Importance of fibrocytes and macrophages as HIV-1 reservoirs

• Project/Area Number: 20H03725
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 54030:Infectious disease medicine-related
• Research Institution: Kumamoto University
• Principal Investigator: Suzu Shinya 熊本大学, ヒトレトロウイルス学共同研究センター, 教授 (80363513)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥17,680,000 (Direct Cost: ¥13,600,000、Indirect Cost: ¥4,080,000); Fiscal Year 2022: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2021: ¥5,720,000 (Direct Cost: ¥4,400,000、Indirect Cost: ¥1,320,000); Fiscal Year 2020: ¥6,630,000 (Direct Cost: ¥5,100,000、Indirect Cost: ¥1,530,000)
• Keywords: 潜伏感染 / HIV-1 / fibrocytes / マクロファージ / HIV / 線維細胞

Outline of Research at the Start

エイズ根絶の障壁はHIV-1潜伏感染であり、T細胞と並ぶHIV-1主要標的「単球・マクロファージ」の解析が重要となってきた。実際、申請者は単球中のfibrocytesと言うサブセットに高頻度に潜伏感染することを発見し、静止期CD4+ T細胞よりも強く潜伏感染する複数の症例を認めた。本研究では症例を重ね、fibrocytesが主要潜伏感染細胞であることを明確にする。定性的解析から定量的解析へレベルを高める。感染サルモデルでも検証し、潜伏感染の解除法も確立する。議論が多いマクロファージでの潜伏感染についても、最近、純化した「ヒト組織常在マクロファージ」を用いた感染実験で明らかにする。

Outline of Final Research Achievements

Like CD4+ T cells, monocytes serve as HIV-1 reservoirs. Here we show that a monocyte fraction expressing CD34 (＝fibrocytes）is more susceptible to HIV-1 infection than CD34-negative major subset. In viremic patients, CD34+ fraction harbored more proviruses. When compared to the major subset, CD34+ fraction expressed HIV-1 receptors CD4 and CCR5 at higher levels and HIV-1 restriction factors MX2 and SAMHD1 at lower levels. Proviruses was also detected in CD34+ fraction of virologically-suppressed patients. CD34+ monocytes were present in lymph nodes, and expressed CD4 and CCR5 at higher levels than the major subset, as in peripheral blood. Those CD34+ monocytes highly expressed CCR7 and S1PR1, critical regulators of in vivo cellular trafficking. Our findings suggest that CD34+ monocytes are infected with residual HIV-1 after migrating into tissues including lymph nodes and return to circulation, which explains the detection of proviruses in the cells even after long-term ART.

Academic Significance and Societal Importance of the Research Achievements

HIV-の克服には潜伏感染細胞の排除が重要である。静止期CD4+ T細胞以外にも近年、単球への潜伏感染も分かってきた。本研究では単球中ではfibrocytesに潜伏感染しやすいことを明らかにした。さらに、長期に抗レトロウイルス療法を行い、血中ウイルス量が検出限界以下になった感染者において、なぜ末梢fibrocytesにHIV-1ウイルスゲノムが存在し得るのかは不明であったが、この根源的な疑問にも一定の答えを出せた。並行して進めた組織マクロファージ解析も合わせ、ミエロイド系の細胞に関する一連の発見はHIV-1潜伏感染細胞の完全排除に向けて、有用かつ重要な情報と期待される。

