宿主間の感染伝播におけるHIVゲノム・病原性の変化に関する研究

• Project Area: Molecular basis of host cell competency in virus infection
• Project/Area Number: 15H01271
• Research Category: Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: National Institute of Infectious Diseases
• Principal Investigator: 俣野 哲朗 国立感染症研究所, エイズ研究センター, センター長 (00270653)
• Project Period (FY): 2015-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥21,580,000 (Direct Cost: ¥16,600,000、Indirect Cost: ¥4,980,000); Fiscal Year 2016: ¥10,790,000 (Direct Cost: ¥8,300,000、Indirect Cost: ¥2,490,000); Fiscal Year 2015: ¥10,790,000 (Direct Cost: ¥8,300,000、Indirect Cost: ¥2,490,000)
• Keywords: ウイルス / 微生物 / 感染症 / 免疫学 / エイズ / 細胞傷害性Tリンパ球 / HLA

Outline of Annual Research Achievements

本研究は宿主遺伝子多様性へのウイルス適応機序の解明を目指し、ウイルスと宿主の相互作用が長期に渡り継続し病態形成にいたるHIV慢性持続感染症を対象として、ウイルス感染・伝播におけるウイルス変異蓄積および病原性変化の機序を知ることを目的とした。特にHIV感染病態に大きな影響を及ぼすMHC遺伝子型に着目し、ヒトHIV感染を最もよく反映するSIV感染サルモデルでの伝播実験におけるウイルスゲノムおよび病原性の変化を解析することとした。
平成25-26年度の本領域公募研究に、低ウイルス量と相関するprotective MHC-IハプロタイプA陽性サルから、A陰性サル2代を経た3代に渡る経静脈SIV伝播実験を行い、伝播に伴いウイルスゲノムに細胞傷害性T細胞（CTL）逃避変異が蓄積することを明らかにした。本研究（平成27-28年度）では、伝播実験で得られた3代伝播SIVのin vitroおよびin vivoでの複製能の解析を進めた。平成27年度には、次世代シークエンサーを用いたウイルスゲノムの解析で、伝播に伴う詳細な変異蓄積パターンを明らかにし、さらに3代伝播SIVのin vitroでの複製能が野生型と比較して低下していることを明らかにした。
平成28年度には、in vitro複製能の低下した3代伝播SIVのin vivo複製能についての詳細な結果を得た。まず、MHC-IハプロタイプA陰性サル６頭における3代伝播SIV感染実験で慢性持続感染が成立することを確認した。一方、MHC-IハプロタイプA陽性サル６頭における3代伝播SIV感染実験では、野生型SIVと比較して、有意に高いセットポイント期の血漿中ウイルス量および有意に早い病態進行を示した。本研究結果は、HIV・SIVの伝播の積み重ねに伴い、ウイルスがin vitro複製能を犠牲にしながらもCTL逃避変異を蓄積し、protective MHC-Iに対する感受性を失っていく方向に進化していく可能性を示す根拠を提供するものとして重要である。

