[30] THE Δ67 COMPLEX OF MUTATIONS ENHANCES THE ABILITY OF HIV-1 REVERSE TRANSCRIPTASE TO EXCISE ZIDOVUDINE, STAVUDINE AND PMPA FROM BLOCKED PRIMERS

12th International HIV Drug Resistance Workshop

10–14 June 2003, Cabo del Sol, Los Cabos, Mexico

THE Δ67 COMPLEX OF MUTATIONS ENHANCES THE ABILITY OF HIV-1 REVERSE TRANSCRIPTASE TO EXCISE ZIDOVUDINE, STAVUDINE AND PMPA FROM BLOCKED PRIMERS

Antivir Ther. 2003; 8:S35 (abstract no. 30)

PL Boyer¹, T Imamichi², SG Sarafianos³, E Arnold³ and SH Hughes¹
¹HIV Drug Resistance Program, NCI-Frederick, Frederick, Md.; ²Clinical Services Program, SAIC-Frederick, Inc., Frederick, Md.; and ³Center for Advanced Biotechnology and Medicine and Rutgers University Chemistry Department, Piscataway, NJ, USA

BACKGROUND: Most patients that receive anti-HIV-1 therapy are treated with drug combinations. Many patients are treated with multiple nucleoside analogues (NRTIs). Viruses that are resistant to multiple NRTIs are an increasing problem. Insertions in the fingers of reverse transcriptase (RT) (most often between amino acids 69 and 70), in combination with T215F/Y, causes enhanced excision of a number of NRTIs. The Δ67 complex (41L/Δ67/T69G/K70R/L74I/K103N/T215Y/ K219Q) has been reported to cause resistance to a number of NRTIs and non-nucleoside inhibitors. We asked whether RT carrying the Δ67 complex mutations could efficiently excise NRTIs.

METHODS: We purified recombinant wild-type HIV-1 RT, RT carrying the Δ67 complex mutations and RT carrying the classical zidovudine (AZT) resistance mutations. These RTs were used to investigate the mechanism(s) of NRTI resistance of the Δ67 complex RT.

RESULTS: The Δ67 complex RT was able to excise AZT, stavudine and PMPA more efficiently than either wild-type RT or AZT-resistant RT. Both the Δ67 complex and the AZT-resistant RT were able to excise PMPA much more efficiently than ddA. In addition, the Δ67 complex RT was able to excise AZT at much lower concentrations of ATP than AZT-resistant RT.

CONCLUSIONS: It would appear that PMPA is relatively susceptible to excision by RTs that carry the classical AZT resistance mutations. PMPA excision is enhanced by RTs carrying the mutations in the Δ67 complex. The ability of RT carrying the Δ67 complex mutations to efficiently excise AZT at low ATP concentrations might provide an advantage for the virus in quiescent cells, where ATP levels are expected to be low. The data suggest that one or more of the Δ67, T69G, L74I or K103N mutations contribute to the ability of the mutant RT to excise AZT at low ATP concentrations.

PRESENTING AUTHOR: SH Hughes

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2003-07-08
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