Functional adaptation of HIV accessory proteins towardimmune-mediated selective pressure

• Project/Area Number: 22390089
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• 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)
• Co-Investigator(Kenkyū-buntansha): MIURA Toshiyuki 長崎大学, 熱帯医学研究所, 客員教授 (00296576)
• Co-Investigator(Renkei-kenkyūsha): GATANAGA Hiroyuki 国立国際医療研究センター, エイズ治療・研究開発センター, 治療開発室長 (10466211)
• Project Period (FY): 2010 – 2012
• Project Status: Completed (Fiscal Year 2012)
• Budget Amount: ¥18,590,000 (Direct Cost: ¥14,300,000、Indirect Cost: ¥4,290,000); Fiscal Year 2012: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2011: ¥5,720,000 (Direct Cost: ¥4,400,000、Indirect Cost: ¥1,320,000); Fiscal Year 2010: ¥7,540,000 (Direct Cost: ¥5,800,000、Indirect Cost: ¥1,740,000)
• Keywords: 感染防御 / ワクチン / ウイルス / 感染症 / 免疫学 / 進化

Research Abstract

Impaired HIV-1 Gag, Pol, and Env function has been described inelite controllers (EC) who spontaneously suppress plasma viremia to < 50 RNA copies/mL;however, activity of the accessory protein Nef remains incompletely characterized. Weexamined the ability of 91 Nef sequences, isolated from plasma of 45 EC and 46 chronicprogressors (CP), to down-regulate HLA class I and CD4, up-regulate HLA class II invariantchain (CD74), enhance viral infectivity, and stimulate viral replication in PBMC. Ingeneral, EC Nef sequences were functional; however, all five activities weresignificantly lower in EC compared to CP. Nef from HLA-B*57-expressing EC exhibited poorerCD4 down-regulation function compared to non-B*57 EC, and the number of EC-specificB*57-associated Nef polymorphisms correlated inversely with 4 of 5 Nef functions in theseindividuals. Results indicate that decreased viral protein function, due in part to hostimmune selection pressures, may be a hallmark of the EC phenotype.

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] Minorcontribution of HLA class I-associatedselective pressure to the variabilityof HIV-1 accessory protein Vpu (2012)
  • Author(s): Zafrul Hasan, Jonathan M Carlson,Hiroyuki Gatanaga, Anh Q. Le, ChansonJ Brumme, Shinichi Oka, Zabrina LBrumme, *Takamasa Ueno
  • Journal Title: Biochem. Biophys. Res. Comm Volume: 421 Issue: 2 Pages: 291-295
  • DOI: 10.1016/j.bbrc.2012.04.002
  • Peer Reviewed
• [Journal Article] Theidentification of a small moleculecompound that reduces HIV-1Nef-mediated viral infectivityenhancement (2011)
  • Author(s): Nopporn Chutiwitoonchai, MasateruHiyoshi, Philip Mwimanzi, TakamasaUeno, Akio Adachi, Hirotaka Ode,Hironori Sato, Oliver T. Fackler,Seiji Okada, Shinya Suzu
  • Journal Title: PLoS ONE Volume: 6(11)
  • 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
• [Journal Article] The identification of a small molecule compound that reduces HIV-1 Nef-mediated viral infectivity enhancement (2011)
  • Author(s): Chutiwitoonchai, N., Hiyoshi, M., Mwimanzi, P., Ueno, T., Adachi, A., Ode, H., Sato, H., Fackler, O. T., Okada, S., and Suzu, S
  • Journal Title: PLoS One Volume: 6 Issue: 11 Pages: e27696-e27696
  • DOI: 10.1371/journal.pone.0027696
  • NAID: 120004058203
  • Peer Reviewed
• [Journal Article] Naturallyarising HIV-1 Nef variants conferringescape from cytotoxic T lymphocytesinfluence viral entry co-receptorexpression and susceptibility tosuperinfection (2010)
  • Author(s): Philip Mwimanzi, Zafrul Hasan, MichiyoTokunaga, Hiroyuki Gatanaga, Shinichi Oka, *Takamasa Ueno
