Sarcoma-associated Herpesvirus Pathogenesis Research Articles

Role of Histamine and Related Signaling in Kaposi's Sarcoma-Associated Herpesvirus Pathogenesis and Oncogenesis.

Although Kaposi's sarcoma-associated herpesvirus (KSHV) has been reported to cause several human cancers including Kaposi's sarcoma (KS) and primary effusion lymphoma (PEL), the mechanisms of KSHV-induced tumorigenesis, especially virus-host interaction network, are still not completely understood, which therefore hinders the development of effective therapies. Histamine, together with its receptors, plays an important role in various allergic diseases by regulating different inflammation and immune responses. Our previous data showed that antagonists targeting histamine receptors effectively repressed KSHV lytic replication. In the current study, we determined that histamine treatment increased cell proliferation and anchorage-independent growth abilities of KSHV-infected cells. Furthermore, histamine treatment affected the expression of some inflammatory factors from KSHV-infected cells. For clinical relevance, several histamine receptors were highly expressed in AIDS-KS tissues when compared to normal skin tissues. We determined that histamine treatment promoted KSHV-infected lymphoma progression in immunocompromised mice models. Therefore, besides viral replication, our data indicate that the histamine and related signaling are also involved in other functions of KSHV pathogenesis and oncogenesis.

Mechanistic insights into the activation of the IKK kinase complex by the Kaposi’s sarcoma herpes virus oncoprotein vFLIP

Constitutive activation of the canonical NF-κB signaling pathway is a major factor in Kaposi’s sarcoma-associated herpes virus pathogenesis where it is essential for the survival of primary effusion lymphoma. Central to this process is persistent upregulation of the inhibitor of κB kinase (IKK) complex by the virally encoded oncoprotein vFLIP. Although the physical interaction between vFLIP and the IKK kinase regulatory component essential for persistent activation, IKKγ, has been well characterized, it remains unclear how the kinase subunits are rendered active mechanistically. Using a combination of cell-based assays, biophysical techniques, and structural biology, we demonstrate here that vFLIP alone is sufficient to activate the IKK kinase complex. Furthermore, we identify weakly stabilized, high molecular weight vFLIP–IKKγ assemblies that are key to the activation process. Taken together, our results are the first to reveal that vFLIP-induced NF-κB activation pivots on the formation of structurally specific vFLIP–IKKγ multimers which have an important role in rendering the kinase subunits active through a process of autophosphorylation. This mechanism of NF-κB activation is in contrast to those utilized by endogenous cytokines and cellular FLIP homologues.

Cellular and viral oncogenes: the key to unlocking unknowns of Kaposi's sarcoma-associated herpesvirus pathogenesis.

Oncogenic viruses carry an extensive arsenal of oncogenes for hijacking cellular pathways. Notably, variations in oncogenes among tumor-producing viruses give rise to different mechanisms for cellular transformation. Specifically, Kaposi's sarcoma-associated herpesvirus (KSHV) is an oncogenic virus able to infect and transform a variety of cell types. The oncogenicity of KSHV disseminates from the virus' ability to induce and encode a wide variety of both cellular and viral oncogenes. Such an array of cellular and viral oncogenes enables KSHV to induce the malignant phenotype of a KSHV-associated cancer. Evolutionarily, KSHV has acquired many oncogenic homologues capable of inducing cell proliferation, cell differentiation, cell survival, and immune evasion. Integration between inducing and encoding oncogenes plays a vital role in KSHV pathogenicity. KSHV is alleged to harbor the highest number of potential oncogenes by which a virus promotes cellular transformation and malignancy. Many KSHV inducing/encoding oncogenes are mainly expressed during the latent phase of KSHV infection, a period required for virus establishment of malignant cellular transformation. Elucidation of the exact mechanism(s) by which oncogenes promote KSHV pathogenicity would not only give rise to potential novel therapeutic targets/drugs but would also add to our understanding of cancer biology. The scope of this review is to examine the roles of the most important cellular and viral oncogenes involved in KSHV pathogenicity.

Altering the Anti-inflammatory Lipoxin Microenvironment: a New Insight into Kaposi's Sarcoma-Associated Herpesvirus Pathogenesis.

KSHV infection has been shown to upregulate several host proinflammatory factors, which aid in its survival and pathogenesis. The influence of KSHV infection on anti-inflammatory molecules is not well studied. Since current treatment methods for KS and PEL are fraught with unwanted side effects and low efficiency, the search for new therapeutics is therefore imperative. The use of nature's own molecule lipoxin as a drug is promising. This study opens up new domains in KSHV research focusing on how the virus modulates lipoxin secretion and warrants further investigation of the therapeutic potential of lipoxin using in vitro cell models for KS and PEL.

Role of host microRNAs in Kaposi's sarcoma-associated herpesvirus pathogenesis.

MicroRNAs (miRNAs) are small non-coding RNA species that can bind to both untranslated and coding regions of target mRNAs, causing their degradation or post-transcriptional modification. Currently, over 2500 miRNAs have been identified in the human genome. Burgeoning evidence suggests that dysregulation of human miRNAs can play a role in the pathogenesis of a variety of diseases, including cancer. In contrast, only a small subset of human miRNAs has been functionally validated in the pathogenesis of oncogenic viruses, in particular, Kaposi’s sarcoma-associated herpesvirus (KSHV). KSHV is the etiologic agent of several human cancers, such as primary effusion lymphoma (PEL) and Kaposi’s sarcoma (KS), which are mostly seen in acquired immune deficiency syndrome (AIDS) patients or other immuno-suppressed subpopulation. This review summarizes recent literature outlining mechanisms for KSHV/viral proteins regulation of cellular miRNAs contributing to viral pathogenesis, as well as recent findings about the unique signature of miRNAs induced by KSHV infection or KSHV-related malignancies.

The contribution of systems biology and reverse genetics to the understanding of Kaposi’s sarcoma-associated herpesvirus pathogenesis in endothelial cells

Kaposi's sarcoma-associated herpesvirus (KSHV)/human herpesvirus-8 is the causative agent of the endothelial cell-derived tumour Kaposi's sarcoma. Herpesviruses possess large complex genomes which provide many options to regulate cellular physiology during the viral life cycle and in the course of tumourigenicity. Novel techniques of systems biology and reverse genetics are increasingly applied to dissect the complex interaction of KSHV with endothelial cells. This review will outline novel results and pitfalls of these technologies in the elucidation of KSHV pathogenicity.

Contribution of viral and cellular cytokines to Kaposi’s sarcoma-associated herpesvirus pathogenesis

Kaposi's sarcoma (KS)-associated herpesvirus is associated with the proliferative/malignant disorders KS, primary effusion lymphoma (PEL), and multicentric Castleman's disease (MCD) in patients with AIDS. In spite of recent advances in the treatment of KS, PEL and MCD represent therapeutic challenges. Recent advances in dissecting the pathogenesis of these diseases have indicated that the viral cytokine IL-6 and the cellular cytokines/growth factors IL-10, IL-6, stromal cell-derived factor 1, and vascular endothelial growth factor are important contributors to the growth, survival, and spread of PEL and MCD and are therefore potential targets for drug development.