Research Products

• [Journal Article] iPS cell-derived model to study the interaction between tissue macrophage and HIV-1 (2023)
  • Author(s): Eltalkhawy Youssef M、Takahashi Naofumi、Ariumi Yasuo、Shimizu Jun、Miyazaki Kazuo、Senju Satoru、Suzu Shinya
  • Journal Title: Journal of Leukocyte Biology Volume: - Issue: 1 Pages: 53-67
  • DOI: 10.1093/jleuko/qiad024
  • Peer Reviewed
• [Journal Article] Inhibitory and Stimulatory Effects of IL-32 on HIV-1 Infection (2022)
  • Author(s): Nasser Hesham、Takahashi Naofumi、Eltalkhawy Youssef M.、Reda Omnia、Lotfi Sameh、Nasu Kanako、Sakuragi Jun-ichi、Suzu Shinya
  • Journal Title: The Journal of Immunology Volume: 209 Issue: 5 Pages: 970-978
  • DOI: 10.4049/jimmunol.2200087
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] M-CSFR expression in the embryonal component of hepatoblastoma and cell-to-cell interaction between macrophages and hepatoblastoma (2022)
  • Author(s): Li Lianbo、Irie Tomoaki、Yoshii Daiki、Komohara Yoshihiro、Fujiwara Yukio、Esumi Shigeyuki、Kadohisa Masashi、Honda Masaki、Suzu Shinya、Matsuura Toshiharu、Kohashi Kenichi、Oda Yoshinao、Hibi Taizo
  • Journal Title: Medical Molecular Morphology Volume: 55 Issue: 3 Pages: 236-247
  • DOI: 10.1007/s00795-022-00323-y
  • Peer Reviewed / Open Access
• [Journal Article] IL-34 in hepatoblastoma cells potentially promote tumor progression via autocrine and paracrine mechanisms (2022)
  • Author(s): Irie T, Yoshii D, Komohara Y, Fujiwara Y, Kadohisa M, Honda M, Suzu S, Matsuura T, Kohashi K, Oda Y, Hibi T
  • Journal Title: Cancer Med Volume: 11 Issue: 6 Pages: 1441-1453
  • DOI: 10.1002/cam4.4537
  • Peer Reviewed / Open Access
• [Journal Article] M-Sec induced by HTLV-1 mediates an efficient viral transmission (2021)
  • Author(s): Hiyoshi M, Takahashi N, Eltalkhawy YM, Noyori O, Lotfi S, Panaampon J, Okada S, Tanaka Y, Ueno T, Fujisawa JI, Sato Y, Suzuki T, Hasegawa H, Tokunaga M, Satou Y, Yasunaga JI, Matsuoka M, Utsunomiya A, Suzu S
  • Journal Title: PLoS Pathog Volume: 17 Issue: 11 Pages: e1010126-e1010126
  • DOI: 10.1371/journal.ppat.1010126
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Establishment of bone marrow-derived M-CSF receptor-dependent self-renewing macrophages (2020)
  • Author(s): Nasser H, Adhikary P, Abdel-Daim A, Noyori O, Panaampon J, Kariya R, Okada S, Ma W, Baba M, Takizawa H, Yamane M, Niwa H, Suzu S.
  • Journal Title: Cell Death Discovery Volume: 63 Issue: 1 Pages: 63-63
  • DOI: 10.1038/s41420-020-00300-3
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] M-Sec facilitates intercellular transmission of HIV-1 through multiple mechanisms (2020)
  • Author(s): Lotfi Sameh、Nasser Hesham、Noyori Osamu、Hiyoshi Masateru、Takeuchi Hiroaki、Koyanagi Yoshio、Suzu Shinya
  • Journal Title: Retrovirology Volume: 17 Issue: 1 Pages: 20-20
  • DOI: 10.1186/s12977-020-00528-y
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] CD34陽性単球におけるHIV-1感染 (2022)
  • Author(s): 鈴 伸也, Youssef Eltalkhawy, 高橋尚史
  • Organizer: 日本エイズ学会
• [Presentation] iPS cell-derived model to study the interaction between tissue macrophage and HIV-1 (2022)
  • Author(s): Youssef M. Eltalkhawy, Naofumi Takahashi, Yasuo Ariumi, Jun Shimizu, Kazuo Miyazaki, Satoru Senju, Shinya Suzu
  • Organizer: 日本エイズ学会
• [Presentation] iPS-derived myeloid line (iPS-ML) as a model to study HIV-1 infection in macrophages (2021)
  • Author(s): Youssef M. Eltalkhawy, Naofumi Takahashi, Shinya Suzu
  • Organizer: 日本エイズ学会
• [Presentation] Self-renewing macrophages: how they can proliferate, whether they exist in humans, and how they are involved in HIV-1 infection (2021)
  • Author(s): Shinya Suzu, Hesham Nasser, Youssef M. Eltalkhawy, Hiroshi Niwa, Takatsugu Ishimoto, and Naofumi Takahashi
  • Organizer: Kumamoto AIDS Seminar
  • Int'l Joint Research
• [Presentation] Bone marrow-derived macrophages with un-limited self-renewing capacity (2020)
  • Author(s): Hesham Nasser, Partho Adhikary, Amira Abdel-Daim, Osamu Noyori, Hitoshi Takizawa, Ryusho Kariya, Seiji Okada, Shinya Suzu
  • Organizer: 第82回日本血液学会
• [Presentation] M-CSF-dependent physiological self-renewing macrophages are derived from adult mouse bone marrow (2020)
  • Author(s): Hesham Nasser, Partho Adhikary, Amira Abdel-Daim, Osamu Noyori, Jutatip Panaampon, Ryusho Kariya, Seiji Okada, Wenjuan Ma, Masaya Baba, Hitoshi Takizawa, Mariko Yamane, Hitoshi Niwa, Shinya Suzu
  • Organizer: 21st Kumamoto AIDS Seminar
  • Int'l Joint Research
• [Presentation] Induced Pluripotent cells Differentiated into Macrophages (iPS-ML) as model to study HIV-1 infection in different types of Macrophages (2020)
  • Author(s): Mohammed Youssef Eltalkhawy, Hesham Nasser, Shinya Suzu
  • Organizer: 21st Kumamoto AIDS Seminar
  • Int'l Joint Research
• [Presentation] M-Sec accelerates cell to cell transmission of HIV-1 through multiple mechanisms (2020)
  • Author(s): Sameh Lotfi, Hesham Nasser, Osamu Noyori, Masateru Hiyoshi, Hiroaki Takeuchi, Yoshio Koyanagi, Shinya Suzu
  • Organizer: 21st Kumamoto AIDS Seminar
  • Int'l Joint Research