  • Journal Title: Biochem. Biophys. Res.Comm Volume: 403 Pages: 422-427
  • Peer Reviewed
• [Journal Article] Failure of effectorfunction of human CD8+ T cells inNOD/SCID/JAK3-/- immunodeficient micetransplanted with human CD34+hematopoietic stem cells (2010)
  • Author(s): Yoshinori Sato, Hiroshi Takata, NaokiKobayashi, Sayaka Nagata, NaomiNakagata, Takamasa Ueno, MasafumiTakiguchi
  • Journal Title: PLoS ONE Volume: 5(10) Issue: 10 Pages: e13109-e13109
  • DOI: 10.1371/journal.pone.0013109
  • Peer Reviewed
• [Journal Article] Dynamicinterplay between viral adaptation andimmune recognition during HIV-1infection (2010)
  • Author(s): Chihiro Motozono, Philip Mwimanzi,*Takamasa Ueno
  • Journal Title: Protein & Cell Volume: 1 Pages: 514-519
  • Peer Reviewed
• [Journal Article] Differentin vivo effects of HIV-1immunodominant epitope-specific CTLson selection of escape mutant viruses (2010)
  • Author(s): Koizumi H, Hashimoto M, Fujiwara M,Murakoshi H, Chikata T, Borghan MA,Hachiya A, Kawashima Y, Takata H, UenoT, Oka S, Takiguchi M
  • Journal Title: Journal of Virology Volume: 84 Pages: 5508-5519
  • Peer Reviewed
• [Journal Article] Naturally arising HIV-1 Nef variants conferring escape from cytotoxic T lymphocytes influence viral entry co-receptor expression and susceptibility to superinfection (2010)
  • Author(s): Philip Mwimanzi, et al
  • Journal Title: Biochem.Biophys.Res.Comm. Volume: 403 Pages: 422-427
  • Peer Reviewed
• [Journal Article] Dynamic interplay between viral adaptation and immune recognition during HIV-1 infection (2010)
  • Author(s): Chihiro Motozono
  • Journal Title: Protein & Cell Volume: 1 Pages: 514-519
  • Peer Reviewed
• [Presentation] and the Acute HIVand International HIV Controllersstudy group. Reduced HIV-1 NefFunction in Acute/Early Individualswho become Viremic Controllers (2013)
  • Author(s): X. Kuang, A Le, P Mwimanzi, T Markle,R Danroth, T Ueno, T Miura, B Walker,Z Brumme, M Brockman
  • Organizer: 20thConference on Retroviruses andOpportunistic Infections (CROI)
  • Place of Presentation: Georgia World Congress Center, Atlanta,USA
• [Presentation] The impact of a single amino acid difference in CDR3・onTCR・・・cross-reactivity、ワークショップ 32 ヒト免疫、 (2012)
  • Author(s): Chihiro Motozono, John S. Bridgeman,Masaaki Miyazawa, Andrew K. Sewell andTakamasa Ueno
  • Organizer: 第41回日本免疫学会総会・学術集会
  • Place of Presentation: 神戸国際会議場、兵庫
• [Presentation] Genetic and functional analysesof HIV-1 Nef in elite controllers (2012)
  • Author(s): 上 野 貴 将 、 Mwimanzi Philip 、 MarkleTristan、緒方陽子、 徳永美知代、MahitiMacdonald、 三浦聡之、 Pereyra Florencia、Walker Bruce、 Brumme Zabrina、 BrockmanMark
  • Organizer: 第60回日本ウイルス学会学術集会
  • Place of Presentation: グランキューブ大阪(大阪国際会議場)
• [Presentation] HLA class I-mediatedsequence polymorphism in HIV-1accessory protein Vpu (2012)
  • Author(s): Zafrul Hasan, J. Carlson, H. Gatanaga,A. Le, C. Brumme, S. Oka, Z. Brumme,Takamasa Ueno
  • Organizer: The 13thKUMAMOTO AIDS Seminar and GCOE JointInternational Symposium
  • Place of Presentation: Hotel NikkoKumamoto and Aso Resort GrandvrioHotel, Kumamoto, Japan
• [Presentation] HIV-1 immune escape andcross-reactivity profiles ofvirus-specific cytotoxic Tlymphocytes, YIS-A Session II (2012)
  • Author(s): Chihiro Motozono, John J. Miles,Zafrul Hasan, Hiroyuki Gatanaga,Meribe Stanley, Shinichi Oka, MasaakiMiyazawa, Andrew K. Sewell, TakamasaUeno
