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Reversal of HIV Drug Resistance and Novel Strategies to Curb HIV Infection: The Viral Infectivity Factor Vif as a Target and Tool of Therapy

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Due to the high genetic variability of human immunodeficiency virus (HIV), treatment of AIDS (acquired immunodeficiency syndrome) patients with inhibitors of reverse trancriptase (RT) and drugs blocking the viral protease regularly results in the accumulation of drug resistant HIV variants and treatment failure. The sensitivity of clinically derived resistant HIV-1 strains to nucleotide RT inhibitors could be restored, however, in several laboratories by pharmacological depletion of the appropriate endogenous deoxynucleotide triphosphate (dNTP), and such a manipulation (induction of dCTP pool imbalance during reverse transcription in the presence of a non-nucleoside RT inhibitor) altered the mutation spectrum of the HIV-1 genome, resulting in a lower level of HIV resistance to certain drugs. The cytoplasmic singlestranded DNA cytidine deaminases APOBEC3G and APOBEC3F block HIV replication by introducing premature stop codons into the viral genome. We suggest that the resulting crippled, defective HIV (dHIV) variants could interfere with replication of "wild type" viruses and curbe disese progression in long term non-progressor individuals. Vif, an accessory protein encoded by HIV, counteracts APOBEC3G/F action. We speculate that small molecule inhibitors of Vif could permit lethal or sublethal mutagenesis of HIV genomes. We suggest that an artificial dHIV construct carrying a mutated vif gene (coding for a Vif protein unable to block APOBEC3G/F) could have a therapeutic effect as well in HIV infected individuals and AIDS patients.

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Keywords: APOBEC3G; Human immunodeficiency virus (HIV); Vif; antiretroviral therapy; dNTP pool; defective HIV (dHIV); drug resistance; mutation spectrum

Document Type: Research Article

Affiliations: Microbiological Research Group, National Center for Epidemiology, H-1529 Budapest, Piheno u. 1,Hungary.

Publication date: July 1, 2006

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  • Current Drug Targets aims to cover the latest and most outstanding developments on the medicinal chemistry and pharmacology of molecular drug targets e.g. disease specific proteins, receptors, enzymes, genes. Each issue of the journal will be devoted to a single timely topic, with series of in-depth reviews, written by leaders in the field, covering a range of current topics on drug targets. These issues will be organized and led by a guest editor who is a recognized expert in the overall topic. As the discovery, identification, characterisation and validation of novel human drug targets for drug discovery continues to grow; this journal will be essential reading for all pharmaceutical scientists involved in drug discovery and development.
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