3rd Conference on Retroviruses and Opportunistic Infections Washington, DC - January 28-February 1, 1996

Conf Retroviruses Opportunistic Infect 1996 Jan 28-Feb 1; 3rd:53 (abstract no. 2)

Tachedjian G, Mellors J, Hooker DJ, Deacon NJ, Birch C, Mills J
Macfarlane Burnet Centre for Medical Research, Fairfield, Australia.

PFA is a DNA polymerase inhibitor active against herpesviruses and HIV-1. As AZT and PFA may be used concurrently in HIV-1 infected individuals, the potential of HIV-1 to develop co-resistance to these inhibitors was examined. Exposure of wild-type HIV-1 to escalating concentrations of AZT and PFA resulted in a PFA -resistant (PFA-R) virus with K70R V751 and K219R mutations. Despite AZT resistance-associated mutations, this strain was phenotypically susceptible to AZT. A mixture of AZT-R molecular clones was also exposed to increasing PFA concentrations in the absence or presence of 0.2 mu AZT. These selection experiments both yielded strains that were PFA-R and AZT-S, with a significant delay in the emergence of PFA-R virus in the presence of AZT. Their genotypes were M41L, K70R W88G, T215Y, and M41L, D67N, S68N, K70R, W88S, T215Y and L260V, respectively, indicating suppression of AZT-resistance by novel mutations. Mutations at codon 88 have previously been reported in PFA-R HIV-1 clinical isolates from AIDS patients which were susceptible to AZT despite the presence of up to four AZT resistance mutations. To define the role of codon 88 mutations in suppression of AZT resistance, W88G and W88S were introduced into both wild-type and AZT-R genotypes (L41M, D67N, K70R and T215Y; MQ). W88G and W88S conferred 5 and 2 fold PFA resistance in a wild-type background while W88G also conferred hypersusceptibility to AZT (4 fold). Introduction of W88G into the highly AZT-R background of MQ showed complete suppression of phenotypic AZT resistance and 3.5 fold PFA resistance. In contrast, W88S partially suppressed AZT resistance while eliminating PFA resistance in this MQ backbone indicating that this mutation is not sufficient to completely suppress AZT resistance. In summary, mutants of HIV-1 co-resistant to AZT and PFA could not be selected in vitro. AZT resistance was suppressed by PFA-R mutations, and PFA-R HIV- I is hypersusceptible to AZT. Taken together, these data suggest that clinical trials of combination therapy with PFA and AZT or their analogs should be considered.

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Copyright © 1996 - Foundation for Retrovirology and Human Health . Reproduction of this abstract (other than one copy for personal reference) must be cleared through the Foundation for Retrovirology and Human Health.