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Identification of broadly neutralizing antibodies to HIV-1 and its correlates with host genetic factors

Research Project

Project/Area Number 19H03703
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Review Section Basic Section 54030:Infectious disease medicine-related
Research InstitutionKumamoto University

Principal Investigator

UENO Takamasa  熊本大学, ヒトレトロウイルス学共同研究センター, 教授 (10322314)

Co-Investigator(Kenkyū-buntansha) 桑田 岳夫  熊本大学, ヒトレトロウイルス学共同研究センター, 特任准教授 (70346063)
Project Period (FY) 2019-04-01 – 2022-03-31
Project Status Completed (Fiscal Year 2021)
Budget Amount *help
¥17,420,000 (Direct Cost: ¥13,400,000、Indirect Cost: ¥4,020,000)
Fiscal Year 2021: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000)
Fiscal Year 2020: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000)
Fiscal Year 2019: ¥6,760,000 (Direct Cost: ¥5,200,000、Indirect Cost: ¥1,560,000)
KeywordsHIV-1 / neutralizing antibody / Tanzania / HIV感染症 / 中和抗体 / HIV/AIDS
Outline of Research at the Start

HIV-1変異株を広範に中和することのできる感染者が1%以下と極めて稀に見つかり、分離された一部の中和抗体(bnAb)が、著明な抗ウイルス効果を示すことが最近分かって来た。しかしながら、これらは偶発的な発見に依存しているため、bnAbは未だごく少数の感染者からしか分離されていない。抗体が形成可能なバラエティを考えれば、さらに優れた機能を持つ抗体が存在するはずである。本研究では、世界で蔓延する主要なウイルスサブタイプが混合して蔓延するアフリカ地域で大規模に集めた未治療感染者検体をもとに、戦略的なスクリーニング系を構築して、bnAbの分離をシステミックに実施する。

Outline of Final Research Achievements

Broadly reactive neutralizing antibodies have been isolated so far from limited number of individuals. In this study, based on the Tanzania cohort where multiple subtypes and inter-subtype recombinant forms co-circulate, we attempted to look for HIV-1-infected patients who have broadly reactive neutralizing antibody responses. Plasma samples isolated from treatment-naive and treatment failure individuals (N >400) were tested for neutralizing capacity against 15 envelopes of global panels. We found that three individuals appeared to have neutralizing activity toward greater than 70% envelope species tested. Moreover, by testing possible correlation with clinical markers, we found that greater potency of broadly neutralizing activity associated with plasma viral load and the level of IL-21, providing an important clue toward understanding broadly neutralizing antibody responses to HIV-1.

Academic Significance and Societal Importance of the Research Achievements

抗ウイルス薬へのアクセスが向上し、HIV感染者の予後は劇的に改善された。しかし、いまだに3700万人のHIV感染者がおり、エイズは世界レベルの脅威であり続けている。このため、HIV-1変異株を広範に中和できる抗体を新たな治療薬として開発する研究が注目を集めている。しかし、興味深いことに中和抗体は極めて少数の感染者からしか分離されていない。本研究では、複数のHIV-1変異株が複雑に絡み合って流行するタンザニアにおいて、中和活性に優れた複数の症例を見出した。さらに、中和活性と関連する因子の一部を同定したことで、優れた中和抗体の探索と治療薬としての開発に大きく前進した。

Report

(4 results)
  • 2021 Annual Research Report   Final Research Report ( PDF )
  • 2020 Annual Research Report
  • 2019 Annual Research Report
  • Research Products

    (20 results)

All 2021 2020 2019 Other

All Int'l Joint Research (3 results) Journal Article (11 results) (of which Int'l Joint Research: 9 results,  Peer Reviewed: 11 results,  Open Access: 8 results) Presentation (6 results) (of which Int'l Joint Research: 3 results,  Invited: 1 results)

  • [Int'l Joint Research] ムヒンビリ健康科学大学/国立ムヒンビリ病院(タンザニア)

    • Related Report
      2021 Annual Research Report
  • [Int'l Joint Research] ムヒンビリ健康科学大学/国立ムヒンビリ病院(タンザニア)

    • Related Report
      2020 Annual Research Report
  • [Int'l Joint Research] ムヒンビリ健康科学大学(タンザニア)

    • Related Report
      2019 Annual Research Report
  • [Journal Article] Acquired HIV drug resistance among children and adults receiving antiretroviral therapy in Tanzania: a national representative survey protocol2021

