The study for elucidating the mechanisms of HIV-1's EFdA resistance.

2018 Fiscal Year Final Research Report

• Project/Area Number: 17K15710
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Virology
• Research Institution: Tohoku University (2018); National Center for Global Health and Medicine (2017)
• Principal Investigator: Hayashi Hironori 東北大学, 医学系研究科, 助教 (00752916)
• Project Period (FY): 2017-04-01 – 2019-03-31
• Keywords: HIV / 逆転写酵素 / EFdA

Outline of Final Research Achievements

EFdA was developed as a HIV-1 reverse transcriptase (RT) inhibitor and has been under the clinical trial. In this study, we purified the reverse transcriptase from EFdA resistant HIV-1 variants (RT-EFdA-R) and screened the crystallization conditions. Additionally, we employed the analysis by molecular dynamics to determine the EFdA resistant mechanisms of RT. As the result, an amino acid mutation (M184V) would decreas Van der Waals (VdW) interactions between EFdA and RT-EFdA-R. Thus, the M184V would decrease binding affinity of EFdA. However, EFdA keep strong interactions with F160, which is an amino acid locating at the cavity close to the active center of RT with and without M184V substitution. Notably, the introduction of amino acid mutation, F160A, eliminate growth ability of HIV-1. Thus, HIV-1 hardly introduced the mutation. This was the reason for the high genetic barrier of EFdA. These data shed light on developing the novel RT inhibitors.

Free Research Field

ウイルス学　分子生物学

Academic Significance and Societal Importance of the Research Achievements

EFdAは、HIV-1に対する抗ウイルス療法を1日1回から1週間又は1か月に1回へと変える可能性を有している。また、このような化合物はHIV-1の二次感染を予防する為にも非常に有用でありその社会貢献度は計り知れない。この様に医療、社会、国民衛生に重要な化合物に対してHIV-1が耐性を獲得する機序を詳細に解析する事は、医療の面からも重要であり、また、EFdAがハイジェネティックバリアを発揮する機序は新規化合物の開発に資するため学術的にも非常に有用である。