Identification of HHV8 in early Kaposi's sarcoma: implications for Kaposi's sarcoma pathogenesis

Abstract

Aims-Kaposi's sarcoma is a vascular tumour of uncertain pathogenesis possibly caused by an infectious agent, identified in high risk groups. Accumulating solution phase polymerase chain reaction (PCR) and seroepidemiological data suggest that a previously undescribed herpes DNA virus (human herpesvirus 8 (HHV8)) is the causative agent. Using a unique cohort of early Kaposi's sarcoma, the precise cell type infected with HHV8 in such lesions was identified to elucidate further the role of HHV8 in the pathobiology of Kaposi's sarcoma. Methods-Sixteen cases of early Kaposi's sarcoma (derived from skin and lymph node) were assessed for the presence of HHV8 using both standard solution phase PCR and TaqMan PCR to the KS330 Bam region of HHV8. In situ amplification was also performed on a selected group in an attempt to identify the candidate infected cells. Results-Using both conventional solution phase and TaqMan PCR, 87% of cases were positive. In addition, HHV8 amplicons were localised in situ to endothelial and spindle cell proliferations in early Kaposi's sarcoma. The HHV8 viral load varied from lesion to lesion. Conclusions-The presence of HHV8 in early lesions supports a role for HHV8 in the pathogenesis of Kaposi's sarcoma. Coupled with recent seroepidemiological studies, these results suggest that HHV8 is the aetiological agent of Kaposi's sarcoma. Its precise interaction with other factors known to be involved in the development of Kaposi's sarcoma, including cytokines and anti-apoptosis genes, requires elucidation.

Induction of CCL20 production by Kaposi sarcoma–associated herpesvirus: role of viral FLICE inhibitory protein K13-induced NF-κB activation

“…4 KSHV infection has been detected in the endothelial cells of early KS lesions and is thought to contribute to their phenotypic transformation into spindle cells. [6][7][8] This hypothesis is supported by in vitro studies showing that microvascular and macrovascular endothelial cells latently infected with KSHV acquire a spindle cell morphology. [9][10][11] More importantly, these KSHV-infected endothelial cells were shown to up-regulate the expression of genes encoding several proinflammatory and angiogenic cytokines and chemokines that have been previously implicated in the pathogenesis of KS lesions, such as interleukin-6 (IL-6), IL-8, IL-1, GRO-1, monocyte chemotactic protein-1 (MCP-1), NAP-2, Rantes, and CXCL16.…”

Induction of spindle cell morphology in human vascular endothelial cells by human herpesvirus 8-encoded viral FLICE inhibitory protein K13

“…Histologically, KS is characterized by the presence of distinctive proliferating spindle-like cells, activated endothelial cells, fibroblast, smooth muscle cells and infiltrating inflammatory cells (Masood et al, 1993;Ensoli and Gallo, 1995). The spindle cells in KS are believed to arise from HHV8-infected endothelial cells and, consistent with this notion, HHV8-infected endothelial cells have been detected in the very early lesions of KS before the appearance of extensive spindle cell formation (Beckstead et al, 1985;Corbeil et al, 1991;Kennedy et al, 1998). HHV8 has also been shown to infect both microand macro-vascular endothelial cells in vitro, which is associated with the expression of latency-associated genes and acquisition of spindle cell morphology (Flore et al, 1998;Moses et al, 1999;Ciufo et al, 2001).…”

Effect of highly active antiretroviral therapy on survival among HIV‐infected men with Kaposi sarcoma or non‐Hodgkin lymphoma

“…Human herpes virus 8 (HHV-8) has been linked to KS in HIV-infected individuals. [31][32][33] HAART may also lead to an increase in host T-cell immunity to HHV-8, also known as Kaposi sarcoma related herpes virus (KSHV), which could result in enhanced control of the virus and its oncogenic properties. 34 Support for this hypothesis is that there is a CD8 ϩ cytotoxic T-cell response to KSHV that is lower among those infected with HIV-1.…”