Lymphatic Reprogramming by Kaposi Sarcoma Herpes Virus Promotes the Oncogenic Activity of the Virus-Encoded G-protein Coupled Receptor.

Aug 2012

Aguilar B, Choi I, Choi D, Chung HK, Lee S, Yoo J, Lee YS, Maeng YS, Lee HN, Park E, Kim KE, Kim NY, Baik JM, Jung JU, Koh CJ, Hong YK.

Source

Surgery and Biochemistry and Molecular Biology, University of Southern California.

Abstract

Kaposi sarcoma (KS), the most common cancer in HIV-positive individuals, is caused by endothelial transformation mediated by the KS herpes virus (KSHV)-encoded G-protein coupled receptor (vGPCR). Infection of blood vascular endothelial cells (BECs) by KSHV reactivates an otherwise silenced embryonic program of lymphatic differentiation. Thus, KS tumors express numerous lymphatic endothelial cell (LEC)-signature genes. A key unanswered question is how lymphatic reprogramming by the virus promotes tumorigenesis leading to KS formation. In this study, we present evidence that this process creates an environment needed to license the oncogenic activity of vGPCR. We found that the G-protein regulator RGS4 is an inhibitor of vGPCR that is expressed in BECs, but not in LECs. RGS4 was downregulated by the master regulator of LEC differentiation PROX1, which is upregulated by KSHV and directs KSHV-induced lymphatic reprogramming. Moreover, we found that KSHV upregulates the nuclear receptor LRH1, which physically interacts with PROX1 and synergizes with it to mediate repression of RGS4 expression. Mechanistic investigations revealed that RGS4 reduced vGPCR-enhanced cell proliferation, migration, VEGF expression and Akt activation and to suppress tumor formation induced by vGPCR. Our findings resolve long-standing questions about the pathological impact of KSHV-induced reprogramming of host cell identity, and they offer biological and mechanistic insights supporting the hypothesis that a lymphatic microenvironment is more favorable for KS tumorigenesis.

Cancer Research

or

PubMed

Lymphangioma-Like Kaposi Sarcoma.

August 2012

We report on a recent lesion in a 75-year-old woman who

had been diagnosed with classic Kaposi sarcoma (KS) 8 years earlier, at which time she presented with plaques on the right thigh and right forearm (Fig. 1A) and no metastasis was detected. Findings from the initial biopsy of the forearm lesions were compatible with nodular KS.

During the 8-year follow-up, the patient developed 7 recurrent skin tumors on the forearm and legs. Each tumor had the same clinical appearance in the form of plaques (Fig. 1B), and no systemic involvement was detected at any time. The lesions were treated with liposomal doxorubicin. Biopsies were taken from the forearm at each recurrence and histology continued to show findings consistent with nodular KS mixed with lymphangioma-like areas. 

These areas were comprised of irregularly-dilated ectatic vascular spaces in the reticular dermis that were lined by moderately atypical endothelial cells. These spaces were greater in number and size than normal lymphatic vessels (Fig. 2). Immunohistochemistry showed strong CD34 positivity. Endothelial cells lining the lymphangioma-like areas of the tumor were

also positive on staining with human herpes virus type 8

(HHV-8) antibody (Fig. 2C) and the lymphatic endothelial

marker podoplanin (D2-40) (Fig. 2D). Based on these findings, the patient was diagnosed with lymphangioma-like KS.

Seven months after completing the most recent cycle of

chemotherapy with doxorubicin, the patient presented with a serious recurrence consisting of localized, multinodular, ulcerated lesions on both legs but more severe on the right thigh; severe lymphedema was also noted (Fig. 1C). She was given radiotherapy, second-line chemotherapy with paclitaxel (taxol), and thorough local treatments. At the time of writing the lesions remained ulcerated and had not changed in size. The patient attended scheduled follow-up visits and did not show signs of systemic spread of disease.

Full Text Article with Diagnostic Images

Elsevier

Highly active antiretroviral therapy-associated flare of oropharyngeal kaposi sarcoma.

August 2012

Tesuven K. Naidu, MBChB(Natal), FCORL(SA), MMed(ORL)(UKZN); Pratistad

Kaposi sarcoma (KS) is a human herpesvirus 8–associated multifocal, angioproliferative tumor that occurs in cutaneous, mucocutaneous, and visceral locations. The presentation of KS in the oral cavity is of prognostic importance as it may be the initial manifestation of generalized KS or even the sentinel clue to human immunodeficiency virus (HIV) infection and AIDS. Oral cavity KS is also associated with higher death rates when compared with cutaneous KS alone. Furthermore, oral cavity KS is a prognostic marker of an individual's response to highly active antiretroviral therapy (HAART). Despite the role of HAART in effecting stabilization, regression, and a significant reduction in the incidence and morbidity of KS, adverse clinical events that are temporally associated with the onset of HAART are being increasingly recognized. Immune reconstitution inflammatory syndrome (IRIS) is characterized by an exuberant immune-mediated inflammatory response to latent antigenic triggers after the initiation or resumption of HAART. It results in the appearance or recurrence of previously treated or undetected opportunistic infections, the flare of viral infections, and the development of neoplasms. To date, however, airway obstruction as a manifestation of a KS flare after HAART is undocumented in the global literature (to our knowledge).

Full Text Article

Otolaryngology - Head & Neck Surgery

Clinical Manifestations of Kaposi Sarcoma Herpesvirus Lytic Activation: Multicentric CastlemanDisease (KSHV-MCD) KSHV Inflammatory Cytokine Syndrome

Clinical Manifestations of Kaposi Sarcoma Herpesvirus Lytic Activation: Multicentric CastlemanDisease (KSHV-MCD) and the KSHV Inflammatory Cytokine Syndrome.

