HIV-1 Nef dysregulates innate immunity of macrophages and plays a role in AIDS pathogenesis

• Project/Area Number: 20590481
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Virology
• Research Institution: National Institute of Infectious Diseases
• Principal Investigator: YOKOTA Yasuko National Institute of Infectious Diseases, 免疫部, 室長 (20182701)
• Project Period (FY): 2008 – 2010
• Project Status: Completed (Fiscal Year 2010)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2010: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2009: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2008: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
• Keywords: マイクロファージ / 自然免疫系シグナル / 病原性 / HIV-1 Nef / サイトカイン / マクロファージ / 自然免疫機能障害

Research Abstract

In order to clarify a role of HIV-1 Nef on the AIDS pathogenesis, we analyzed the innate immune function of macrophages through the stimulation of TLR5 and IL-10 receptor beta, expressions of which were suppressed by Nef. A cytokine production profile of macrophages via these signaling was disturbed by Nef expression. Unfortunately, immunodeficient mice reconstituted with human cord blood stem cells were poor in the macrophage development and, therefore, not a good model to study Nef function in vivo.

Research Products

• [Journal Article] Distinct fucosylation of M cells and epithelial cells by Futl and Fut2, respectively, in response to intestinal environmental stress. (2011)
  • Author(s): Terahara, K., Nochi, T., Yoshida, M., Takahashi, Y., Goto, Y., Hatai, H., Kurokawa, S., Ho Jang, M., Kweon, M-N., Domino, S.E., Hiroi, T., Yuki, Y., Tsunetsugu-Yokota, Y., Kobayashi, K., Kiyono, H.
  • Journal Title: Biochem.Biophy.Res.Comm. Volume: 404 Pages: 822-828
  • Peer Reviewed
• [Journal Article] Mammalian microRNAs.: post-transcriptional gene regulation in RNA virus infection and therapeutic applications. (2010)
  • Author(s): Tsunetsugu-Yokota Y., Yamamoto, T.
  • Journal Title: Frontiers in Microbiology 1 Pages: 1-9
  • Peer Reviewed
• [Journal Article] Mammalian microRNAs : post-transcriptional gene regulation in RNA virus infection and therapeutic applications. (2010)
  • Author(s): Tsunetsugu-Yokota, Y., Yamamoto, T.
  • Journal Title: Frontiers in Microbiology Volume: 1 Pages: 1-9
  • Peer Reviewed
• [Journal Article] Identification of a novel Vpr-binding compound that inhibits HIV-1 multiplication in macrophages by chemical array. (2010)
  • Author(s): Hagiwara, K., Murakami, T., Xue, G.Shimizu, Y., Takeda, E., Hashimoto, Y., Honda, K., Kondoh, Y., Osada, H., Tsunetsugu-Yokota, Y., Aida, Y.
  • Journal Title: Biochem.Biophy.Res.Comm. Volume: 401 Pages: 40-45
  • Peer Reviewed
• [Journal Article] siRNA inhibiting HIV-1 reactivation restores function of HIV-specific CD4+T cells in chronically HIV-infected individuals. (2009)
  • Author(s): Yamamoto T., Samri A., Mitsuki Y-Y., Mizukoshi F., Kobayashi K., Inoue J.-I., Autran B., Tsunetsugu-Yokota Y.
  • Journal Title: AIDS 23 Pages: 2265-2275
  • Peer Reviewed
• [Journal Article] Polyfunctional T-cell induction in neutralizing antibody-triggered simian immunodeficiency virus control. (2009)
  • Author(s): Yamamoto T., Iwamoto N., Yamamoto H., Tsukamoto T., Kuwano T., Takeda A., Kawada M., Tsunetsugu-Yokota Y., Matano T.
  • Journal Title: J.Virol. 83 Pages: 5514-5524
  • Peer Reviewed
• [Journal Article] Selective transmission of R5 HIV-1 over X4 HIV-1 at the dendritic cell-T cell infectious synapse is determined by the T cell activation state. (2009)
  • Author(s): Yamamoto T., Tsunetsugu-Yokota Y., Mitsuki Y-Y, Mizukoshi F., Terahara K., Inagaki Y., Yamamoto N., Kobayashi K., Inoue J-I.
