Kaposi's Sarcoma-Associated Herpesvirus Subversion of the Anti-Inflammatory Response in Human Skin Cells Reveals Correlates of Latency and Disease Pathogenesis.

KSHV is the etiologic agent for Kaposi's sarcoma (KS), a neoplasm that manifests most aggressively as multifocal lesions on parts of human skin with a propensity for inflammatory reactivity. However, mechanisms that control evolution of KS from a benign hyperplasia to the histologically complex cutaneous lesion remain unknown. In this study, we found that KSHV induces proteomic and morphological changes in melanocytes and melanoma-derived cell lines, accompanied by deregulation of the endogenous anti-inflammatory responses anchored by the MC1-R/ α -MSH signaling axis. We also identified two skin-derived cell lines that displayed differences in ability to support long-term KSHV infection and mapped this dichotomy to differences in (a) NF- κ B activation status, (b) processing and expression of KSHV latency-associated nuclear antigen isoforms putatively associated with the viral lytic cycle, and (c) susceptibility to virus-induced changes in expression of key anti-inflammatory response genes that antagonize NF- κ B, including MC1-R, POMC, TRP-1, and xCT. Viral subversion of molecules that control the balance between latency and lytic replication represents a novel correlate of KSHV pathogenesis and tropism in skin and underscores the potential benefit of harnessing the endogenous anti-inflammatory processes as a therapeutic option for attenuating cutaneous KS and other proinflammatory outcomes of KSHV infection in high-risk individuals.

Interactions between Hsp90 and oncogenic viruses: implications for viral cancer therapeutics.

Oncogenic viruses are the etiologic agents for a significant proportion of human cancers, but effective therapies and preventative strategies are lacking for the majority of virus-associated cancers. Targeting of virus-induced signal transduction or virus-host protein interactions may offer novel therapeutic strategies for viral cancers. Heat shock protein 90 (Hsp90) is a well-characterized, multifunctional molecular chaperone involved in regulation of signal transduction, transcriptional activation, oncogenic protein stabilization, and neovascularization-pathogenic elements relevant to viral cancer pathogenesis. This review will summarize mechanistic concepts involving regulation of viral oncogenesis by both intracellular and extracellular Hsp90, as well as current therapeutic implications of these data.

Extracellular Hsp90 serves as a co-factor for NF-κB activation and cellular pathogenesis induced by an oncogenic herpesvirus.

The Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiologic agent of Kaposi's sarcoma (KS)-the most common tumor associated with HIV infection and an important cause of morbidity and mortality in this patient population. The majority of patients with KS exhibit little or no clinical response to existing therapies. The nuclear factor-kappaB (NF-κB) family of transcription factors plays a critical role in facilitating cancer pathogenesis associated with oncogenic viruses, and a better understanding of how cellular factors regulate NF-κB activation in the context of KSHV infection may facilitate development of new therapies for KS. Existing data implicate heat shock protein-90 associated with the cell surface (csHsp90) as a co-factor in cancer cell migration and invasion, and we recently reported that csHsp90 serves as a co-factor for mitogen-activated protein kinase (MAPK) activation during de novo KSHV infection. However, whether csHsp90 regulates NF-κB activation, or cellular pathogenesis associated with KS, has not been established. We have found that csHsp90 serves as an important co-factor for canonical NF-κB activation by KSHV during de novo infection of primary human cells relevant to KS. Furthermore, our correlative functional studies reveal that csHsp90 inhibition suppresses KSHV-induced, NF-κB-dependent secretion of the pro-migratory factors interleukin-8 and vascular endothelial growth factor as well as invasiveness for primary cells following de novo infection. These data implicate csHsp90 in KSHV-mediated activation of NF-κB and associated pathogenesis, and support the potential utility of targeting csHsp90 as a therapeutic approach for KS.

Successful treatment of a locally invasive cryptococcoma mimicking primary thyroid cancer with fluconazole.

A patient with no immune compromise and no constitutional or pulmonary symptoms presented with an enlarging neck mass abutting the thyroid gland and extending through the pleura into the lung. Microbiologic evaluation revealed a diagnosis of cryptococcoma, and the patient responded well to oral fluconazole therapy. To the authors' knowledge, this is the first case describing a locally invasive cryptococcoma mimicking a primary thyroid malignancy in the absence of systemic symptoms.

Pivotal advance: Kaposi's sarcoma-associated herpesvirus (KSHV)-encoded microRNA specifically induce IL-6 and IL-10 secretion by macrophages and monocytes.

Macrophages are an important source of inflammatory cytokines generated during the innate immune response,but in the microenvironment of certain tumors,macrophages promote tumor progression through their preferential secretion of cytokines that support tumor cell growth and suppress antitumoral immune responses. KSHV is the causative agent of KS and lymphomas preferentially arising in immuno compromised patients, and specific cytokines, including IL-6 and IL-10, have been implicated in KSHV-associated cancer pathogenesis. However, the contribution of KSHV-infected macrophages to the cytokine milieu within KSHV-related tumors is unclear. We found that individual KSHV-encoded miRNA induce IL-6 and IL-10 secretion independently and additively by murine macrophages and human myelomonocytic cells. Bioinformatics analysis identified KSHV miRNA binding sites formiR-K12-3 and miR-K12-7 within the 3'UTR of the basic region/leucine zipper motif transcription factor C/EBPbeta, a known regulator of IL-6 and IL-10 transcriptional activation.Subsequent immunoblot analyses revealed that miR-K12-3 and miR-K12-7 preferentially reduce expression of C/EBPbeta p20 (LIP), an isoform of C/EBPbeta known to function as a negative transcription regulator. In addition,RNA interference specifically targeting LIP induced basal secretion of IL-6 and IL-10 by macrophages.Taken together, these data support a role for KSHV miRNA in the programming of macrophage cytokine responses in favor of KSHV-related tumor progression.