system
Medical AI Inquiry: You was designed to assist in medical decision-making based on the provided user questions. It is crucial to provide accurate and comprehensive information to receive a well-informed response.  Labels: OBJECTIVE, METHODS, METHODS, RESULTS. Meshes: Anti-HIV Agents, Cells, Cultured, Clone Cells, Drug Resistance, Viral, Furans, HIV Infections, HIV Integrase, HIV-1, Humans, Mutation, Phenotype, Polymerase Chain Reaction, Triazoles, Virus Replication.
user
Do multiple mutations in human immunodeficiency virus-1 integrase confer resistance to the clinical trial drug S-1360? Context: Study of HIV-1 resistance development to the diketo analogue S-1360, the first HIV-1 integrase strand transfer inhibitor that has entered clinical development. HIV-1(IIIB) was passaged in cell culture in the presence of increasing concentrations of S-1360 (IIIB/S-1360(res)). The IIIB/S-1360(res) strains selected for 30, 50 and 70 passages in the presence of S-1360 were evaluated genotypically by sequencing analysis and phenotypically using the MT-4/MTT assay. Multiple mutations, nine in total, emerged progressively in the catalytic domain of integrase as a result of the selection process. They included T66I and L74M that have both been associated with resistance against the diketo acid L-708,906. After 30, 50 and 70 passages in the presence of S-1360, IIIB/S-1360(res) displayed a four-, eight- and more than 62-fold reduced susceptibility for S-1360, respectively. Phenotypic cross-resistance to L-708,906 was modest for the IIIB/S-1360(res) strain selected during 50 passages, but pronounced for the strain selected during 70 passages. Interesting, all IIIB/S-1360(res) strains remained fully susceptible to the pyranodipyrimidine V-165, an integrase DNA binding inhibitor. Recombination of the mutant integrase genes into wild-type background by integrase-chimeric virus technology entirely reproduced the resistance profile of the IIIB/S-1360(res) strains. As for the replication kinetics of the selected and recombined strains, reduced replication fitness was measured for all strains when compared with their respective wild-type strains.
assistant
The accumulation of integrase mutations coincided with an increasing level of (cross-)resistance of IIIB/S-1360(res). Integrase-chimeric virus technology confirmed that the integrase mutations are indeed fully responsible for the resistance phenotype of IIIB/S-1360. Final Decision: yes