  • Journal Title: PLoS Pathogen 5
  • Peer Reviewed
• [Journal Article] Activation of HIV-1 Gag-specific CD8+ T cells by yeast-derived VLP-pulsed dendritic cells is influenced by the level of mannose on the VLP antigen. (2009)
  • Author(s): Mizukoshi F., Yamamoto T., Mitsuki Y-y., Terahara K., Kawana-Tachikawa A., Kobayashi K., Iwamoto A., Morikawa Y., Tsunetsugu-Yokota Y.
  • Journal Title: Microbes Infect. 11 Pages: 191-197
  • Peer Reviewed
• [Journal Article] Selective transmission of R5 HIV-1 over X4 HIV-1 at the dendritic cell-T cell infectious synapse is determined by the T cell activation state. (2009)
  • Author(s): Yamamoto T., Tsunetsugu-Yokota Y., Mitsuki Y-Y, Mizukoshi F., Terahara K., Inagaki Y., Yamamoto N., Kobayashi K., Inoue J-I.
  • Journal Title: PLoS Pathogen. 5
  • Peer Reviewed
• [Journal Article] siRNA inhibiting HIV-1 reactivation restores function of HIV-specific CD4+ T cells in chronically HIV-infected individuals (2009)
  • Author(s): Yamamoto, T., Samri, A., Mitsuki, Y-Y., Mizukoshi, F., Kobayashi, K., Inoue, J.-I., Autran, B., Tsunetsugu-Yokota, Y.
  • Journal Title: AIDS 23 Pages: 2265-2275
  • Peer Reviewed
• [Journal Article] Expression of newly identified secretory CEACAM1 isoforms in the intestinal epithelium (2009)
  • Author(s): Terahara, K., Yoshida, M., Taguchi, F., Igarashi, O., Nochi, T., Gotoh, Y., Yamamoto, T., Tsunetsugu-Yokota, Y., Beauchemin, N., Kiyono, H.
  • Journal Title: BBRC 383 Pages: 340-346
  • Peer Reviewed
• [Journal Article] Polyfunctional T-cell induction in neutralizing antibody-triggered simian immunodeficiency virus control (2009)
  • Author(s): amamoto, T., Iwamoto, N., Yamamoto, H., Tsukamoto, T., Kuwano, T., Takeda, A., Kawada, M., Tsunetsugu-Yokota, Y., Matano, T.
  • Journal Title: J.Virol. 83 Pages: 5514-5524
  • Peer Reviewed
• [Journal Article] Selective transmission of R5 HIV-1 over X4 HIV-1 at the dendritic cell-T cell infectious synapse is determined by the T cell activation state (2009)
  • Author(s): Yamamoto, T., Tsunetsugu-Yokota, Y., Mitsuki, Y-Y, Mizukoshi, F., Terahara, K., Inagaki, Y., Yamamoto, N., Kobayashi, K., Inoue, J-I.
  • Journal Title: PLoS Pathogen 5
  • Peer Reviewed
• [Journal Article] Activation of HIV-1 Gag-specific CD8^+ T cells by yeast-derived VLP-pulsed dendritic cells is influenced by the level of mannose on the VLP antigen (2009)
  • Author(s): Mizukoshi, F., Yamamoto, T., Mitsuki, Y-y., Terahara, K., Kawana-Tachikawa, A., Kobayashi, K., Iwamoto, A., Morikawa, Y., Tsunetsugu-Yokota, Y.
  • Journal Title: Microbes Infect. 11 Pages: 191-197
  • Peer Reviewed
• [Journal Article] Activation of HIV-1 Gag-specific CD8^+ T cells by yeast-derived VLP-pulsed dendritic cells is influenced by the level of mannose on the VLP antigen (2009)
  • Author(s): Mizukoshi, F., Yamamoto, T., Mitsuki, Y-y., Terahara, K., Kawana-Tachikawa, A., Kobayashi, K., Iwamoto, A., Morikawa, Y., Tsunetsugu-Yokota, Y.
