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Analysis of the infection dynamics and the host gene expression by the viral latency specific genes

Research Project

Project/Area Number 16390136
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Virology
Research InstitutionOsaka University

Principal Investigator

UEDA Keiji  Osaka University, Graduate School of Medicine, Associate Professor, 医学系研究科, 助教授 (00221797)

Co-Investigator(Kenkyū-buntansha) YAMANISHI Koichi  Osaka University, Graduate School of Medicine, Professor, 医学系研究科, 教授 (10029811)
Project Period (FY) 2004 – 2005
Project Status Completed (Fiscal Year 2005)
Budget Amount *help
¥15,100,000 (Direct Cost: ¥15,100,000)
Fiscal Year 2005: ¥4,700,000 (Direct Cost: ¥4,700,000)
Fiscal Year 2004: ¥10,400,000 (Direct Cost: ¥10,400,000)
KeywordsKSHV / latency / replication / maintenance / heterochromatin / Suv39H1 / PARP1 / LANA / RTA / RTA誘導因子 / PEL / 複製・分配・維持 / インスレーター / マトリックス / γヘルペスウイルス / カポジ肉腫関連ヘルペスウイルス / ヘテロクロマチン因子 / 末端反復配列
Research Abstract

We analyzed why the viral gene expression was extremely limited to a few genes in the latency, and how the viral genome replicated and was maintained at the same copy number according to the host cell cycles.
We cloned the almost full length of terminal repeats (TR) of the Kaposi's sarcoma-associated herpesvirus (KSHV) in the bacmid, and tested whether the genome replicated and was maintained in the cells with or without viral latency specific gene products such as LANA (ORF73). We found that the bacmid replicated only in the presence of LANA and was maintained at the same copy number only under the selective pressure using G418, the resistant gene against which is encoded in the vector. This suggested that TR and LANA should be enough for the viral genome replication but not for the viral genome maintenance. Then, are there elements in the genome other than TR for the viral genome maintenance? We tried whether the full viral genome cloned in a bacmid was maintained or not. The results … More showed that there was no element responsible for the viral genome maintenance. The selective pressure, hygromycin selection in this case, was always required for the maintenance. Thus, there could be other reason why the KSHV genome was maintained at the same copy number in the infected cells, especially in the primary effusion lymphoma originated cell lines.
KSHV gene expression is quite limited in the latency. There are only four genes such as LANA, v-cyc, v-FLIP and kaposin expressing in the latency. These genes are clustered side by side. We found that LANA interacted with a cellular gene called Suv39H1, which is a histone H3 methyl transferase and recruits heterochromatin factor such as HP1α. Chromatin immunoprecipitation analysis (ChIP) showed that Suv39H1 and HP1α were located on the TR as well as LANA. Thus, the viral genome could be in the heterochromatin state by LANA and this could be one of the mechanisms why the viral gene expression was quite limited to the several genes.
TR and LANA seem to have an important role for the viral replication and genome maintenance. LANA binds with a specific sequence within TR and executes the viral replication and maintenance and regulates the viral gene expression in the latency. We focused on the TR and tried to identify TR binding proteins with an exhaustive approach by preparing a TR DNA column. We identified several proteins binding to the column, several of which were infected cell specific and the other were still TR DNA specific but not infected cell specific. One of them was poly (ADP-ribose) polymerase 1 (PARP1). We characterized this factor and found that this bound to the specific sequence within TR very near the LANA binding site. The direct interaction between PARP1 and LANA with the immunoprecipitaion analysis but LANA was proved to be ADP-ribosylated by PARP1. PARP1 activity is modulated by some drugs. Hydroxy Urea at the low concentration increases PARP1 activity and 3-aminobenzamide (3-ABA) decreases the activity. Using these drugs, it was shown the higher ribosylation of LANA resulted in the lower copy number of the viral genome and the lower ribosylation did in the higher copy number in the infected cells. Less

Report

(3 results)
  • 2005 Annual Research Report   Final Research Report Summary
  • 2004 Annual Research Report
  • Research Products

    (35 results)

All 2006 2005 2004 Other

All Journal Article (35 results)

  • [Journal Article] KSHV RTA induces a transcriptional represser, HEY1 that represses rta promoter.2006

    • Author(s)
      Yada, K., et al.
    • Journal Title

      Biochem, Biophys.Res.Comm. In press

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] KSHVの遺伝子とその産物.ヘルペスウイルス学-基礎・臨床研究の進歩-2006

    • Author(s)
      矢田住織 et al.
    • Journal Title

      日本臨床 64

      Pages: 538-542

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] KSHVの潜伏感染と再活性化機構.ヘルペスウイルス学-基礎・臨床研究の進歩-2006

