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Reactive Oxygen Species Hydrogen Peroxide Mediates Kaposi's Sarcoma-Associated Herpesvirus Reactivation from Latency

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      Abstract

      Kaposi's sarcoma-associated herpesvirus (KSHV) establishes a latent infection in the host following an acute infection. Reactivation from latency contributes to the development of KSHV-induced malignancies, which include Kaposi's sarcoma (KS), the most common cancer in untreated AIDS patients, primary effusion lymphoma and multicentric Castleman's disease. However, the physiological cues that trigger KSHV reactivation remain unclear. Here, we show that the reactive oxygen species (ROS) hydrogen peroxide (H2O2) induces KSHV reactivation from latency through both autocrine and paracrine signaling. Furthermore, KSHV spontaneous lytic replication, and KSHV reactivation from latency induced by oxidative stress, hypoxia, and proinflammatory and proangiogenic cytokines are mediated by H2O2. Mechanistically, H2O2 induction of KSHV reactivation depends on the activation of mitogen-activated protein kinase ERK1/2, JNK, and p38 pathways. Significantly, H2O2 scavengers N-acetyl-L-cysteine (NAC), catalase and glutathione inhibit KSHV lytic replication in culture. In a mouse model of KSHV-induced lymphoma, NAC effectively inhibits KSHV lytic replication and significantly prolongs the lifespan of the mice. These results directly relate KSHV reactivation to oxidative stress and inflammation, which are physiological hallmarks of KS patients. The discovery of this novel mechanism of KSHV reactivation indicates that antioxidants and anti-inflammation drugs could be promising preventive and therapeutic agents for effectively targeting KSHV replication and KSHV-related malignancies.

      Author Summary

      Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiologic agent of all clinical forms of Kaposi's sarcoma (KS) and several other malignancies. The life cycle of KSHV consists of latent and lytic phases. While establishment of viral latency is essential for KSHV to evade host immune surveillances, viral lytic replication promotes KSHV-induced malignancies. In this study, we show that the reactive oxygen species (ROS) hydrogen peroxide (H2O2) induces KSHV reactivation from latency. Furthermore, induction of KSHV reactivation by oxidative stress, hypoxia, and proinflammatory and proangiogenic cytokines, which are physiological hallmarks in all clinical forms of KS patients, is mediated by H2O2. Significantly, antioxidants inhibit H2O2-induced KSHV lytic replication in culture and in a mouse model of KSHV-induced lymphoma. These results show that ROS is likely an important physiological cue that triggers KSHV replication. The discovery of this novel mechanism of KSHV reactivation indicates that antioxidants and anti-inflammation drugs might be promising preventive and therapeutic agents for effectively targeting KSHV replication and KSHV-related malignancies.

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      Most cited references 71

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      Identification of herpesvirus-like DNA sequences in AIDS-associated Kaposi's sarcoma.

      Representational difference analysis was used to isolate unique sequences present in more than 90 percent of Kaposi's sarcoma (KS) tissues obtained from patients with acquired immunodeficiency syndrome (AIDS). These sequences were not present in tissue DNA from non-AIDS patients, but were present in 15 percent of non-KS tissue DNA samples from AIDS patients. The sequences are homologous to, but distinct from, capsid and tegument protein genes of the Gammaherpesvirinae, herpesvirus saimiri and Epstein-Barr virus. These KS-associated herpesvirus-like (KSHV) sequences appear to define a new human herpesvirus.
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        Kaposi's sarcoma-associated herpesvirus-like DNA sequences in AIDS-related body-cavity-based lymphomas.

        DNA fragments that appeared to belong to an unidentified human herpesvirus were recently found in more than 90 percent of Kaposi's sarcoma lesions associated with the acquired immunodeficiency syndrome (AIDS). These fragments were also found in 6 of 39 tissue samples without Kaposi's sarcoma, including 3 malignant lymphomas, from patients with AIDS, but not in samples from patients without AIDS. We examined the DNA of 193 lymphomas from 42 patients with AIDS and 151 patients who did not have AIDS. We searched the DNA for sequences of Kaposi's sarcoma-associated herpesvirus (KSHV) by Southern blot hybridization, the polymerase chain reaction (PCR), or both. The PCR products in the positive samples were sequences and compared with the KSHV sequences in Kaposi's sarcoma tissues from patients with AIDS. KSHV sequences were identified in eight lymphomas in patients infected with the human immunodeficiency virus. All eight, and only these eight, were body-cavity-based lymphomas--that is, they were characterized by pleural, pericardial, or peritoneal lymphomatous effusions. All eight lymphomas also contained the Epstein-Barr viral genome. KSHV sequences were not found in the other 185 lymphomas. KSHV sequences were 40 to 80 times more abundant in the body-cavity-based lymphomas than in the Kaposi's sarcoma lesions. A high degree of conservation of KSHV sequences in Kaposi's sarcoma and in the eight lymphomas suggests the presence of the same agent in both lesions. The recently discovered KSHV DNA sequences occur in an unusual subgroup of AIDS-related B-cell lymphomas, but not in any other lymphoid neoplasm studied thus far. Our finding strongly suggests that a novel herpesvirus has a pathogenic role in AIDS-related body-cavity-based lymphomas.
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          JNK1: a protein kinase stimulated by UV light and Ha-Ras that binds and phosphorylates the c-Jun activation domain.

           M. T. Deng,  Tzu-I Wu,  B Su (1994)
          The ultraviolet (UV) response of mammalian cells is characterized by a rapid and selective increase in gene expression mediated by AP-1 and NF-kappa B. The effect on AP-1 transcriptional activity results, in part, from enhanced phosphorylation of the c-Jun NH2-terminal activation domain. Here, we describe the molecular cloning and characterization of JNK1, a distant relative of the MAP kinase group that is activated by dual phosphorylation at Thr and Tyr during the UV response. Significantly, Ha-Ras partially activates JNK1 and potentiates the activation caused by UV. JNK1 binds to the c-Jun transactivation domain and phosphorylates it on Ser-63 and Ser-73. Thus, JNK1 is a component of a novel signal transduction pathway that is activated by oncoproteins and UV irradiation. These properties indicate that JNK1 activation may play an important role in tumor promotion.
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            Author and article information

            Affiliations
            [1 ]Tumor Virology Program, Greehey Children's Cancer Research Institute, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States of America
            [2 ]Department of Pediatrics, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States of America
            [3 ]Department of Molecular Medicine, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States of America
            [4 ]Cancer Therapy and Research Center, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States of America
            Oregon Health & Science University, United States of America
            Author notes

            Conceived and designed the experiments: SJG FY. Performed the experiments: FY FZ RGB TJ XL TK SJG. Analyzed the data: FY SJG. Contributed reagents/materials/analysis tools: FY MG SJG. Wrote the paper: FY SJG.

            Contributors
            Role: Editor
            Journal
            PLoS Pathog
            plos
            plospath
            PLoS Pathogens
            Public Library of Science (San Francisco, USA )
            1553-7366
            1553-7374
            May 2011
            May 2011
            19 May 2011
            : 7
            : 5
            3098240
            21625536
            PPATHOGENS-D-10-00054
            10.1371/journal.ppat.1002054
            (Editor)
            Ye et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
            Counts
            Pages: 14
            Categories
            Research Article
            Biology
            Microbiology
            Molecular Cell Biology
            Medicine
            Infectious Diseases
            Viral Diseases
            Oncology
            Basic Cancer Research

            Infectious disease & Microbiology

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