Exposure of HIV-1 to a combination of two carbohydrate-binding agents markedly delays drug resistance development and selects for virus strains with compromised fitness.

OBJECTIVES We investigated the effect of combining two potent carbohydrate-binding agents (CBAs) with a complementary resistance profile (based on different N-glycan deletion selections in the HIV envelope glycoprotein gp120) on drug resistance development and viral fitness. METHODS A long-term selection procedure was used to obtain virus strains resistant to the mannose-specific Hippeastrum hybrid agglutinin (HHA), the mannose-recognizing monoclonal antibody 2G12 and the combination of both compounds. The env genes of the mutant viruses were sequenced and the infectivity potential and phenotypic resistance profile of the virus strains were examined in CD4+ T lymphocyte C8166 cell cultures. RESULTS The long-term exposure of HIV-1 to CBAs resulted in the selection of virus isolates containing deletions of several high-mannose-type N-glycans in their envelope. The generation of virus strains phenotypically resistant to the combination of both CBAs took markedly longer than the generation of virus strains resistant to the single compounds. The mutant HIV strains derived from the HHA/2G12 combination exposure showed much lower genotypic and phenotypic resistance than those isolated from the virus selection experiments with the single compounds. It was further shown that the CBA-resistant viruses had significantly decreased infectivities. CONCLUSIONS The data revealed that CBAs are interesting anti-HIV drug candidates with an increased antiviral potential upon internal combination.