  • Journal Title: Microbes Infect 11 Pages: 191-197
  • Peer Reviewed
• [Journal Article] Erythromycin-derivatives inhibit HIV-1 replication in macrophages through modulation of MAPK activity to induce small isoform of C/EBPβ. (2008)
  • Author(s): Komuro I., Sunazuka T., Akagawa S.K., Tsunetsugu-Yokota Y., Iwamoto A., Omura S.
  • Journal Title: PNAS 105 Pages: 12509-12514
  • Peer Reviewed
• [Journal Article] Erythromycin-derivatives inhibit HIV-1 replication in macrophages through modulation of MAPK activity to induce small is oform of C/EBP□. (2008)
  • Author(s): Komuro, I., Sunazuka, T., Akagawa, S. K., Tsunetsugu-Yokota, Y., Iwamoto, A., Omura, S.
  • Journal Title: PNAS 105 Pages: 12509-12514
  • Peer Reviewed
• [Presentation] Factors crucial for the preferential propagation of R5-tropic HIV-1 in the early phase of HIV-1 infection. (2010)
  • Author(s): Tsunetsugu-Yokota Y., Terahara K.
  • Organizer: The 5th Japanese-German HIV-Symposium.
  • Place of Presentation: 東京都
• [Presentation] The impact of chemokine receptor usage of HIV-1 in the pathogenesis of HIV infection. (2010)
  • Author(s): Tsunetsugu-Yokota Y
  • Organizer: The 10th Awaji International Forum on Infection and Immunity.
  • Place of Presentation: 兵庫県
• [Presentation] HIV-1感染モデルとしてのヒト化マウスの妥当性とX4およびR5 HIV-1感染 (2010)
  • Author(s): 石毛真行、寺原和孝、光木裕也、渋沢謙太郎、小林和夫、岡田誠治、横田(恒次)恭子
  • Organizer: 第58回ウイルス学会
  • Place of Presentation: 徳島県
• [Presentation] Factors crucial for the preferential propagation of R5-tropic HIV-1 in the early phase of HIV-1 infection. (2010)
  • Author(s): Tsunetsugu-Yokota, Y., Terahara, K.
  • Organizer: The 5th Japanese-German HIV-Symposium
  • Place of Presentation: 東京
• [Presentation] Characteristic activation/differentiation phenotype of CD4+ T cells and their distinct susceptibility to X4-type and/or R5-type HIV-1 infection in humanized NOD/SCID/Jak3-null mice. (2010)
  • Author(s): Terahara, K., Ishige, M., Mitsuki, Y-y, Shibusawa, K., Watanabe, S., Okada, S., Kobayashi, K., Tsunetsugu-Yokota, Y.
  • Organizer: The 14^<th> International Congress of Immunology
  • Place of Presentation: 神戸
• [Presentation] The impact of chemokine receptor usage of HIV-1 in the pathogenesis of HIV infection. (2010)
  • Author(s): Tsunetsugu-Yokota, Y.