    • Author(s)
      大崎恵理子 et al.
    • Journal Title

      日本臨床 64

      Pages: 589-593

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] カポジ肉腫関連ヘルペスウイルス(ヒトヘルペスウイルス8)感染と発癌.特集:発癌ウイルス2006

    • Author(s)
      上田啓次
    • Journal Title

      臨床とウイルス 33

      Pages: 317-322

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] KSHV and its gene products.2006

    • Author(s)
      Yada, K., Yada, K., Ueda, K.
    • Journal Title

      Nippon Rinsho. 64

      Pages: 538-542

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Mechanism of the latency and reactivation of KSHV.2006

    • Author(s)
      Ohsaki, E., Yada, K., Ueda, K.
    • Journal Title

      Nippon Rinsho. 64

      Pages: 589-593

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Kaposi's sarcoma-associated herpesvirus (human herpesvirus 8) infection and its related cancer.2006

    • Author(s)
      Ueda, K.
    • Journal Title

      Clinical Virology 33

      Pages: 317-322

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Alteration in gene expression profile by full-length hepatitis B virus genome.2005

    • Author(s)
      Nakanishi, F., et al.
    • Journal Title

      Inervirology 48

      Pages: 77-83

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] エイズ流行で危倶されるカポジ肉腫関連ヘルペスウイルス感染と腫瘍発生2005

    • Author(s)
      上田啓次
    • Journal Title

      最新医学 60

      Pages: 252-259

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] KSHV-感染症からみた腫瘍2005

    • Author(s)
      上田啓次
    • Journal Title

      分子細胞治療 4

      Pages: 42-47

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Alteration in gene expression profile by fill-length hepatitis B virus genome.2005

    • Author(s)
      Nakanishi, F., Ohkawa, K., Ishida, H., Hosui, A., Sato, A., Hiramatsu, N., Ueda, K., Takehara, T., Kasahara, A., Sasaki, Y., Hori, M., Hayashi, N.
    • Journal Title

      Inervirology 48(2-3)

      Pages: 77-83

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Kaposi's Sarcoma-associated Herpesvirus and its Oncogenic Activity in the AIDS Epidemic Era.2005

    • Author(s)
      Ueda, K.
    • Journal Title

      Medical Frontline 60

      Pages: 252-259

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Kaposi's sarcoma-associated herpesvirus.2005

    • Author(s)
      Ueda, K.
    • Journal Title

      Cellular Molecular Medicine. 4

      Pages: 42-47

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Alteration in gene expression profile by full-length hepatitis B virus genome.2005

    • Author(s)
      Nakanishi, F.
    • Journal Title

      Intervirology 48

      Pages: 77-83

    • Related Report
      2005 Annual Research Report
  • [Journal Article] エイズ流行で危惧されるカポジ肉腫関連ヘルペスウイルス感染と腫瘍発生2005

    • Author(s)
      上田啓次
    • Journal Title

      最新医学 60

      Pages: 252-259

    • Related Report
      2005 Annual Research Report
  • [Journal Article] KSHV-感染症からみた腫瘍2005

    • Author(s)
      上田啓次
    • Journal Title

      分子細胞治療 4(5)

      Pages: 42-47

    • Related Report
      2005 Annual Research Report
  • [Journal Article] カポジ肉腫関連ヘルペスウイルス(ヒトヘルペスウイルス8)感染と発癌2005

    • Author(s)
      上田啓次
    • Journal Title

      臨床とウイルス 33(5)2

      Pages: 317-322

    • NAID

      10017122798

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Involvement of p38 signaling pathway in interferon-α-mediated antiviral activity toward hepatitis C virus.2004

    • Author(s)
      Ishida, H., et al.
    • Journal Title

      Biochem, Biophys.Res.Comm. 321

      Pages: 722-727

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] PARP1(poly [ADP-ribose] polymerase 1) binds with Kaposi's sarcoma-associated herpesvirus(KSHV) terminal repeat sequence and modulated KSHV replication in latency.2004

    • Author(s)
      Ohsaki, E., et al.
    • Journal Title

      J.Virol. 78

      Pages: 9936-9946

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Posttranscriptional regulator of Kaposi's sarcoma-associated herpesvirus interacts with RNA-binding protein PCBP1 and controls gene expression through the IRES.2004

    • Author(s)
      Nishimura, K., et al.
    • Journal Title

      Virology 325

      Pages: 364-378

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Hepatitis C virus core functions as a suppressor of cyclin-dependent kinase-activating kinase and impairs cell cycle progression.2004

    • Author(s)
      Ohkawa, K., et al.
    • Journal Title

      J.Biol.Chem. 279

      Pages: 11719-11726

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Accumulation of heterochromatin components on the terminal repeat sequence of Kaposi's sarcoma-associated herpesvirus mediated by the latency-associated nuclear antigen.2004