Research Progress Status

28年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

28年度が最終年度であるため、記入しない。

Research Products

• [Int'l Joint Research] Fred Hutchinson Cancer Research Center/International AIDS Vaccine Initiative/NIH/NIAID(米国)
• [Int'l Joint Research] University College Dublin(アイルランド)
• [Int'l Joint Research] NIHE(ベトナム)
• [Int'l Joint Research] IAVI/NIH/NIAID(米国)
• [Int'l Joint Research] NIHE(ベトナム)
• [Journal Article] Biphasic CD8+ T-cell defense in elite SIV control by acute-phase passive neutralizing antibody immunization (2016)
  • Author(s): Iseda S, Takahashi N, Poplimont H, Nomura T, Seki S, Nakane T, Nakamura M, Shi S, Ishii H, Furukawa S, Harada S, Naruse TK, Kimura A, Matano T, Yamamoto H
  • Journal Title: J Virol Volume: 90 Issue: 14 Pages: 6276-6290
  • DOI: 10.1128/jvi.00557-16
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Association of lymph-node antigens with lower Gag-specific central-memory and higher Env-specific effector-memory CD8+ T-cell frequencies in a macaque AIDS model (2016)
  • Author(s): Ishii H, Matsuoka S, Nomura T, Nakamura M, Shiino T, Sato Y, Iwata-Yoshikawa N, Hasegawa H, Mizuta K, Sakawaki H, Miura T, Koyanagi Y, Naruse TK, Kimura A, Matano T
  • Journal Title: Sci Rep Volume: 6 Issue: 1 Pages: 30153-30153
  • DOI: 10.1038/srep30153
  • NAID: 120006346255
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Recursion-based depletion of human immunodeficiency virus-specific naive CD4+ T cells may facilitate persistent viral replication and chronic viraemia leading to acquired immunodeficiency syndrome (2016)
  • Author(s): Tsukamoto T, Yamamoto H, Okada S, Matano T
  • Journal Title: Med Hypotheses Volume: 94 Pages: 81-85
  • DOI: 10.1016/j.mehy.2016.06.024
  • Peer Reviewed
• [Journal Article] Augmentation of anti-SIV activity in CD8+ cells by neutralizing but not non-neutralizing antibodies in the acute phase (2016)
  • Author(s): Yamamoto H, Iseda S, Nakane T, Nomura T, Takahashi N, Seki S, Nakamura M, Ishii H, Matano T
  • Journal Title: AIDS Volume: 30 Pages: 2391-2394
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] First complete genome sequence of a simian foamy virus isolate from a cynomolgus macaque (2016)
  • Author(s): Sakai K, Ami Y, Suzaki Y, Matano T
  • Journal Title: Genome Announc Volume: 4 Issue: 6
  • DOI: 10.1128/genomea.01332-16
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Patterns of HIV/SIV prevention and control by passive antibody immunization (2016)
  • Author(s): Yamamoto H, Matano T
  • Journal Title: Front Micobiol Volume: 7 Pages: 1739-1739
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Development of an AIDS vaccine using Sendai virus vectors (2015)
  • Author(s): Ishii H, Matano T
  • Journal Title: Vaccine Volume: 33 Issue: 45 Pages: 6061-6065
  • DOI: 10.1016/j.vaccine.2015.06.114
  • Peer Reviewed
• [Journal Article] Longitudinal detection and persistence of minority drug-resistant populations and their effect on salvage therapy (2015)
  • Author(s): Nishizawa M, Matsuda M, Hattori J, Shiino T, Matano T, Sugiura W
  • Journal Title: PLoS ONE Volume: 10 Issue: 9 Pages: e0135941-e0135941
  • DOI: 10.1371/journal.pone.0135941
  • Peer Reviewed / Open Access
• [Journal Article] Broadening of Virus-Specific CD8+ T-Cell Responses Is Indicative of Residual Viral Replication in Aviremic SIV Controllers (2015)
  • Author(s): Takushi Nomura, Hiroyuki Yamamoto, Hiroshi Ishii, Hirofumi Akari, Taeko K. Naruse, Akinori Kimura, Tetsuro Matano
  • Journal Title: PLOS Pathogens Volume: 11 Issue: 11 Pages: e1005247-e1005247
  • DOI: 10.1371/journal.ppat.1005247
  • NAID: 120005763387
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] Oleanolic acid derivative OKS3-019 as a novel bifunctional HIV-1 entry inhibitor (2017)
  • Author(s): Harada S, Ogihara K, Hikichi Y, Matano T, Narumi T, Yoshimura K
  • Organizer: Conference on Retroviruses and Opportunistic Infections 2017
