3rd International Workshop on HIV Drug Resistance 2-5 August 1994, Kauai, Hawaii, USA

IN VITRO GENERATION AND CHARACTERISATION OF FOSCARNET-RESISTANT HIV-1

Int Wkshop HIV Drug Res 1994 Aug 2-5;3:23 (abstract no. 22)

G. Tachedjian, A. Gurusinghe, D. Hooker, N. Deacon, J. Mills and C. Birch*
Macfarlane Burnet Centre for Medical Research and *VIDRL, Fairfield Hospital, Victoria, Australia

Foscarnet (phosphonoformic acid) is a pyrophosphate analogue used in the treatment of CMV retinitis and acyclovir-resistant herpes simplex infections in AIDS patients. Foscarnet is also an inhibitor of HIV-1 at the reverse transcriptase level, and therefore long-term administration in patients may result in the emergence of foscarnet-resistant (Fos-R) virus. To investigate the potential for Fos-R HIV to emerge in vivo we have generqted a resistant variant by in vitro selection in MT-2 cells. The variant was biologically cloned in the presence of varying· inhibitory concentrations of foscarnet and compared to the original sensitive isolate with respect to sensitivity to foscarnet and to zidovudine, azidodideoxyuridine, dideoxycytidine (ddC), dideoxyinosine (ddI), TIBO and nevirapine. The nucleotide sequence of the entire reverse transcriptase gene was also determined. Following 6 passages in increasing concentrations of foscarnet, a resistant virus emerged with 5-fold decreased sensitivity to foscarnet at the IC₅₀ level. Nucleotide sequence analysis of four clones revealed the changes Glu89 to Lys or Leu92 to lIe. Compared to foscarnet-sensitive HIV-1, variants with the 89 or 92 changes showed hypersensitivity to azido-based nucleoside analogues and non-nucleoside reverse transcriptase inhibitors, while identical sensitivity profiles were observed in the presence of ddC and ddI. These results and the potential for Fos-R virus to arise in vivo, have important implications in treatment strategies involving foscarnet.

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1994-08-02
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