  • Organizer: The 10^<th> Awaji International Forum on Infection and Immunity
  • Place of Presentation: 淡路島
• [Presentation] HIV1感染モデルとしてのヒト化マウスの妥当性とX4およびR5 HIV1感染 (2010)
  • Author(s): 石毛真行、寺原和孝、光木裕也、渋沢謙太郎、小林和夫、岡田誠治、横田(恒次)恭子
  • Organizer: 第58回ウイルス学会
  • Place of Presentation: 徳島
• [Presentation] 樹状細胞を標的としたHIV-1増殖抑制shRNA発現レンチウィルスの開発 (2009)
  • Author(s): 渋沢謙太郎、光木裕也、寺原和孝、柳雄介、小林和夫、横田(恒次)恭子
  • Organizer: 第39回日本免疫学会
  • Place of Presentation: 大阪
• [Presentation] CD4標的レンチウイルスベクターの開発 (2009)
  • Author(s): 土屋貴嗣、光木裕也、寺原和孝、渋沢謙太郎、小林和夫、渡邉俊樹、横田(恒次)恭子
  • Organizer: 第32会日本分子生物学会
  • Place of Presentation: 横浜
• [Presentation] HIV-1感染と麻疹ウイルス感染が相互の及ぼす影響およびその機構の解析 (2009)
  • Author(s): 光木裕也、水越文徳、渋沢謙太郎、寺原和孝、竹田誠、柳雄介、森川裕子、山岡昇司、横田(恒次)恭子
  • Organizer: 第57回ウイルス学会
  • Place of Presentation: 東京
• [Presentation] ウイルス感染に対する生体防御機能とワクチン (2009)
  • Author(s): 横田恭子
  • Organizer: 第27回日本耳鼻咽喉科免疫アレルギー学会
  • Place of Presentation: 千葉
• [Presentation] Nef蛋白質発現に伴うマクロファージの自然免疫機能異常に関する解析 (2008)
  • Author(s): 水越文徳、山本拓也、光木裕也、寺原和孝、小林和夫、横田(恒次)恭子
  • Organizer: 第22回日本エイズ学会
  • Place of Presentation: 大阪
  • Year and Date: 2008-11-27
• [Presentation] 樹状細胞の抗原提示に伴う感染シナプスを介したR5型HIV-1選択的伝播機構の解析 (2008)
  • Author(s): 山本拓也、光木裕也、水越文徳、寺原和孝、稲垣好雄、山本直樹、横田(恒次)恭子
  • Organizer: 第56回ウイルス学会
  • Place of Presentation: 岡山
  • Year and Date: 2008-10-28
• [Presentation] 樹状細胞の抗原提示に伴う感染シナプスを介したR5型HIV-1選択的伝播機構の解析 (2008)
  • Author(s): 山本拓也, 光木裕也, 水越文徳, 寺原和孝, 稲垣好雄, 山本直樹, 横田(恒次)恭子
  • Organizer: 第56回ウイルス学会
  • Place of Presentation: 岡山市
  • Year and Date: 2008-10-28
• [Presentation] HIV-1 Nef dysregulates the innate immune function of macrophages. (2008)
  • Author(s): Terahara K., Mizukoshi F., Yamamoto T., Mitsuki Y-Y, Tsuchiya T., Kobayashi K., Tsunetsugu-Yokota Y.
  • Organizer: The 8th Awaji International Forum of Infection and Immunity
  • Place of Presentation: 兵庫
  • Year and Date: 2008-09-10
• [Presentation] HIV-1 Nef dysregulates the innate immune function of macro phages (2008)
  • Author(s): Terahara, K., Mizukoshi, F., Yamamoto, T., Mitsuki, Y-Y, Tsuchiya, T., Kobayashi, K., Tsunetsuau-Yokota, Y.
  • Organizer: The 8^<th> Awaji International Forum of Infection and Immunity
  • Place of Presentation: 兵庫県淡路市
  • Year and Date: 2008-09-10
• [Book] レトロウイルス進化におけるAIDS、病原体の進化による疾病、特集:生活習慣病HA進化病である、成人病と生活習慣病 (2009)
  • Author(s): 横田(恒次)恭子
  • Total Pages: 5
  • Publisher: 東京医学社
• [Book] Transmission of HIV from dendritic cells to CD4+ T cells : a promising target for vaccination and therapeutic intervention" in AIDS vaccines, HIV receptors and AIDS research. (2008)
  • Author(s): Tsunetsugu-Yokota Y.(Kendow, L.B. ed.)
  • Total Pages: 12
  • Publisher: Nova Biomedical Books Inc
• [Book] Transmission of HIV from dendritic cells to CD4^+ T cells : a promising target for vaccination and therapeutic intervention"in AIDS vaccines, HIV receptors and AIDS research (2008)
  • Author(s): Tsunetsugu-Yokota, Y., Kendow, L. B., ed.
  • Total Pages: 12
  • Publisher: Nova Biomedical Books Inc.
• [Remarks] ホームページ等