Elucidation of the mechanism of HIV entry step and the development of novel anti-HIV drug through the analysis of the inhibitory effects on the oligomerization of the chemokine receptors

2020 Fiscal Year Final Research Report

• Project/Area Number: 18K08436
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 54030:Infectious disease medicine-related
• Research Institution: Kumamoto University
• Principal Investigator: Nakata Hirotomo 熊本大学, 病院, 准教授 (40628492)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Keywords: HIV感染 / ケモカイン受容体 / CXCR4 / CCR5 / 抗HIV薬

Outline of Final Research Achievements

Based on the analysis of the crystal structure of CXCR4, we identified several residues that are assumed to be key residues for CXCR4 oligomerization. Then we introduced mutations to these residues, and investigated the influence of these substitution on the CXCR4 oligomerization through several assays. We also tested how the CXCR4 mutations affect the HIV infectivity. We found that the mutation(s), which disrupted the CXCR4 oligomerization, also reduced the HIV infectivity against these CXCR4 expressed cell. These results suggested that the state of CXCR4 oligomerization is favorable for HIV entry to host cells. Further research will lead us to clarify the mechanism of HIV entry step in detail and the development of novel anti-HIV medicine.

Free Research Field

感染症

Academic Significance and Societal Importance of the Research Achievements

HIV感染にはCD4と共にCXCR4・CCR5などのケモカイン受容体がコレセプターとして必要であるが、感染が成立する際のこれらの受容体の詳細な動態は解明されていない。今回CXCR4に多量体形成を阻害する変異を導入したところ、多量体形成阻害によりHIV感染性が低下する傾向が示された。この結果はHIV感染にCXCR4の多量体が必要であることを示しており、このケモカイン受容体の動態の更なる解析はHIVの感染が成立するメカニズムを明らかにし、新規作用機序の薬剤開発につながる可能性がある。