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