    • Author(s)
      Sakakibara, S., et al.
    • Journal Title

      J.Virol. 78

      Pages: 7299-7310

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] カポジ肉腫とヒトヘルペスウイルス82004

    • Author(s)
      上田啓次
    • Journal Title

      Visual Dermatology(目で見る皮膚科学) 3

      Pages: 164-167

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Involvement of p38 signaling pathway in interferon-a-mediated antiviral activity toward hepatitis C virus.2004

    • Author(s)
      Ishida, H., Ohkawa, K., Hosui, A., Hiramatsu, N., Kanto, T., Ueda, K., Takehara, T., Hayshi, N.
    • Journal Title

      Biochem.Biophys.Res.Comm. 321

      Pages: 722-727

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] PARP1 (poly[ADP-ribose] polymerase 1) binds with Kaposi's sarcoma-associated herpesvirus (KSHV) terminal repeat sequence and modulated KSHV replication in latency.2004

    • Author(s)
      Ohsaki, E., Ueda, K., Sakakibara, S., Do, E., Yada, K., Yamanishi, K.
    • Journal Title

      J.Virol. 78(18)

      Pages: 9936-9946

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Posttranscriptional regulator of Kaposi's sarcoma-associated herpesvirus interacts with RNA-binding protein PCBP1 and controls gene expression through the IRES.2004

    • Author(s)
      Nishimura, K., Ueda, K., Guwanan, E., Sakakibara, S., Do, E., Ohsaki, E., Yada, K., Okuno, T., Yamanishi, K.
    • Journal Title

      Virology 325

      Pages: 364-378

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Hepatitis C virus core functions as a suppressor of cyclin-dependent kinase-activating kinase and impairs cell cycle progression.2004

    • Author(s)
      Ohkawa, K., Ishida, H., Nakanishi, F., Hosui, A., Ueda, K., Takahara, T., Hori, M., Hayashi, N.
    • Journal Title

      J.Biol.Chem. 279(12)

      Pages: 11719-11726

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Accumulation of heterochromatin components on the terminal repeat sequence of Kaposi's sarcoma-associated herpesvirus mediated by the latency-associated nuclear antigen.2004

    • Author(s)
      Sakakibara, S., Ueda, K., Nishimura, K., Ohsaki, E., Do, E., Yamanishi, K.
    • Journal Title

      J.Virol. 78(14)

      Pages: 7299-7310

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Kaposi's sarcoma and its causative agent, HHV8.2004

    • Author(s)
      Ueda, K.
    • Journal Title

      Visual Dermatology 3

      Pages: 164-167

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] PARP1 (poly(ADP-ribose) polymerase 1) Binds with Kaposi's sarcoma-Associated Herpesvirus (KSHV) Terminal Repeat Sequence and Modulates KSHV Replication in Latency.2004

    • Author(s)
      Ohsaki, E.
    • Journal Title

      J.Virology 78・18

      Pages: 9936-9946

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Accumulation of heterochromatin components on the terminal repeat sequence of Kaposi's sarcoma-associated herpesvirus mediated by the latency-associated nuclear antigen.2004

    • Author(s)
      Sakakibara, S.
    • Journal Title

      J.Virology 78・14

      Pages: 7299-7310

    • Related Report
      2004 Annual Research Report
  • [Journal Article] A Posttranscriptional Regulator of Kaposi's Sarcoma-Associated Herpesvirus Interacts with RNA-binding Protein PCBP1 and Controls Gene Expression through the IRES.2004

    • Author(s)
      Nishimura, K.
    • Journal Title

      Virology 325・2

      Pages: 364-378

    • Related Report
      2004 Annual Research Report
  • [Journal Article] KSHV RTA induces a transcriptional repressor, HEY1 that represses rta promoter.

    • Author(s)
      Yada, K., Do, E., Sakakibara, S., Ohsaki, E., Ito, E., Watanabe, S., Ueda, K.
    • Journal Title

      Biochem, Biophys.Res.Comm. (In press)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] KSHVの遺伝子とその産物.ヘルペスウイルス学-基礎・臨床研究の進歩-

    • Author(s)
      矢田佳織
    • Journal Title

      日本臨床 (印刷中)

    • Related Report
      2005 Annual Research Report
  • [Journal Article] KSHVの潜伏感染と再活性化機構.ヘルペスウイルス学-基礎・臨床研究の進歩-

    • Author(s)
      大崎恵理子
    • Journal Title

      日本臨床 (印刷中)

    • Related Report
      2005 Annual Research Report

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Published: 2004-04-01   Modified: 2016-04-21  

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