  • Place of Presentation: Seattle, WA, US
  • Year and Date: 2017-02-14
  • Int'l Joint Research
• [Presentation] Molecular epidemiology of HIV-1 in Ghana (2017)
  • Author(s): Matsuoka S, Nii-Trebi N, Takeda S, Amoa-Bosompem MA, Ofori SB, Yoshimura K, Ampofo W, Ishikawa K Matano T
  • Organizer: Korea-Japan Joint Seminar on HIV/AIDS
  • Place of Presentation: Seoul, South Korea
  • Year and Date: 2017-01-14
  • Int'l Joint Research
• [Presentation] SIV感染サルエイズモデルにおいて逃避変異に対して交差反応性を示すCTL応答の解析 (2016)
  • Author(s): 石井洋、城森萌、関紗由里、松岡佐織、俣野哲朗
  • Organizer: 第30回日本エイズ学会学術集会
  • Place of Presentation: 鹿児島
  • Year and Date: 2016-11-24
• [Presentation] サルエイズモデルにおけるウイルス複製の長期制御メカニズム (2016)
  • Author(s): 俣野哲朗
  • Organizer: 第30回日本エイズ学会学術集会
  • Place of Presentation: 鹿児島
  • Year and Date: 2016-11-24
  • Invited
• [Presentation] Virus-host immune interaction in SIV infection (2016)
  • Author(s): Matano T
  • Organizer: The 17th Kumamoto AIDS Seminar
  • Place of Presentation: Kumamoto, Japan
  • Year and Date: 2016-11-01
  • Int'l Joint Research / Invited
• [Presentation] SIV can evolve to be less sensitive to potent CD8+ T cells after multiple transmissions (2016)
  • Author(s): Nomura T, Yamamoto H, Terahara K, Seki S, Matano T
  • Organizer: 第64回日本ウイルス学会学術集会
  • Place of Presentation: 札幌
  • Year and Date: 2016-10-25
• [Presentation] Multiple transmissions of SIV adapted to protective MHC alleles in rhesus macaques (2016)
  • Author(s): Seki S, Nomura T, Nishizawa M, Matano T
  • Organizer: The 34th annual symposium on non-human primate models for AIDS
  • Place of Presentation: New Orleans, LA, USA
  • Year and Date: 2016-10-12
  • Int'l Joint Research
• [Presentation] Accumulation of MHC-I-associated viral genome mutations in multiple SIV transmissions (2016)
  • Author(s): Seki S, Nomura T, Nishizawa M, Yokoyama M, Sato H, Matano T
  • Organizer: The 15th Awaji International Forum on Infection and Immunity
  • Place of Presentation: Awaji, Japan
  • Year and Date: 2016-09-09
  • Int'l Joint Research
• [Presentation] HIVと宿主免疫の相互作用 (2016)
  • Author(s): 俣野哲朗
  • Organizer: 愛媛大学プロテオサイエンスセンター第３回学術シンポジウム
  • Place of Presentation: 松山
  • Year and Date: 2016-02-13
  • Invited
• [Presentation] Virus evolution accumulating MHC-I-associated mutations in multiple SIV transmissions (2015)
  • Author(s): Matano T
  • Organizer: Seminar at Tulane National Primate Research Center
  • Place of Presentation: Covington, LA, USA
  • Year and Date: 2015-12-14
  • Invited
• [Presentation] Virus evolution with accumulation of CD8+ T-cell escape mutations after multiple SIV transmissions among MHC-I-mismatched macaques (2015)
  • Author(s): Matano T
  • Organizer: 第63回日本ウイルス学会学術集会
  • Place of Presentation: 福岡
  • Year and Date: 2015-11-22
  • Invited
• [Presentation] Lasting viral control by CD8+ T cells in a macaque AIDS model (2015)
  • Author(s): Matano T
  • Organizer: 13th International Symposium on Molecular Basis of Viral Diseases
  • Place of Presentation: 東京
  • Year and Date: 2015-11-20
  • Invited
• [Presentation] Viral genome mutations resulting in escape from protective MHC-I-associated CD8+ T cells can be maintained after multiple SIV transmissions among MHC-I-mismatched macaques (2015)
  • Author(s): Seki S, Nomura T, Nishizawa M, Yokoyama M, Sato H, Miura T, Koyanagi Y, Matano T
  • Organizer: The 33rd annual symposium on non-human primate models for AIDS
  • Place of Presentation: Monterey, CA, USA
  • Year and Date: 2015-10-15
  • Int'l Joint Research
• [Presentation] SIV CTL escape mutations resulting in loss of viral fitness can be maintained after transmission into MHC-I-mismatched hosts (2015)
  • Author(s): Nomura T, Seki S, Nishizawa M, Harada S, Yoshimura K, Matano T
  • Organizer: The 8th IAS Conference on HIV Pathogenesis, Treatment and Prevention
  • Place of Presentation: Vancouver, BC, Canada
  • Year and Date: 2015-07-21
  • Int'l Joint Research