A study of chemokine receptor dynamics and its inhibitor(s) in HIV infection

• Project/Area Number: 26461510
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Infectious disease medicine
• Research Institution: Kumamoto University
• Principal Investigator: Nakata Hirotomo 熊本大学, 医学部附属病院, 講師 (40628492)
• Research Collaborator: Maeda Kenji ; Iwami Shingo
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2016: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2015: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2014: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: HIV感染症 / CCR5 / 侵入阻害薬 / HIV感染 / ケモカイン / CCR5阻害剤

Outline of Final Research Achievements

We constructed wild type CCR5(CCR5-WT) and mutant CCR5(CCR5-MT), which loses susceptibility against HIV, coexpressing cells and tested HIV infectivity using these cells.10% and 50% levels of CCR5-MT expression reduced the susceptibility against HIV by 50% and almost 100% compared with only CCR5-WT espressing cells, respectively. This result strongly suggested that multiple CCR5 are required for the HIV entry step. Next we developed a mathematical model based on the correlation between the ratio of CCR5-MT expression and HIV susceptibility, and estimated the numbers of CCR5 required for the HIV infection. As a result we quantitatively estimated 6-8 CCR5s are required for gp120 trimer-CCR5 interaction. These data revealed a part of the entry step of HIV infection.

Research Products

• [Journal Article] C-5-Modified Tetrahydropyrano-Tetrahydofuran-Derived Protease Inhibitors (PIs) Exert Potent Inhibition of the Replication of HIV-1 Variants Highly Resistant to Various PIs, including Darunavir (2015)
  • Author(s): Aoki, M. Hayashi, H. Yedidi, R. S. Martyr, C. D. Takamatsu, Y. Aoki-Ogata, H. Nakamura, T. Nakata, H. Das, D. Yamagata, Y. Ghosh, A. K. Mitsuya, H.
  • Journal Title: Journal of Virology Volume: 90 Issue: 5 Pages: 2180-94
  • DOI: 10.1128/jvi.01829-15
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] EFdA, a reverse transcriptase inhibitor , potently blocks HIV -1 ex vivo infection of Langerhans cells within epithelium (2014)
  • Author(s): Matsuzawa T, Kawamura T, Ogawa Y, Maeda K, Nakata H, Moriishi K, Koyanagi Y, Gatanaga H, Shimada S, Mitsuya H
  • Journal Title: J Invest Dermatol Volume: 134(4) Issue: 4 Pages: 1158-61
  • DOI: 10.1038/jid.2013.467
  • Peer Reviewed / Open Access
• [Journal Article] Delayed emergence of HIV-1 variants resistant to 4’-ethynyl-2-fluoro-2’-deoxyadenosine: comparative sequential passage study with lamivudine, tenofovir, emtricitabine and BMS-986001 (2013)
  • Author(s): Kenji Maeda, Darshan V Desai, Manabu Aoki, Hirotomo Nakata, Eiichi N Kodama, Hiroaki Mitsuya
  • Journal Title: Antiviral Therapy Volume: 19 Issue: 2 Pages: 179-189
  • DOI: 10.3851/imp2697
  • Peer Reviewed / Open Access
• [Presentation] 新規CCR5阻害剤GRL-007の抗HIV活性の検討 (2014)
  • Author(s): 中田 浩智, Debananda Das, 前田 賢次, Kalapala Venkateswara Rao, Arun K. Ghosh, 満屋 裕明
  • Organizer: 日本エイズ学会
  • Place of Presentation: 大阪国際会議場
  • Year and Date: 2014-12-03 – 2014-12-05