Understanding of the impact of infection microenvironment in HIV reactivation and cell-to-cell transmission

2022 Fiscal Year Final Research Report

• Project/Area Number: 20H03498
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 49060:Virology-related
• Research Institution: Yokohama City University
• Principal Investigator: RYO Akihide 横浜市立大学, 医学研究科, 客員教授 (20363814)
• Co-Investigator(Kenkyū-buntansha): 中林 潤 東京医科歯科大学, 統合教育機構, 教授 (80322733)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: HIV / エイズ / 感染症 / 微小環境 / 宿主因子

Outline of Final Research Achievements

In this research project, we found that treatment of three-dimensional infected cell models with type I interferon markedly reduced the amount of viral cell-to-cell spread from infected to uninfected cells.　A protein-protein interaction analysis revealed that the transmembrane protein MAL accumulated HIV-1 Gag protein in the host endosomal compartment, leading to its degradation in lysosomes. We searched for host factors that are cleaved by HIV-encoded proteases. We found that PR specifically cleaved the TBK1 and markedly reduced the kinase activity of TBK1. In fact, in HIV PR-expressing cells, nuclear translocation of IRF3 and production of type I IFN were reduced upon innate immune signals.　We analyzed the molecular mechanism of HIV-2 latency under hypoxia and found that the hypoxia-inducible factor HIF-1α induces multiple long non-coding RNAs bound to the transcriptional regulatory region of HIV-2 and suppressed HIV-2 gene expression through an epigenetic regulatory mechanism.

Free Research Field

ウイルス学

Academic Significance and Societal Importance of the Research Achievements

HIV感染症は死亡率が劇的に改善したが、体内に残存するHIV潜伏感染細胞がしばしば再活性化するため根治療法は未だ存在しない。３次元微小環境培養モデルを用いて、ウイルスの再活性化及び細胞間伝播を可視化・定量化し数理モデルを構築、また、ウイルスの挙動変化を規定する責任因子をマルチオミクス解析により包括的に明らかにすることで、HIV伝播を制御する新たな分子機構の解明とHIV感染症の根治を目指した新規治療法を創出することが期待される。