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

A UNIQUE MECHANISM FOR ZIDOVUDINE-RESISTANCE AND EVIDENCE FOR A ZIDOVUDINE-MEDIATED CROSS-RESISTANCE TO OTHER NUCLEOSIDE ANALOGUES BY ZIDOVUDINE-RESISTANT VIRUSES

Antiviral Therapy 1997;2 (Suppl 5):7 (abstract no. 10)

Miguel E Quiñones-Mateu¹, Jamie L Albright¹, James-Paul Marois², Mita Ghosh¹, Stuart FJ Le Grice¹, Charles Hough², Mark A Wainberg² and Eric J Arts^1
1Division of Infectious Diseases, Department of Medicine, Case Western Reserve University, Ohio, USA; and ²McGill AIDS Centre, McGill University, Montreal, Quebec, Canada

At the meeting last year in Whistler, we reported that zidovudine may stimulate reverse transcription in MT-4 cells infected with zidovudine-resistant virus. We now show that this zidovudine-mediated stimulation occurs in MT-4, Jurkat, or peripheral blood mononuclear cells infected with virus containing the T215Y and/or M41L mutations but not with virus containing the K70R mutation. A zidovudine- or nucleoside analogue-mediated stimulation of reverse transcription was not observed in these cells infected with wild-type, ddC-resistant (K65R) or lamivudine-resistant (M184V) viruses. Development of zidovudine-resistance in patients undergoing zidovudine monotherapy is associated with an initial appearance of K70R virus, which is later replaced by virus containing the T215Y change. In patients undergoing zidovudine plus didanosine or zalcitabine combination therapy, the onset of zidovudine-resistance correlates with the appearance of the T215Y mutation or, to a lesser extent, the multi-drug resistant mutations (A62V, V75I, F77L, F116Y and Q151M) but rarely the K70R mutation. Failure of zalcitabine or didanosine, in combination with zidovudine, to inhibit HIV-1 replication is not associated with an appearance of zalcitabine- or didanosine-resistant mutations. We now show that T215Y virus does confer multi-nucleoside analogue resistance similar to that observed with the A62V/V75I/F77L/ F116Y/Q151M virus. M41L/T215Y, K70R and T215Y viruses were resistant to zidovudine and sensitive to zalcitabine and didanosine. However, IC₅₀ values for didanosine and zalcitabine increased five-fold with M41L/T215Y and T215Y viruses in the presence of zidovudine. This increase is comparable to the level of HIV-1 resistance to zalcitabine and didanosine observed with mutations K65R and L74V, respectively. Zidovudine-mediated cross-resistance was not observed with the K70R virus, corresponding to a lack of zidovudine-mediated stimulation of reverse transcription with this mutant. These results suggest that the mechanism of zidovudine resistance is not simply a preference of TTP over zidovudine-TP but rather a stimulation of the T215Y RT overriding the antiviral effects of zidovudine or other nucleoside analogues. We now have biochemical evidence supporting the zidovudine-mediated stimulation and cross-resistance effects. It appears that zidovudine-5´-monophosphate, the major zidovudine metabolite in cells, may act as a co-factor for the polymerase activity of recombinant HIV-1 RTs containing the M41L, T215Y and/or K219E mutations.

Download PDF of this abstract.

1997-06-25
10

Copyright © 1997 - International Medical Press Ltd. Reproduction of this abstract (other than one copy for personal reference) must be cleared through the International Medical Press Ltd. 2-4 Idol Lane, London EC3R 5DD UK.