AEGiS-10IAC: HIV drug resistance: molecular basis and clinical significance.

10th International AIDS Conference

Yokohama, Japan — Aug 7-12, 1994

HIV drug resistance: molecular basis and clinical significance.

Int Conf AIDS 1994 Aug 7-12; 10:5 (abstract no. PS24)
Wainberg MA; McGill University AIDS Centre, Montreal, Quebec, Canada.

OBJECTIVE: It is now been over five years since the initial isolation of HIV variants resistant to AZT. Numerous investigators have now shown that HIV drug resistance can be selected against a wide variety of nucleoside and non-nucleoside antagonists of viral reverse transcriptase (RT), as well as against peptide inhibitors of HIV protease. These studies have been performed both by viral passage in increasing concentrations of antiviral drugs, as well as by isolation of resistant viruses from patients.

METHODS: Cloning and sequencing of relevant viral pol and protease DNA has identified a number of resistance-conferring mutation sites, that have been confirmed by site-directed mutagenesis. Many of these mutations map to the active sites of the viral protease and RT and, as well, to the nucleoside-binding domain of the latter.

RESULTS: In some cases, patterns of cross-resistance have emerged, such that a single mutation may confer resistance to more than one drug, e.g. as is the case for ddC, 3TC, and ddI. In other instances, introduction of certain resistance-conferring mutations into viruses that display resistance to AZT may actually increase sensitivity to the latter drug. Studies on mutated RT proteins have shown that they may no longer incorporate certain forms of triphosphorylated nucleoside analogs.

DISCUSSION: Resistance-conferring mutations can be directly identified in the plasma and cellular virus of patients receiving anti-viral therapy. Monitoring patients for total viral burden, as well as percentage of mutated viral genotypes, associated with drug resistance, may provide an important tool for evaluation of anti-HIV drugs during the course of antiviral chemotherapy.

Keywords: AEGIS, Anti-HIV Agents, Zidovudine, Didanosine, Zalcitabine, Drug Resistance, Reverse Transcriptase Inhibitors, RNA-Directed DNA Polymerase, Nucleosides, Lamivudine, Antiviral Agents, Pharmaceutical Preparations, Mutation, HIV Protease, Human, genetics, ICA10
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PS24