Characterization of the Latent K15 Protein of Kaposi's Sarcoma-associated Herpesvirus and Identification of Compounds that Disrupt Viral Latency Public Deposited

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  • March 20, 2019
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  • Moyo, Tamara Kay Nun
    • Affiliation: School of Medicine, Department of Microbiology and Immunology
Abstract
  • The Kaposi's sarcoma-associated herpesvirus (KSHV) persists in a latent state in the healthy host without apparent disease. However, in circumstances of diminished immune responsiveness, latent KSHV infection has been linked to three neoplastic diseases, including Kaposi's sarcoma, primary effusion lymphoma and multicentric Castleman's disease. Cytokines, chemokines and growth factors play important roles in all three KSHV-associated malignancies, stimulating tumor cell proliferation and neovascularization. The restricted expression of viral proteins during latency minimizes the risk of immune recognition and also limits the number of potential therapeutic targets. Currently, no drugs successfully target KSHV latency. Thus there is no cure. One potential therapeutic target is the latent membrane protein K15. Multiple K15 isoforms result from alternative splicing of the K15 message. However, all K15 isoforms are membrane-bound and share a long cytoplasmic tail with several conserved signaling motifs. Given its location and potential signaling capacities, we investigated the function of the K15 protein in B lymphocytes. We show that K15 expression alters the cytokine milieu. K15 induces interleukin-6 (IL-6) expression by activation of AP-1 transcription factors. IL-6 secretion is increased by K15 alone or in the context of viral infection. The viral IL-6 homolog is also induced by K15, stressing the important role of IL-6 cytokine signaling in viral pathogenesis. Paradoxically, K15 also activates the STAT1 protein, normally shown to be active in the interferon response. Our studies suggest that K15 signaling may enhance cell survival and promote viral latency. Therefore, K15 might be a promising target for new pharmaceuticals. In order to screen samples for activity against latent viral infection, we developed a fluorescence-based screening assay that we used to identify antiviral agents without bias to mechanism. Of 81 plant extracts screened, we found two potential hits that were relatively non-toxic to uninfected cells, highly toxic to naturally infected cells, and that exhibited selective viral inhibition in a latent model of infection. These extracts may achieve their antiviral effects by disrupting the latency associated nuclear antigen (LANA) which tethers the viral episome to the host cell chromosome, ensuring the latent virus is not lost from the dividing cell population.
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  • Damania, Blossom
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