Characterization of AZT susceptibility of biological SIVmac and molecular clones, and emergence of AZT resistant mutants in vitro.

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Characterization of AZT susceptibility of biological SIVmac and molecular clones, and emergence of AZT resistant mutants in vitro.

Symp Nonhum Primate Models AIDS. 1992 Nov 17-20;10:abstract no. 108. Unique Identifier : AIDSLINE PRIM10/93200941
Van Rompay KK; Marthas ML; Lohman BL; Pedersen NC; California Regional Primate Research Center, University of; California, Davis 95616.

Abstract: BACKGROUND: It is not known whether AZT resistant HIV mutants, which emerge in HIV following long-term AZT therapy, have altered pathogenicity. Therefore, it is still controversial whether or not to discontinue AZT administration in these people. Because it is not possible to study pathogenicity of AZT resistant HIV mutants in humans, the SIV-rhesus macaque model can be suitable to study the clinical implications of AZT resistance. GOALS: (1) To use in vitro selection to generate AZT resistant SIV mutants, and (2) to study and characterize the pathogenic potential of AZT resistant SIV mutants in macaques. METHODS: Characterization of SIV for AZT susceptibility was facilitated by the development of an assay based on reduction of viral infectivity by AZT. Titration of viral infectivity (using CEM x 174 cells in 96-well plates, followed after 5 days by p27 antigen measurement and calculation of infectious titer according to Reed and Muench) shows that AZT reduces infectivity in a dose-dependent way. The Inhibitory Concentration which reduces infectivity by 50% (IC50) for unselected SIVmac (biological SIVmac and the molecular clones 1A11 and 239) all fall within a narrow range (0.07-0.2 microM). RESULTS: By propagating and repeatedly passaging cell-free virus in CEM x 174 cells in the presence of AZT, significant increases in IC50 were noticed, indicating increased AZT resistance. CONCLUSION: Further selection, purification and identification of the molecular basis of AZT resistance will allow to introduce the resistant genotypes into pathogenic clones and investigate its implications on in vivo pathogenicity.

Keywords: Acquired Immunodeficiency Syndrome/DRUG THERAPY Animal Cell Line Drug Resistance, Microbial/*GENETICS Genotype Human HIV/*DRUG EFFECTS/PHYSIOLOGY/PATHOGENICITY Macaca mulatta *Mutation Virulence/GENETICS Virus Replication/*DRUG EFFECTS Zidovudine/*PHARMACOLOGY ABSTRACT
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