lys103Asn HIV-1 RT

Antiviral Therapy 1997;2 (Suppl 5):9 (abstract no. 13)

Yu Hsiou¹, Jianping Ding¹, Kalyan Das¹, Art Clark Jr¹, Paul AJ Janssen², Jörg-Peter Kleim³, Manfred Rösner³, Stephen H Hughes⁴ and Edward Arnold^1
1Center for Advanced Biotechnology and Medicine (CABM) and Rutgers University Chemistry Department, 679 Hoes Lane, Piscataway, NJ 08854-5638, USA; ²Center for Molecular Design, Janssen Research Foundation, Antwerpsesteenweg 37, B-2350, Vosselaar, Belgium; ³Hoechst AG, General Pharma Research, G 838, 65926 Frankfurt, Germany; and ⁴ABL-Basic Research Program, NCI-Frederick Cancer Research and Development Center, Building 539, PO Box B, Frederick, MD 21702-1201, USA.

Substitution of asparagine for lysine at position 103 of HIV-1 reverse transcriptase (RT) is a resistance mutation commonly seen during monotherapy with many non-nucleoside RT inhibitors (NNRTIs). The Lys103Asn RT variant confers relatively high-level resistance (~50-100-fold) against nevirapine, alpha-APA, TIBO and BHAP [1,2,3,4]. We have determined the crystal structure of unliganded Lys103Asn mutant HIV-1 RT at 2.7 Å resolution. Significant differences occur in the loop region containing the Lys103Asn mutation in the p66 subunit. We have determined the structures of the Lys103Asn HIV-1 mutant RT complexed with HBY 097 at 2.8 Å resolution, and with alpha-APA at 3.0 Å resolution. Both HBY 097 and alpha-APA bind in the hydrophobic pocket near the polymerase active site in a similar manner in wild-type HIV-1 RT and the Lys103Asn mutant. This suggests that the interactions of the inhibitors with both wild-type and Lys103Asn mutant HIV-1 RT are quite similar. In particular, the loop region containing the Lys103Asn mutation in the p66 subunit adopts a similar conformation to that observed in the wild-type HIV-1 RT/inhibitor complexes; only subtle changes in the mutant RT/inhibitor complexes are seen, mainly in the NNIBP region. The results suggests that the differences in the structures of unbound Lys103Asn and wild-type HIV-1 RT may explain the resistance of this mutant to NNRTIs.

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2. Demeter L, Resnick L, Nawaz T, Timpone Jr JG, Batts D & Reichman RC. Phenotypic and genotypic analysis of ateviridine (ATV) susceptibility of HIV-1 isolates obtained from patients receiving combination therapy with ATV and zidovudine. Third Workshop on Viral Resistance, 1993, Gaithersburg, Maryland, USA.

3. Richman DD. Resistance of clinical isolates of human immunodeficiency virus to antiretroviral agents. Antimicrob Agents Chemother. 1993 Jun;37(6):1207-13.

4. Staszewski S, Miller V, Kober A, Colebunders R, Vandercam B, Delescluse J, Clumeck N, Van Wanzeele F, De Brabander M, De Cree J, Moeremans M, Andries K, Bouch C, Stoffels P & Jansen PAJ. Evaluation of the efficacy and tolerance of RO89439 (loviride) and placebo in asymptomatic HIV-1-infected patients. Antivir Ther. 1996 Jan;1(1):42-50.

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