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Review
. 2017 Oct 19;372(1732):20160275.
doi: 10.1098/rstb.2016.0275.

Kaposi sarcoma herpesvirus pathogenesis

Giuseppe Mariggiò  1   2 , Sandra Koch  1   2 , Thomas F Schulz  3   2
Affiliations
Review

Kaposi sarcoma herpesvirus pathogenesis

Giuseppe Mariggiò et al. Philos Trans R Soc Lond B Biol Sci. .

Abstract

Kaposi sarcoma herpesvirus (KSHV), taxonomical name human gammaherpesvirus 8, is a phylogenetically old human virus that co-evolved with human populations, but is now only common (seroprevalence greater than 10%) in sub-Saharan Africa, around the Mediterranean Sea, parts of South America and in a few ethnic communities. KSHV causes three human malignancies, Kaposi sarcoma, primary effusion lymphoma, and many cases of the plasmablastic form of multicentric Castleman's disease (MCD) as well as occasional cases of plasmablastic lymphoma arising from MCD; it has also been linked to rare cases of bone marrow failure and hepatitis. As it has colonized humans physiologically for many thousand years, cofactors are needed to allow it to unfold its pathogenic potential. In most cases, these include immune defects of genetic, iatrogenic or infectious origin, and inflammation appears to play an important role in disease development. Our much improved understanding of its life cycle and its role in pathogenesis should now allow us to develop new therapeutic strategies directed against key viral proteins or intracellular pathways that are crucial for virus replication or persistence. Likewise, its limited (for a herpesvirus) distribution and transmission should offer an opportunity for the development and use of a vaccine to prevent transmission.This article is part of the themed issue 'Human oncogenic viruses'.

Keywords: DNA damage response; KSHV; KSHV-related diseases; aberrant angiogenesis; innate immune evasion; viral infection.

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Conflict of interest statement

We have no competing interests.

Figures

Figure 1.
Figure 1.
Histology of a KS tumour infiltrating a lymph node (250× magnification). (a) HE staining showing the typical histological features such as elongated spindle cells, abnormal vessels with thinned epithelium and extravasated erythrocytes. (b) Immunohistochemistry staining for CD34 to indicate the endothelial origin of the spindle cells. (c) Immunohistochemistry staining for LANA, showing tumour cells with a latent KSHV infection.
Figure 2.
Figure 2.
Schematic of KSHV-promoted activation of STAT3, PI3 K/Akt, MAPK and PLCγ/NFAT pathways contributing to proliferation and migration of KSHV-infected endothelial cells. The transmembrane viral proteins vGPCR, K1 and K15 as well as the viral IL6 homologue vIL6, kaposin B and ORF36 activate PLCγ, Akt, MAPK and STAT3 pathways. Some of these could be promising targets to inhibit the development of Kaposi's sarcoma.
Figure 3.
Figure 3.
KSHV-induced activation of NF-κB and Notch signalling pathways involved in atypical spindle cell differentiation and survival. The viral proteins vFLIP and vGPCR mediate the atypical differentiation of endothelial cells by triggering the Notch signalling pathway; in addition, the vFLIP–IKKγ interaction activates the pro-survival NF-κB pathway.
Figure 4.
Figure 4.
The role of the DDR machinery in KSHV lytic (a) and latent (b) replication. DDR signalling induced by the sensing of viral DNA leads to a cell cycle block and ultimately favours KSHV lytic replication (a). Subsequently, the neutralization of p53 and p73 activity by viral proteins, e.g. LANA, removes the cell cycle block and allows KSHV latent replication (b). TR, terminal repeats.
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