Analysis of multiple factors involved in the co-existence of R5 and X4 HIV-1s in the infected individuals

• Project/Area Number: 19K08932
• 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: Maeda Yosuke 熊本大学, 大学院生命科学研究部(医), 准教授 (30284764)
• Project Period (FY): 2019-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2021: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2019: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: HIV-1 / エイズ病態 / コレセプタースイッチ / コレセプター / CCR5 / CXCR4 / 混合感染 / coreceptor / AIDS

Outline of Research at the Start

HIV-1にはコレセプターとしてCCR5を使用して感染するR5ウイルスと，CXCR4を使用して感染するR5X4やX4ウイルスがある。一般には感染初期から後期にわたりR5ウイルスが持続感染しているが，感染後期にはCXCR4を利用するウイルスにスイッチするケースがあり，病態の悪化と関連している。本研究では同一個体からコレセプター利用性の異なる複数のウイルスを分離して，それぞれのウイルスがどのような機序で感染個体内で共存・維持されているかを明らかにする。このようなウイルスのスイッチの機序を解明することはHIV-1の感染免疫病態の理解，さらにはHIV-1治療・治癒に貢献することが期待される。

Outline of Final Research Achievements

HIV-1 is transmitted by CCR5-using HIV-1, and induces persistent infection. However, CXCR4-using X4 virus emerges in approximately half of HIV-1-infected individuals at late stage with higher viral load and disease progression called AIDS. However, it has been not fully understand how HIV-1 induces coreceptor switch from R5 to X4. In this study, we focused on subtype A/E in drug users (IDUs) in Vietnam, and found higher prevalence of X4 virus, and mixed infection with R5 virus. Nest generation analysis revealed that the frequency of mixed infection was much higher, indicating the role of mixed infection for the coreceptor switch from R5 to X4 at late stage. Interestingly, we further found that the viral load in mixed infection was significantly higher compared to that in homogenous infection. Take together, mixed infection of R5 and X4 may be involved in coreceptor switch and associated with higher viral load in late stage of infection.

Academic Significance and Societal Importance of the Research Achievements

HIV-1の中でR5ウイルスが基本的なウイルスに対して，X4ウイルスは感染後期のAIDSに観察されることが知られているが，このようなウイルスのスイッチがどのような機序でおこっているのかは明らかでなかった。今回の研究により，両者が同じ感染者に共存している場合，R5とX4ウイルスのどちらのウイルスが主要な集団となるかは，それぞれのウイルスの増殖できる生体内環境によることを明らかにした。したがって，今後の研究により，どのような生体内環境の変化がR5ウイルスからX4ウイルスへのスイッチにつながるのかが明らかとなれば，AIDSへの進行を防ぐHIV-1の新たな治療戦略につながることが期待される。