    • Author(s)
      Rugemalila Joan、Kamori Doreen、Maokola Werner、Mizinduko Mucho、Barabona Godfrey、Masoud Salim、Mlunde Linda B、Mutagonda Ritah Francis、Ruhago George、Mushi Jeremiah、Sambu Veryeh、Ueno Takamasa、Mutayoba Beatrice、Njau Prosper、Nagu Tumaini、Aboud Said、Sunguya Bruno F
    • Journal Title

      BMJ Open

      Volume: 11 Issue: 12 Pages: e054021-e054021

    • DOI

      10.1136/bmjopen-2021-054021

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Seroprevalence of Human Herpesvirus Infections in Newly Diagnosed HIV-Infected Key Populations in Dar es Salaam, Tanzania2021

    • Author(s)
      Kamori Doreen、Joachim Agricola、Mizinduko Mucho、Barabona Godfrey、Mahiti Macdonald、Kibwana Upendo、Majigo Mtebe、Masoud Salim、Mwandigha Ambele M.、Ueno Takamasa、Mmbaga Elia、Lyamuya Eligius
    • Journal Title

      International Journal of Microbiology

      Volume: 2021 Pages: 1-7

    • DOI

      10.1155/2021/4608549

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Advanced baseline immunosuppression is associated with elevated levels of plasma markers of fungal translocation and inflammation in long-term treated HIV-infected Tanzanians2021

    • Author(s)
      Barabona Godfrey、Mahiti Macdonald、Toyoda Mako、Kamori Doreen、Masoud Salim、Judicate George P.、Sunguya Bruno、Lyamuya Eligius、Ueno Takamasa
    • Journal Title

      AIDS Research and Therapy

      Volume: 18 Issue: 1

    • DOI

      10.1186/s12981-021-00381-9

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Aromatic Side Chain at Position 412 of SERINC5 Exerts Restriction Activity toward HIV-1 and Other Retroviruses2021

    • Author(s)
      Tan Toong Seng、Toyoda Mako、Tokunaga Kenzo、Ueno Takamasa
    • Journal Title

      Journal of Virology

      Volume: 95 Issue: 18

    • DOI

      10.1128/jvi.00634-21

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Phenotypic and Genotypic Co-receptor Tropism Testing in HIV-1 Epidemic Region of Tanzania Where Multiple Non-B Subtypes Co-circulate2021

    • Author(s)
      Judicate George P.、Barabona Godfrey、Kamori Doreen、Mahiti Macdonald、Tan Toong Seng、Ozono Seiya、Mgunya Amina Shaban、Kuwata Takeo、Matsushita Shuzo、Sunguya Bruno、Lyamuya Eligius、Tokunaga Kenzo、Ueno Takamasa
    • Journal Title

      Frontiers in Microbiology

      Volume: 12 Pages: 703041-703041

    • DOI

      10.3389/fmicb.2021.703041

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Impact of Human Leukocyte Antigen-Associated Polymorphisms on Variability of HIV-1 Accessory and Regulatory Proteins2021

    • Author(s)
      Kamori Doreen、Hasan Zafrul、Carlson Jonathan、Kawana-Tachikawa Ai、Gatanaga Hiroyuki、Oka Shinichi、Ueno Takamasa
    • Journal Title

      AIDS Research and Human Retroviruses

      Volume: - Issue: 12 Pages: 962-966

    • DOI

      10.1089/aid.2021.0055

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] SARS-CoV-2 D614G spike mutation increases entry efficiency with enhanced ACE2-binding affinity2021

    • Author(s)
      Ozono Seiya、Zhang Yanzhao、Ode Hirotaka、Sano Kaori、Tan Toong Seng、Imai Kazuo、Miyoshi Kazuyasu、Kishigami Satoshi、Ueno Takamasa、Iwatani Yasumasa、Suzuki Tadaki、Tokunaga Kenzo
    • Journal Title

      Nature Communications

      Volume: 12 Issue: 1 Pages: 848-848

    • DOI

      10.1038/s41467-021-21118-2

    • Related Report
      2020 Annual Research Report 2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Circulating HIV-1 Integrase Genotypes in Tanzania: Implication on the Introduction of Integrase Inhibitors-Based Antiretroviral Therapy Regimen2020

    • Author(s)
      Masoud Salim、Kamori Doreen、Barabona Godfrey、Mahiti Macdonald、Sunguya Bruno、Lyamuya Eligius、Ueno Takamasa
    • Journal Title

