XI International HIV Drug Resistance Workshop: Basic Principles and Clinical Implications Seville, Spain, 2–5 July 2002

BACKGROUND: Most studies of drug-resistance mutations have been focused mainly on HIV-1. Studies on HIV-2 have been much more limited due to the low number of HIV-2 infected individuals compared to HIV-1. Moreover, HIV-2 is predominantly found in West Africa, where treatment is often not available. Overall there is little overlap sequence identity between HIV-1 and HIV-2 viral genomes. Proteases display approximately 50% identity, and their structure is highly similar. We have investigated in this report the possibility that the presence of genotypic changes in the protease of HIV-2 protease can be associated with resistance to protease inhibitors.

METHODS: Blood samples from seven HIV-2-infected patients who had been under protease-inhibitor therapy for more than 6 months were examined. All patients were in regular follow-up in a hospital located in Lisbon, Portugal. Protease genes were amplified directly from proviral DNA extracted from peripheral blood mononuclear cells of patients and DNA sequences were analysed. In vitro viral culture with increasing concentrations of indinavir and saquinavir was performed with HIV-2_ROD clone. For direct mutagenesis the protease gene of HIV-2_ROD was used. The recombinant viral assay (RVA) was constructed by deletion of the protease gene and introduction of a unique restriction site in an env-deleted HIV-2_ROD clone. Intracellular recombination was achieved between HIV-2 vector and protease coding regions. Resultant virus were used to infect P4 cells expressing β-galactosidase in presence of increasing concentrations of protease-inhibitor drugs.

RESULTS: Using the RVA assay, natural susceptibility of HIV-2 primary isolates to indinavir and saquinavir was found to be 4.5 times higher than HIV-1. Phenotypic analysis of protease genes amplified from HIV-2-infected patients showed the presence of mutations G17Q, I82F, R72A, M76V, T12P that confer resistance to indinavir and saquinavir. These mutations are not reported to confer protease inhibitor resistance to HIV-1. In vitro selection pressure with indinavir and saquinavir showed the appearance of similar mutations to HIV-1. Direct mutagenesis in protease of HIV- 2 showed that mutations which confer resistance to HIV-1 do not have similar effect in the resistance of HIV-2 to indinavir and saquinavir.

CONCLUSION: HIV-2 can develop alterations in the protease gene that confer resistance to indinavir and saquinavir. Moreover, the indinavir and saquinavir resistance mutations pattern in HIV-2 protease are not similar to HIV-1. Similarly, HIV-1 resistance mutations to these drugs are not interchangeable with HIV-2.

PRESENTING AUTHOR: J Goncalves

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2002-07-02
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