Third International Congress Drug Therapy in HIV Infection 3-7 November 1996 Glasgow, UK

VIRAL DIVERSITY IN THE AFTERMATH OF CHEMOTHERAPY: BIOCHEMICAL AND TISSUE CULTURE STUDIES ON ISOLATED VIRUSES.

M.A. Weinberg
McGill University AIDS Centre, Jewish General Hospital, Montreal, Canada.

Int Cong Drug Therapy HIV 1996 Nov 3-7;3:Abstract No. 4.3
AIDS 1996, Vol. 10 (Suppl. 2);S3

We studied the effect of different mutation sites in HIV RT, selected by chemotherapy, on viral growth characteristics and enzyme behaviour.

Recombinant wild-type and mutant RTs have been expressed and studied in cell-free assays. In addition, viral populations were studied for growth characteristics and drug resistance.

Treatment with inhibitors of HIV reverse transcriptase (RT) results in viral forms that may differ qualitatively from pre-existing species and from each other. For example, the M184V and K65R substitutions, that are selected by 3TC and ddC, confer diminished and increased processivity, respectively, to HIV RT. The MI84V but not the K65R mutation also results in a higher fidelity RT, as determined in both cell-free and viral replication assays.

Infection of cells with AZT-resistant variants, in the presence of drug, led to enhanced synthesis of viral DNA. This finding was observed only with AZT-resistant viruses, but not viruses resistant to ddC, ddI, or 3TC. These results suggest an explanation for the failure of RTs, containing AZT resistance mutations, to behave as drug-resistant in cell-free assays.

The use of triple drug therapy (Nevirapine/AZT/ddl) has led to non-detectable levels of virus in plasma in over 75% of patients who were previously drug naïve. In most cases in which viruses were recovered, they remained sensitive to each of these drugs. However, several patients who were non-compliant in regard to use of ddl developed resistance to Nevirapine, although not to either AZT or ddI. Sequencing studies revealed the presence of mutations associated with Nevirapine resistance in these samples. The triple combination can therefore suppress both viral load and the emergence of drug resistance. However, non-compliance may lead to resistance to Nevirapine, even in cases in which viral burden remains low.

Presenting author: M.A. Weinberg

1996-11-03
4.3

Originally published in AIDS Volume 10, Supplement 2 and hosted with permission of the publisher Lippincott Williams & Wilkins, 250 Waterloo Road, London, SE1 8RD, UK. Tel: +44 (0)20 7981 0700 Fax: +44 (0) 7981 0701

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