      AIDS Research and Human Retroviruses

      Volume: - Issue: 6 Pages: 539-543

    • DOI

      10.1089/aid.2020.0021

    • Related Report
      2020 Annual Research Report 2019 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] An HIV-1 Nef genotype that diminishes immune control mediated by protective human leucocyte antigen alleles2020

    • Author(s)
      Mwimanzi Francis、Ngare Isaac、Toyoda Mako、Mori Masahiko、Mann Jaclyn、Ndung’u Thumbi、Goulder Phillip、Ueno Takamasa
    • Journal Title

      AIDS

      Volume: 34 Issue: 9 Pages: 1325-1330

    • DOI

      10.1097/qad.0000000000002559

    • Related Report
      2020 Annual Research Report 2019 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Impaired ability of Nef to counteract SERINC5 is associated with reduced plasma viremia in HIV-infected individuals2020

    • Author(s)
      Toyoda Mako、Kamori Doreen、Tan Toong Seng、Goebuchi Kageaki、Ohashi Jun、Carlson Jonathan、Kawana-Tachikawa Ai、Gatanaga Hiroyuki、Oka Shinichi、Pizzato Massimo、Ueno Takamasa
    • Journal Title

      Scientific Reports

      Volume: 10 Issue: 1

    • DOI

      10.1038/s41598-020-76375-w

    • Related Report
      2020 Annual Research Report 2019 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Pre-treatment and acquired HIV drug resistance in Dar es Salaam, Tanzania in the era of tenofovir and routine viral load monitoring2019

    • Author(s)
      Barabona Godfrey、Mahiti Macdonald、Masoud Salim、Mbelele Peter、Mgunya Amina Shaban、Minja Lilian、Sunguya Bruno、Shigemi Urara、Matsuda Masakazu、Hachiya Atsuko、Iwatani Yasumasa、Lyamuya Eligius、Ueno Takamasa
    • Journal Title

      Journal of Antimicrobial Chemotherapy

      Volume: 74 Issue: 10 Pages: 3016-3020

    • DOI

      10.1093/jac/dkz272

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Presentation] Differential sensitivity of patient-derived envelope sequences to SERINC5-mediated restriction of HIV-1 infectivity2021

    • Author(s)
      Emmanuel Nkuwi, George P. Judicate, Toong Seng Tan, Godfrey Barabona, Mako Toyoda, Takamasa Ueno
    • Organizer
      Cold Spring Harbor Laboratory Meetings-Retroviruses
    • Related Report
      2021 Annual Research Report
    • Int'l Joint Research
  • [Presentation] HIV-1の多型性から宿主との関連性を探る2021

    • Author(s)
      上野貴将
    • Organizer
      日本エイズ学会学術集会
    • Related Report
      2021 Annual Research Report
    • Invited
  • [Presentation] Plasma IL-21 associates with HIV-1 Neutralizing Potency of polyclonal IgG in the periphery2021

    • Author(s)
      Isaac Ngare, Takeo Kuwata, Godfrey Barabona, Takamasa Ueno
    • Organizer
      11th IAS Conference on HIV Science
    • Related Report
      2021 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Maraviroc less sensitive HIV-1 variants in a region where multiple non-B subtypes co-circulate2021

    • Author(s)
      George P. Judicate, Godfrey Barabona, Doreen Kamori, Macdonald Mahiti, Takeo Kuwata, Bruno Sunguya, Eligius Lyamuya, Takamasa Ueno
    • Organizer
      HIV research for prevention (HIVR4P)
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Functional characterization of HIV-1 envelopes from Tanzania where multiple non-B co-circulates2020

    • Author(s)
      George P. Judicate, Godfrey Barabona, Doreen Kamori, Macdonald Mahiti, Takeo Kuwata, Bruno Sunguya, Eligius Lyamuya, Takamasa Ueno
    • Organizer
      第34回日本エイズ学会学術集会
    • Related Report
      2020 Annual Research Report
  • [Presentation] Inflammatory biomarkers but not latent reservoir size is associated with degree of immunosuppression in Tanzanians treated at advanced HIV disease2020

    • Author(s)
      Godfrey Barabona, Macdonald Mahiti, Mako Toyoda, Doreen Kamori, Salim Masoud, George P Judicate, Bruno Sunguya, Eligius Lyamuya, Takamasa Ueno
    • Organizer
      第34回日本エイズ学会学術集会
    • Related Report
      2019 Annual Research Report

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Published: 2019-04-18   Modified: 2023-01-30  

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