2012

Polizzotto MN, Uldrick TS, Hu D, Yarchoan R.

Source

HIV/AIDS Malignancy Branch, Center for Cancer Research, National Cancer Institute Bethesda, MD, USA.

Abstract

Soon after the discovery of Kaposi sarcoma (KS)-associated herpesvirus (KSHV), it was appreciated that this virus was associated with most cases of multicentric Castleman disease (MCD) arising in patients infected with human immunodeficiency virus. It has subsequently been recognized that KSHV-MCD is a distinct entity from other forms of MCD. Like MCD that is unrelated to KSHV, the clinical presentation of KSHV-MCD is dominated by systemic inflammatory symptoms including fevers, cachexia, and laboratory abnormalities including cytopenias, hypoalbuminemia, hyponatremia, and elevated C-reactive protein. Pathologically KSHV-MCD is characterized by polyclonal, IgM-lambda restricted plasmacytoid cells in the intrafollicular areas of affected lymph nodes. A portion of these cells are infected with KSHV and a sizable subset of these cells express KSHV lytic genes including a viral homolog of interleukin-6 (vIL-6). Patients with KSHV-MCD generally have elevated KSHV viral loads in their peripheral blood. Production of vIL-6 and induction of human (h) IL-6 both contribute to symptoms, perhaps in combination with overproduction of IL-10 and other cytokines. Until recently, the prognosis of patients with KSHV-MCD was poor. Recent therapeutic advances targeting KSHV-infected B cells with the anti-CD20 monoclonal antibody rituximab and utilizing KSHV enzymes to target KSHV-infected cells have substantially improved patient outcomes. Recently another KSHV-associated condition, the KSHV inflammatory cytokine syndrome (KICS) has been described. Its clinical manifestations resemble those of KSHV-MCD but lymphadenopathy is not prominent and the pathologic nodal changes of KSHV-MCD are absent. Patients with KICS exhibit elevated KSHV viral loads and elevation of vIL-6, homolog of human interleukin-6 and IL-10 comparable to those seen in KSHV-MCD; the cellular origin of these is a matter of investigation. KICS may contribute to the inflammatory symptoms seen in some patients with severe KS or primary effusion lymphoma. Additional research is needed to better define the clinical spectrum of KICS and its relationship to KSHV-MCD. In additional, research is needed to better understand the pathogenesis and epidemiology of both KICS and KSHV-MCD, as well as the optimal therapy for both of these disorders.

Frontiers

The rare case of laryngeal lesion in idiopathic (classic) Kaposi's sarcoma.

Nov-Dec 2011

[Article in Russian]

[No authors listed]

Abstract

The case report of laryngeal Kaposi's sarcoma (KS) in 59 year old HIV-negative man infected by herpes virus 8 (HHV-8) is in the paper. The primary onset of KS was on the legs. Lesion of laryngeal mucosa was developed sequentially, resulted in laryngeal stenosis and led to application of tracheostome. The skin and laryngeal mucosa lesions had homotypic histological structure and corresponded to early manifestation of KS preceded tumor node appearance.

PubMed

The Kaposi's Sarcoma-Associated Herpesvirus ORF57 Protein and Its Multiple Roles in mRNA Biogenesis.

Jackson BR, Noerenberg M, Whitehouse A.

Source

Institute of Molecular and Cellular Biology and Astbury Centre for Structural Molecular Biology, University of Leeds Leeds, UK.

Abstract

Post-transcriptional events which regulate mRNA biogenesis are fundamental to the control of gene expression. A nascent mRNA is therefore steered through multimeric RNA-protein complexes that mediate its capping, splicing, polyadenylation, nuclear export, and ultimately its translation. Kaposi's sarcoma-associated herpesvirus (KSHV) mRNA transport and accumulation protein, or ORF57, is a functionally conserved protein found in all herpesviruses which plays a pivotal role in enhancing viral gene expression at a post-transcriptional level. As such, ORF57 has been implicated in multiple steps of RNA biogenesis, including augmenting viral splicing, protecting viral RNAs from degradation to enhancing viral mRNA nuclear export and translation. In this review, we highlight the multiple roles of KSHV ORF57 in regulating the post-transcriptional events which are fundamental to the control of virus gene expression.

Frontier in Virology

Selective killing of Kaposi's sarcoma-associated herpesvirus lytically infected cells with a recombinant immunotoxin targeting the viral gpK8.1A envel

Selective killing of Kaposi's sarcoma-associated herpesvirus lytically infected cells with a recombinant immunotoxin targeting the viral gpK8.1A envelope glycoprotein.

Mar 2012

Chatterjee D, Chandran B, Berger EA.

Source

Laboratory of Viral Diseases; National Institute of Allergy and Infectious Diseases; National Institutes of Health; Bethesda, MD USA.

Abstract

Kaposi sarcoma-associated herpesvirus (KSHV, human herpesvirus 8) is etiologically associated with three neoplastic syndromes: Kaposi sarcoma and the uncommon HIV-associated B-cell lymphoproliferative disorders primary effusion lymphoma and multicentric Castleman disease. The incidence of the latter B-cell pathology has been increasing in spite of antiretroviral therapy; its association with lytic virus replication has prompted interest in therapeutic strategies aimed at this phase of the virus life cycle. We designed and expressed a recombinant immunotoxin (2014-PE38) targeting the gpK8.1A viral glycoprotein expressed on the surface of the virion and infected cells. We show that this immunotoxin selectively kills KSHV-infected cells in dose-dependent fashion, resulting in major reductions of infectious virus release. The immunotoxin and ganciclovir, an inhibitor of viral DNA replication, showed marked reciprocal potentiation of antiviral activities. These results suggest that the immunotoxin, alone or in combination, may represent a new approach to treat diseases associated with KSHV lytic replication.

PubMed