Targeting Kaposi's Sarcoma-Associated Herpesvirus ORF21 Tyrosine Kinase and Viral Lytic Reactivation by Tyrosine Kinase Inhibitors Approved for Clinical Use (original) (raw)
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Recent Advances in Developing Treatments of Kaposi’s Sarcoma Herpesvirus-Related Diseases
Viruses
Kaposi-sarcoma-associated herpesvirus (KSHV) or human herpesvirus 8 (HHV-8) is the causative agent of several malignancies, including Kaposi’s sarcoma (KS), primary effusion lymphoma (PEL), and multicentric Castleman’s disease (MCD). Active KSHV replication has also been associated with a pathological condition called KSHV inflammatory cytokine syndrome (KICS), and KSHV may play a role in rare cases of post-transplant polyclonal lymphoproliferative disorders. Several commonly used herpesviral DNA polymerase inhibitors are active against KSHV in tissue culture. Unfortunately, they are not always efficacious against KSHV-induced diseases. To improve the outcome for the patients, new therapeutics need to be developed, including treatment strategies that target either viral proteins or cellular pathways involved in tumor growth and/or supporting the viral life cycle. In this review, we summarize the most commonly established treatments against KSHV-related diseases and review recent dev...
Kaposi sarcoma-associated herpesvirus (KSHV): Molecular biology and oncogenesis
2009
Kaposi sarcoma-associated herpesvirus (KSHV) is a double-stranded DNA herpesvirus belonging to the c-herpesvirinae subfamily. KSHV has been associated with the development of three neoplastic diseases: Kaposi sarcoma (KS), primary effusion lymphoma (PEL), and multicentric Castleman disease (MCD). In this review, we discuss the three KSHV-associated malignancies, KSHV genome, latent and lytic aspects of the viral lifecycle, putative viral oncogenes, as well as therapeutic regimens used for the treatment of KS, PEL, and MCD.
Biology and oncogenicity of the Kaposi sarcoma herpesvirus K1 protein
Reviews in Medical Virology, 2015
The Kaposi sarcoma-associated herpesvirus (KSHV), or human herpesvirus 8, is a gammaherpesvirus etiologically linked to the development of Kaposi sarcoma, primary effusion lymphomas, and multicentric Castleman disease in humans. KSHV is unique among other human herpesviruses because of the elevated number of viral products that mimic human cellular proteins, such as a viral cyclin, a viral G protein-coupled receptor, anti-apoptotic proteins (e.g. v-bcl2 and v-FLIP), viral interferon regulatory factors, and CC chemokine viral homologues. Several KSHV products have oncogenic properties, including the transmembrane K1 glycoprotein. KSHV K1 is encoded in the viral ORFK1, which is the most variable portion of the viral genome, commonly used to discriminate among viral genotypes. The extracellular region of K1 has homology with the light chain of lambda immunoglobulin, and its cytoplasmic region contains an immunoreceptor tyrosine-based activation motif (ITAM). KSHV K1 ITAM activates several intracellular signaling pathways, notably PI3K/AKT. Consequently, K1 expression inhibits proapoptotic proteins and increases the lifespan of KSHV-infected cells. Another remarkable effect of K1 activity is the production of inflammatory cytokines and proangiogenic factors, such as vascular endothelial growth factor. KSHV K1 immortalizes primary human endothelial cells and transforms rodent fibroblasts in vitro; moreover, K1 induces tumors in vivo in transgenic mice expressing this viral protein. This review aims to consolidate and discuss the current knowledge on this intriguing KSHV protein, focusing on activities of K1 that can contribute to the pathogenesis of KSHV-associated human cancers.