Research Products

• [Int'l Joint Research] National Hospital of Tropical Medicine(ベトナム)
• [Journal Article] Plasma N-Cleaved Galectin-9 Is a Surrogate Marker for Determining the Severity of COVID-19 and Monitoring the Therapeutic Effects of Tocilizumab (2023)
  • Author(s): Iwasaki-Hozumi Hiroko、Maeda Yosuke、Niki Toshiro、Chagan-Yasutan Haorile、Bai Gaowa、Matsuba Takashi、Furushima Daisuke、Ashino Yugo、Hattori Toshio
  • Journal Title: International Journal of Molecular Sciences Volume: 24 Issue: 4 Pages: 3591-3591
  • DOI: 10.3390/ijms24043591
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Control of HIV-1 Replication by CD8+ T Cells Specific for Two Novel Pol Protective Epitopes in HIV-1 Subtype A/E Infection. (2022)
  • Author(s): Nguyen HT, Kuse N, Zhang Y, Murakoshi H, Maeda Y, Tamura Y, Maruyama R, Tran GV, Nguyen TV, Nguyen KV, Oka S, Chikata T, Takiguchi M.
  • Journal Title: Journal of Virology Volume: 96 Issue: 19
  • DOI: 10.1128/jvi.00811-22
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Resistance of SARS-CoV-2 variants to neutralization by antibodies induced in convalescent patients with COVID-19 (2021)
  • Author(s): Kaku Y, Kuwata T, Zahid HM, Hashiguchi T, Noda T, Kuramoto N, Biswas S, Matsumoto K, Shimizu M, Kawanami Y, Shimura K, Onishi C, Muramoto Y, Suzuki T, Sasaki J, Nagasaki Y, Minami R, Motozono C, Toyoda M, Takahashi H, Kishi H, Fujii K, Tatsuke T, Ikeda T, Maeda Y, Ueno T, Koyanagi Y, Iwagoe H, Matsushita S.
  • Journal Title: Cell Reports Volume: 36 Issue: 2 Pages: 109385-109385
  • DOI: 10.1016/j.celrep.2021.109385
  • Peer Reviewed / Open Access
• [Journal Article] High Levels of the Cleaved Form of Galectin-9 and Osteopontin in the Plasma Are Associated with Inflammatory Markers That Reflect the Severity of COVID-19 Pneumonia (2021)
  • Author(s): Bai Gaowa、Furushima Daisuke、Niki Toshiro、Matsuba Takashi、Maeda Yosuke、Takahashi Atsushi、Hattori Toshio、Ashino Yugo
  • Journal Title: International Journal of Molecular Sciences Volume: 22 Issue: 9 Pages: 4978-4978
  • DOI: 10.3390/ijms22094978
  • Peer Reviewed / Open Access
• [Journal Article] High levels of the cleaved form of galectin-9 and osteopontin in the plasma are associated with inflammatory markers that reflect the severity of COVID-19 pneumonia (2021)
  • Author(s): Bai G, Furushima D, Niki T, Matsuba T, Maeda Y, Takahashi A, Hattori T, Ashino Y
  • Journal Title: Int J Mol Sci in press Volume: in press
  • Peer Reviewed / Open Access
• [Journal Article] Existence of replication-competent minor variants with different coreceptor usage in plasma from HIV-1-infected individuals (2020)
  • Author(s): Maeda Y, Takemura T, Chikata T, Kuwata T, Terasawa H, Fujimoto R, Kuse N, Akahoshi T, Murakoshi H, Van Tran G, Zhang Y, Pham CH, Pham AHQ, Monde K, Sawa T, Matsushita S, Nguyen TV, Van Nguyen K, Hasebe F, Yamashiro T, Takiguchi M.
  • Journal Title: Journal of Virology Volume: 94 Issue: 12
  • DOI: 10.1128/jvi.00193-20
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Plasma Levels of a Cleaved Form of Galectin-9 Are the Most Sensitive Biomarkers of Acquired Immune Deficiency Syndrome and Tuberculosis Coinfection (2020)
  • Author(s): Padilla ST, Niki T, Furushima D, Bai G, Chagan-Yasutan H, Telan EF, Tactacan-Abrenica RJ, Maeda Y, Solante R, Hattori T
  • Journal Title: Biomolecules Volume: 10 Issue: 11 Pages: 1495-1495
  • DOI: 10.3390/biom10111495
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The Phosphatidylinositol 3-Kinase p110α/PTEN Signaling Pathway Is Crucial for HIV-1 Entry (2019)
  • Author(s): Hamada K, Maeda Y, Mizutani A, Okada S
  • Journal Title: Biological and Pharmaceutical Bulletin Volume: 42 Issue: 1 Pages: 130-138
  • DOI: 10.1248/bpb.b18-00801
  • NAID: 130007542232
  • ISSN: 0918-6158, 1347-5215
  • Year and Date: 2019-01-01
  • Peer Reviewed / Open Access
• [Journal Article] The role of conventional antibodies targeting the CD4 binding site and CD4-induced epitopes in the control of HIV-1 CRF01_AE viruses. (2019)
  • Author(s): Thida W, Kuwata T, Maeda Y, Yamashiro T, Tran GV, Nguyen KV, Takiguchi M, Gatanaga H, Tanaka K, Matsushita S
  • Journal Title: Biochem Biophys Res Commun Volume: 508 Issue: 1 Pages: 46-51
  • DOI: 10.1016/j.bbrc.2018.11.063
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] 天然化合物ライブラリーによる HIV-1放出阻害剤の探索 (2022)
  • Author(s): 田原 由莉歌、戸上 暉大、立石 大、門出 奈美、寺 沢 広美、澤 智裕、前田 洋助、渡邊 高志、藤田 美歌子、門出 和精
  • Organizer: 第６９回日本ウイルス学会学術集会
• [Presentation] High frequency of mixed infection with different coreceptor usage in CRF01_AE-HIV-1-infected intravenous drug users (2021)
  • Author(s): Yosuke Maeda, Takayuki Chikata, Taichiro Takemura, Hiromi Terasawa, Matsufuji Tetsu, Nozomi Kuse, Kazuaki Monde, Tomohiro Sawa, Futoshi Hasebe, Masafumi Takiguchi
  • Organizer: 第６８回日本ウイルス学会学術集会・総会
• [Presentation] The existence of replication-competent minor variants with different coreceptor usage in CRF01_AE HIV-1-infected individuals in northern Vietnam (2019)
  • Author(s): 前田 洋助
  • Organizer: 日本学術振興会研究拠点形成事業シンポジウム
  • Invited
• [Presentation] ウイルスから見たHIV/AIDS (2019)
  • Author(s): 前田 洋助
  • Organizer: 災害・熱帯感染症国際セミナー
  • Invited