2011 Fiscal Year Final Research Report

Identification of novel resistance mechanism of HIV-1 fusion inhibitors

Research Project

Project/Area Number	23890091
Research Category	Grant-in-Aid for Research Activity Start-up
Allocation Type	Single-year Grants
Research Field	Infectious disease medicine
Research Institution	Kyoto University
Principal Investigator	SHIMURA Kazuya 京都大学, ウイルス研究所, 助教 (90613836)
Project Period (FY)	2011
Keywords	HIV / 融合阻害薬 / 耐性機序
Research Abstract	Enfuvirtide(fuzeon ; also known as T-20), an HIV-1 gp41-derived peptide, efficiently inhibits HIV infection by blocking the membrane fusion step between the virus and host cells. We have developed several potential next-generation fusion inhibitors, such as SC34 and SC34EK, which are active against T-20-resistant HIV-1 strains. SC34EK selected several mutations in gp41, and about half of them were located in the C-terminus of gp41, a region specifically called"cytoplasmic tail". This region is believed to be essential for efficient viral infection and replication, though there is no report of fusion inhibitors selecting mutations in the cytoplasmic tail so far. We observed that mutations in the cytoplasmic tail conferred resistance to fusion inhibitors including T-20 and SC34EK, and also impaired viral infection. These results indicate that fusion inhibitor-selected mutations in the cytoplasmic tail are involved in drug susceptibility by influencing viral infection steps.