PLOS Pathogens
Kaposi's sarcoma-associated herpesvirus (KSHV) is the infectious cause of the highly vascularized tumor Kaposi's sarcoma (KS), which is characterized by proliferating spindle cells of endothelial origin, extensive neo-angiogenesis and inflammatory infiltrates. The KSHV K15 protein contributes to the angiogenic and invasive properties of KSHV-infected endothelial cells. Here, we asked whether K15 could also play a role in KSHV lytic replication. Deletion of the K15 gene from the viral genome or its depletion by siRNA lead to reduced virus reactivation, as evidenced by the decreased expression levels of KSHV lytic proteins RTA, K-bZIP, ORF 45 and K8.1 as well as reduced release of infectious virus. Similar results were found for a K1 deletion virus. Deleting either K15 or K1 from the viral genome also compromised the ability of KSHV to activate PLCγ1, Erk1/2 and Akt1. In infected primary lymphatic endothelial (LEC-rKSHV) cells, which have previously been shown to spontaneously display a viral lytic transcription pattern, transfection of siRNA against K15, but not K1, abolished viral lytic replication as well as KSHV-induced spindle cell formation. Using a newly generated monoclonal antibody to K15, we found an abundant K15 protein expression in KS tumor biopsies obtained from HIV positive patients, emphasizing the physiological relevance of our findings. Finally, we used a dominant negative inhibitor of the K15-PLCγ1 interaction to establish proof of principle that pharmacological intervention with K15dependent pathways may represent a novel approach to block KSHV reactivation and thereby its pathogenesis.
Journal of virology, 2018
Kaposi's sarcoma (KS)-associated herpesvirus (KSHV)/human herpesvirus 8 (HHV-8) causes the angiogenic tumor KS and two B-cell malignancies. The KSHV nonstructural membrane protein encoded by the open reading frame (ORF) K15 recruits and activates several cellular proteins, including phospholipase Cγ1 (PLCγ1), components of the NF-κB pathway, as well as members of the Src family of nonreceptor tyrosine kinases, and thereby plays an important role in the activation of angiogenic and inflammatory pathways that contribute to the pathogenesis of KS as well as KSHV productive (lytic) replication. In order to identify novel cellular components involved in the biology of pK15, we immunoprecipitated pK15 from KSHV-infected endothelial cells and identified associated proteins by label-free quantitative mass spectrometry. Cellular proteins interacting with pK15 point to previously unappreciated cellular processes, such as the endocytic pathway, that could be involved in the function of pK1...
Kaposi's sarcoma-associated herpesvirus (KSHV) is the primary aetiological agent of at least three malignancies associated with HIV infection and immunosuppression: Kaposi's sarcoma, primary effusion lymphoma and multicentric Castleman's disease. KSHV encodes proteins that deregulate key checkpoints in the signalling pathways governing cell proliferation, which may ultimately contribute to the virus' oncogenic potential. To alter cellular signalling associated with proliferation, these viral proteins function like growth factor ligands/receptors, signal transduction proteins, transcription factors and cell cycle regulators. This review focuses on the mechanisms by which some KSHV-encoded proteins activate signalling pathways and cell proliferation and their role in the pathogenesis of KSHV-driven mechanisms.
Role of Protein Kinase C in Reactivation of Kaposi's Sarcoma-Associated Herpesvirus
Journal of Virology, 2004
TPA (12-O-tetradecanoylphorbol-13-acetate), a well-known activator of protein kinase C (PKC), can experimentally induce reactivation of Kaposi's sarcoma-associated herpesvirus (KSHV) in certain latently infected cells. We selectively blocked the activity of PKC isoforms by using GF 109203X or rottlerin and demonstrated that this inhibition largely decreased lytic KSHV reactivation by TPA. Translocation of the PKC␦ isoform was evident shortly after TPA stimulation. Overexpression of the dominant-negative PKC␦ mutant supported an essential role for the PKC␦ isoform in virus reactivation, yet overexpression of PKC␦ alone was not sufficient to induce lytic reactivation of KSHV, suggesting that additional signaling molecules participate in this pathway.
Role of Protein Kinase C δ in Reactivation of Kaposi's Sarcoma-Associated Herpesvirus
Journal of Virology, 2004
TPA (12- O -tetradecanoylphorbol-13-acetate), a well-known activator of protein kinase C (PKC), can experimentally induce reactivation of Kaposi's sarcoma-associated herpesvirus (KSHV) in certain latently infected cells. We selectively blocked the activity of PKC isoforms by using GF 109203X or rottlerin and demonstrated that this inhibition largely decreased lytic KSHV reactivation by TPA. Translocation of the PKCδ isoform was evident shortly after TPA stimulation. Overexpression of the dominant-negative PKCδ mutant supported an essential role for the PKCδ isoform in virus reactivation, yet overexpression of PKCδ alone was not sufficient to induce lytic reactivation of KSHV, suggesting that additional signaling molecules participate in this pathway.