  • Organizer: 13thKumamoto AIDS Seminar Global COE JointInternational Symposium
  • Place of Presentation: Aso ResortGRANDVRIO, Kumamoto, Japan
• [Presentation] Functional impairment ofHIV-1 Nef in elite controllers and itscorrelation with immune-mediatedselective pressure (2012)
  • Author(s): T. Ueno
  • Organizer: 13th Kumamoto AIDSSeminar Global COE Joint InternationalSymposium
  • Place of Presentation: Aso Resort GrandvrioHotel,Kumamoto, Japan
• [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
  • Place of Presentation: Aso Resort GrandiovrioHotel, Kumamoto, Japan
• [Presentation] HLA-B35 拘束性 HIV 特異的 TCR は野生型抗原に高い特異性を有する、学術賞ならびに学術奨励賞候補口演 (2012)
  • Author(s): 本園千尋、John J. Miles、宮澤正顯、上野貴将、Andrew K. Sewell
  • Organizer: 第21回組織適合性学会大会
  • Place of Presentation: 明治大学、東京
• [Presentation] Impact of HLA class I-driven geneticvariability in HIV-1 accessory genevpu (2012)
  • Author(s): Zafrul Hasan, J. Carlson, H. Gatanaga,A. Le, S. Oka, Z. Brumme, Takamasa Ueno
  • Organizer: COLD SPRING HARBOR ASIACONFERENCES: Frontiers of Immunologyin Health and Disease
  • Place of Presentation: Suzhou DushuLake Conference Center, China
• [Presentation] Genetic and functional analyses of HIV-1 Nef in elite controllers. (2012)
  • Author(s): Philip Mwimanzi
  • Organizer: 第60回日本ウイルス学会学術集会
  • Place of Presentation: 大阪国際会議場
• [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, ら
  • Organizer: 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
  • Year and Date: 2011-12-02
• [Presentation] Impaired viralinfectivity and viral replicationcapacity by nef alleles from HIV elitecontrollers (2011)
  • Author(s): Philip Mwimanzi, Tristan Markle,Michiyo Tokunaga, Toshiyuki Miura,Eric Martin, Florencia Pereyra, BruceWalker, Zabrina Brumme, Mark Brockman,Takamasa Ueno
  • Organizer: 25th Annual Meeting ofJapanese Society for AIDS Research
  • Place of Presentation: Tokyo Hyatt Regency, Tokyo, Japan
• [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] Population analysis ofviral replication capacity by nefalleles of HIV elite controllers (2011)
  • Author(s): Philip Mwimanzi, Tristan Markle,Michiyo Tokunaga, Toshiyuki Miura,Eric Martin, Florencia Pereyra, BruceWalker, Zabrina Brumme, Mark Brockman,Takamasa Ueno
  • Organizer: 12thKumamoto AIDS Seminar
  • Place of Presentation: Kumamoto, Japan
• [Presentation] Thecross-reactivity footprints ofHIV-specific CTLs (2011)
  • Author(s): Chihiro Motozono, John J. Miles, LindaWooldridge, David A. Price, TakamasaUeno, Andrew K. Sewell
  • Organizer: 12th Kumamoto AIDSSeminar and GCOE Joint InternationalSymposium
  • Place of Presentation: Hotel Nikko Kumamoto and Aso Resort Grandvrio Hotel, Kumamoto,Japan
• [Presentation] Impairment ofviral replication capacity by nefalleles from HIV elite controllers.Frontiers of Retrovirology (2011)
  • Author(s): Philip Mwimanzi, Tristan Markle,Michiyo Tokunaga, Toshiyuki Miura,Eric Martin, Florencia Pereyra, BruceWalker, Zabrina Brumme, MarkBrockman,Takamasa Ueno
  • Organizer: Complexretroviruses, retroelements and theirhosts
  • Place of Presentation: Amsterdam, Netherlands
• [Presentation] Impairment of virioninfectivity by nef alleles from HIVelite controllers (2011)
  • Author(s): Philip Mwimanzi, Tristan Markle,Michiyo Tokunaga, Toshiyuki Miura,Eric Martin, Florencia Pereyra, BruceWalker, Zabrina Brumme, Mark Brockman,Takamasa Ueno
  • Organizer: Nef activity inenhancement of virion infectivity isimpaired in HIV elite controllers
