Elsevier

Current Opinion in Virology

Volume 14, October 2015, Pages 116-128
Current Opinion in Virology

Kaposi Sarcoma-associated Herpesvirus: mechanisms of oncogenesis

https://doi.org/10.1016/j.coviro.2015.08.016Get rights and content

Highlights

  • KSHV/HHV8 causes three human diseases: Kaposi Sarcoma, Primary Effusion Lymphoma and the plasma cell variant of Multicentric Castleman Disease.

  • These occur more commonly in patients with immunodeficiency, including AIDS.

  • KS is heterogeneous, and may represent a spectrum between an angioproliferative disease and a true malignancy.

  • KSHV encodes viral genes that can cause inflammation, angiogenesis and neoplastic transformation.

Kaposi Sarcoma-associated Herpesvirus (KSHV, HHV8) causes three human malignancies, Kaposi Sarcoma (KS), an endothelial tumor, as well as Primary Effusion Lymphoma (PEL) and the plasma cell variant of Multicentric Castleman's Disease (MCD), two B-cell lymphoproliferative diseases. All three cancers occur primarily in the context of immune deficiency and/or HIV infection, but their pathogenesis differs. KS most likely results from the combined effects of an endotheliotropic virus with angiogenic properties and inflammatory stimuli and thus represents an interesting example of a cancer that arises in an inflammatory context. Viral and cellular angiogenic and inflammatory factors also play an important role in the pathogenesis of MCD. In contrast, PEL represents an autonomously growing malignancy that is, however, still dependent on the continuous presence of KSHV and the action of several KSHV proteins.

Introduction

Motivated by strong epidemiological data suggesting the involvement of a sexually transmitted agent as the cause of AIDS-associated Kaposi Sarcoma (KS), Chang, Moore and colleagues identified, in 1994, the first fragments of Kaposi Sarcoma Herpesvirus (KSHV; taxonomic name Human Herpesvirus 8 (HHV8)) in KS tissue [1]. Several groups quickly established that KSHV DNA sequences can be identified in all KS tumors and many case–control and prospective cohort studies demonstrated a strong association between the detection of KSHV DNA by PCR, or of antibodies to KSHV, and concurrent KS, or the subsequent progression to KS [2, 3, 4]. Soon after its discovery KSHV was also found in, and etiologically linked to, two B-cell malignancies, Primary Effusion Lymphoma (PEL) [5] and Multicentric Castleman Disease (MCD) [6]. The accumulating strong epidemiological evidence linking KSHV infection to KS, PEL and MCD, together with accumulating evidence for oncogenic properties of KSHV, led to the classification of KSHV as a class I carcinogen by the International Agency for Research on Cancer (IARC) [7].

In the following sections we briefly review the mechanistic (laboratory) evidence supporting a causative role of KSHV in KS, PEL and MCD, and discuss some of the still controversial issues in this field.

Section snippets

Does Kaposi Sarcoma develop from KSHV-transformed cells?

Kaposi Sarcoma is an unusual tumor. Several of its features suggest that unlike other cancers, it may not result from a transformation event that results in autonomously growing tumor cells, but represents the combined effects of a virus with angiogenic properties and local or systemic inflammation. There are four epidemiological forms of KS: the classic form, first described by Moritz Kaposi in 1872, is characterized by relatively indolent skin tumors predominantly in elderly men of several

The role of KSHV in Primary Effusion Lymphoma

In contrast to KS, Primary Effusion Lymphoma (PEL) is always a monoclonal malignancy. Infection of the malignant B-cells with KSHV is one of the diagnostic criteria, but additional infection with EBV is present in the majority of cases (for a review, see [61]). PEL cells most likely represent post-germinal center B cells with a plasma cell phenotype, as shown by the presence of rearranged immunoglobulin genes, evidence of somatic hypermutation in Ig genes and the non-coding region of the BCL6

The role of KSHV in Multicentric Castleman's Disease

KSHV is associated with the plasma cell variant of Multicentric Castleman's Disease (MCD), which is characterized by the follicular proliferation of B cells and evidence of plasma cell differentiation, along with a strong angiogenic component. As in KS and PEL, the majority of KSHV-infected B-cells in MCD appear to be latently infected, but a significant proportion show evidence of a ‘relaxed latency’ or early lytic gene expression pattern by immunohistochemistry [53, 54]. In particular, vIL6,

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