2022 Fiscal Year Final Research Report

Study of mechanism of HIV resistance to integrase strand transfer inhibitors (INSTI) aiming at development of INSTI-resistance-repellant therapeutics

Research Project

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Project/Area Number	20H03727
Research Category	Grant-in-Aid for Scientific Research (B)
Allocation Type	Single-year Grants
Section	一般
Review Section	Basic Section 54030:Infectious disease medicine-related
Research Institution	National Center for Global Health and Medicine
Principal Investigator	MITSUYA Hiroaki 国立研究開発法人国立国際医療研究センター, その他部局等, 研究所長 (20136724)
Co-Investigator(Kenkyū-buntansha)	青木学熊本保健科学大学, 保健科学部, 教授 (70389542)
Project Period (FY)	2020-04-01 – 2023-03-31
Keywords	HIV-1 / インテグラーゼ阻害剤 / 薬剤耐性
Outline of Final Research Achievements	Five integrase strand transfer inhibitors (INSTIs) have been used for treatment of HIV-1 infection/AIDS. Dolutegravir (DTG), a second-generation INSTI, has more potent antiviral activity with a high genetic barrier to development of drug resistance compared to first-generation INSTIs including raltegravir. Indeed, wild-type HIV-1 fails to develop highly DTG-resistant nature in vitro. However, Q148H/R/K mutations, which do not alter the susceptibility to DTG, facilitate HIV-1 to develop high-level resistance to DTG in patients who receive with DTG-containing regimens. The precise mechanisms by which HIV-1 acquires resistance to second-generation INSTIs such as DTG remain poorly understood. In this study, we attempted to clarify the mechanism of HIV-1’s acquisition of resistance to second-generation INSTIs and to develop anti-HIV-1 drugs, which are highly effective to INSTI-resistant HIV-1 variants with a high genetic barrier to development of drug resistance.
Free Research Field	感染症内科学、血液内科学
Academic Significance and Societal Importance of the Research Achievements	HIVの高度INSTI耐性の発現にはインテグラーゼ（IN）の酵素活性部位を構成する3つのアミノ酸と直接、間接的に相互作用する複数のアミノ酸置換の蓄積が必要である。本研究で明らかにしたINSTI耐性機序は耐性株にも効果のある新規INSTI開発に繋がると思われる。更に、開発中のHIVプロテアーゼ阻害剤GRL-142がINにも直接結合し、ウイルスcDNAの核移行を阻害する新規のHIV複製阻害メカニズムを明らかにした。GRL-142はINSTI耐性HIVに対しても高い活性を発揮することから、世界的な懸念材料となっているINSTI耐性HIVを有する感染者に対する治療薬開発に大きく資すると思われる。