A bioinformatics approach toward understanding interplay betweenchronic virus infections and human antiviral immune responses

• Project/Area Number: 23659232
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Virology
• Research Institution: Kumamoto University
• Principal Investigator: UENO Takamasa 熊本大学, エイズ学研究センター, 准教授 (10322314)
• Project Period (FY): 2011 – 2012
• Project Status: Completed (Fiscal Year 2012)
• Budget Amount: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2011: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000)
• Keywords: 感染防御 / ワクチン / ウイルス / 感染症 / 進化 / ＨＩＶ / 免疫回避

Research Abstract

HIV -1 Nef is required for efficient viral replication and pathogenesis. However , the extent to which Nef ’ s functions are maintained in natural sequences duringchronic infection, and their clinical relevance, remains incompletely characterized. Relativeto a control Nef from HIV -1 strain SF2, HLA class I and CD4 down-regulation activities of46 plasma RNA Nef sequences derived from unique chronic infected individuals weregenerally high and displayed narrow dynamic ranges, whereas Nef-mediated virioninfectivity , PBMC replication and CD74 up-regulation exhibited broader dynamic ranges.80% of patient-derived Nefs were active for at least three functions examined. Functionalco-dependencies were identified, including positive correlations between CD4down-regulation and virion infectivity , replication, and CD74 up-regulation, and betweenCD74 up-regulation and PBMC replication. Nef-mediated virion infectivity inverselycorrelated with patient CD4+ T -cell count. Strong functional co-dependencies and thepolyfunctional nature of patient-derived Nef sequences suggest a phenotypic requirementto maintain multiple Nef functions during chronic infection

Research Products

• [Journal Article] Dynamic range of Nef functionsin chronic HIV-1 infection (2013)
  • Author(s): Philip Mwimanzi, Tristan J Markle,Yoko Ogata, Eric Martin, MichiyoTokunaga, Macdonald Mahiti, Xiaomei TKuang, Bruce D Walker, Zabrina L Brumme,Mark A Brockman and *Takamasa Ueno
  • Journal Title: Virology Volume: 439 Issue: 2 Pages: 74-80
  • DOI: 10.1016/j.virol.2013.02.005
  • Peer Reviewed
• [Journal Article] Attenuation of multiple Neffunctions in HIV-1 elite controllers (2013)
  • Author(s): Philip Mwimanzi, Tristan J Markle,Eric Martin, Yoko Ogata, Xiaomei TKuang, Michiyo Tokunaga, MacdonaldMahiti, Florencia Pereyra, ToshiyukiMiura, Bruce D Walker, Zabrina L Brumme,Mark A Brockman and *Takamasa Ueno
  • Journal Title: Retrovirology Volume: 10 Issue: 1 Pages: 1-1
  • DOI: 10.1186/1742-4690-10-1
  • Peer Reviewed
• [Journal Article] HLA class I down-regulation by HIV-1Nef: What might we learn from naturalsequence variants? (2013)
  • Author(s): Philip Mwimanzi, Tristan J. Markle,Takamasa Ueno, Mark A. Brockman
  • Journal Title: Viruses Volume: 4 Issue: 9 Pages: 1711-1730
  • DOI: 10.3390/v4091711
  • Peer Reviewed
• [Journal Article] Effects of naturally-arising HIV Nefmutations on cytotoxic T lymphocyterecognition and Nef's functionality inprimary macrophages (2011)
  • Author(s): Philip Mwimanzi, Zafrul Hasan, RanyaHassan, Shinya Suzu, Masafumi Takiguchiand*TakamasaUeno
  • Journal Title: etrovirology Volume: 8 Issue: 1 Pages: 50-50
  • DOI: 10.1186/1742-4690-8-50
  • Peer Reviewed
• [Presentation] Nef のウイルスレセプター発現低下機能と病態 (2012)
  • Author(s): 緒方陽子、Philip Mwimanzi、李小光、徳永美知代、Tristan Markle、三浦聡之、Bruce Walker 、Zabrina Brumme 、MarkBrockman、上野貴将
  • Organizer: 第26回日本エイズ学会学術集会・総会
  • Place of Presentation: 慶應義塾大学日吉キャンパス(神奈川)
• [Presentation] Modulation of HIV-1Nef-mediated HLA class Idown-regulation activity duringdisease progression (2012)
  • Author(s): M. Mahiti, P. Mwimanzi, Y. Ogata, M.Tokunaga, B. Walker, Z. Brumme, M.Brockman, T. Ueno
  • Organizer: 13th KumamotoAIDS seminar Aso Resort GrandiovrioHotel
  • Place of Presentation: Kumamoto, Japan
• [Presentation] HIV-1 Nef の遺伝子多型性と機能的可塑性 (2012)
  • Author(s): 上野貴将
  • Organizer: 第14回白馬シンポジウムin 京都
  • Place of Presentation: 京都市国際交流会館
• [Presentation] Nefのウイルスレセプター発現低下機能と病態 (2012)
  • Author(s): 緒方陽子
  • Organizer: 第26回日本エイズ学会学術集会・総会
  • Place of Presentation: 慶應義塾大学日吉キャンパス
  • Invited
• [Presentation] Nef のウイルスレセプター発現低下機能と病態 (2011)
  • Author(s): 緒方陽子、大津家裕仁、Philip Mwimanzi、徳永美知代、Tristan Markle、三浦聡之、Bruce Walker 、Zabrina Brumme 、MarkBrockman、上野貴将
  • Organizer: 一般演題「アクセサリー遺伝子-2」 第25回日本エイズ学会学術集会・総会
  • Place of Presentation: ハイアットリージェンシー東京
• [Presentation] Impact of HLA class I-drivengenetic variability in HIV-1 accessorygenes (2011)
  • Author(s): Zafrul Hasan, J. Carlson, H. Gatanaga,A. Le, C. Brumme, S. Oka, Z. Brumme, T.Ueno
  • Organizer: 2011 The Annual Meeting of theJapanese Society for Immunology
  • Place of Presentation: Chiba,Makuhari Messe, Japan
• [Presentation] Subtle effect of HLA classI-driven selective forces on thevariability of HIV-1 accessory genes (2011)
  • Author(s): Zafrul Hasan, J. Carlson, H. Gatanaga,A. Le, C. Brumme, S. Oka, Z. Brumme, T.Ueno
  • Organizer: 12th Kumamoto AIDS Seminar and GCOEJoint International Symposium
  • Place of Presentation: HotelNikko Kumamoto and Aso ResortGrandvrio Hotel, Kumamoto, Japan
• [Presentation] Effect of HLA class I-mediatedselective pressure on HIV-1 accessorygenes (2011)
  • Author(s): Zafrul Hasan, J. Carlson, H. Gatanaga,A. Le, C. Brumme, S. Oka, Z. Brumme, T.Ueno
  • Organizer: International Union ofMicrobiological Societies 2011Congress: Virus and host response
  • Place of Presentation: Sapporo Convention Center, Sapporo,Japan