  • Place of Presentation: XV,International Congress of Virology,Sapporo Convention Center,Sapporo,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
• [Presentation] Impairment of virioninfectivity by nef alleles from HIVelite controllers (2011)
  • Author(s): Philip Mwimanzi, Tristan Markle,Michiyo Tokunaga, Toshiyuki Miura,Eric Martin, Florencia Pereyra, BruceWalker, Zabrina Brumme, Mark Brockman,Takamasa Ueno
  • Organizer: Keystone SymposiaHIV Evolution
  • Place of Presentation: Genomics andPathogenesis, Canada
• [Presentation] Impact of HLA class I-drivengenetic variability in HIV-1 accessorygenes in Japanese sequences. KeystoneSymposia HIV Evolution (2011)
  • Author(s): Zafrul Hasan, J. Carlson, H. Gatanaga,A. Le, C. Brumme, S. Oka, Z. Brumme, T.Ueno
  • Organizer: Genomics andPathogenesis
  • Place of Presentation: Whistler, Canada
• [Presentation] Impairment of viral replication capacity by nef alleles from HIV elite controllers (2011)
  • Author(s): Philip Mwimanzi, et al
  • Organizer: Frontiers of Retrovirology
  • Place of Presentation: Movenpick Hotel Amsterdam, Netherlands
• [Presentation] Effect of HLA class I-mediated selective pressure on HIV-1 accessory genes (2011)
  • Author(s): Zafrul Hasan, et.al.
  • Organizer: International Union of Microbiological Societies 2011 Congress
  • Place of Presentation: Sapporo Convention Center, Japan
• [Presentation] Impact of HLA class I-driven genetic variability in HIV-1 accessory genes in Japahese sequences (2011)
  • Author(s): Zafrul Hasan, et.al.
  • Organizer: Keystone Symposia HIV Evolution. Genomics and Pathogenesis
  • Place of Presentation: Whistler Convention Center, Canada
• [Presentation] Impairment of virion infectivity by nef alleles from HIV elite controllers (2011)
  • Author(s): Philip Mwimanzi, et al
  • Organizer: Keystone Symposia HIV Evolution. Genomics and Pathogenesis
  • Place of Presentation: Whistler Convention Center, Canada
• [Presentation] Nef activity in downregulation of viral receptors andprotection of HIV superinfection ismodulated by Nef mutations that conferCTL escape during acute infection (2010)
  • Author(s): Mwimanzi, P., Oniangue-Ndza, C., AllenT.M., and Ueno,T
  • Organizer: 11th KUMAMOTO AIDS Seminar GCOE JointInternational Symposium
  • Place of Presentation: Hotel NikkoKumamoto and Aso Grand Vrio Hotel,Kumamoto, Japan
• [Presentation] Implication of the effects of hostimmune responses on the HIV-1 vpu geneevolution (2010)
  • Author(s): Zafrul Hasan, Hiroyuki Gatanaga,Shinichi Oka, and Takamasa Ueno
  • Organizer: 24th Annual Meeting of theJapanese Society for AIDS Research
  • Place of Presentation: Grand Prince Hotel Takanawa, PrinceSakura Tower, Takanawa, Tokyo
• [Presentation] Implication of the effects of hostimmune responses on the HIV-1 vpu geneevolution (2010)
  • Author(s): Zafrul Hasan, Hiroyuki Gatanaga,Shinichi Oka, and Takamasa Ueno
  • Organizer: The 11th KUMAMOTO AIDSSeminar and GCOE Joint InternationalSymposium
  • Place of Presentation: Hotel Nikko Kumamoto andAso Resort Grandvrio Hotel, Kumamoto,Japan
• [Presentation] CTL-escape Nefvariants influence CCR5 downregulation and HIV superinfectionsusceptibility (2010)
  • Author(s): Mwimanzi P., Ueno T
  • Organizer: The 14thInternational Conference ofImmunology (ICI)
  • Place of Presentation: Kobe InternationalExhibition and Portopia Hotel, Kobe,Japan