Kaposi sarcoma-associated herpesvirus (KSHV) is etiologically linked to Kaposi sarcoma (KS), a tumor genetically akin to lymphatic endothelial cells (LECs).
IntroductionKaposi sarcoma (KS) lies at the interface of infection and malignancy. [1][2][3] It is a neoplasm common in para-Mediterranean populations, endemic in parts of sub-Saharan Africa, and frequently seen in patients with AIDS. 3 KS is a tumor of microvascular endothelium and gene-expression microarray (GEM) studies suggest that it belongs to the lymphatic endothelial lineage. 4 KS-associated herpesvirus (KSHV) is linked to the etiopathogenesis of KS 5,6 and certain lymphoproliferations, including primary effusion lymphoma (PEL) 7 and a plasmablastic variant of multicentric Castleman disease (MCD). 8 The risk of developing KS, PEL, and MCD is significantly higher during acquired or iatrogenic immunosuppression. 3,9 Moreover, posttransplantation KS can resolve when immunosuppressive therapy is reduced, 9 and the introduction of effective antiretroviral therapy for HIV infection has led to a decline in KS incidence. 3 These observations indicate that disruption of host-pathogen equilibrium promotes the precipitation of these neoplasms.Herpesviruses have evolved elaborate mechanisms to modulate host immune responses. 10 EBV is the prototype of a cancerinducing human herpesvirus. [11][12][13] EBV modulates cellular antiviral responses in various ways, including down-regulation of major histocompatibility complex (MHC) proteins 14 and blocking proteasomal degradation and antigen synthesis. 15,16 However, EBV also enhances antiviral immune responses by way of its latent membrane protein 1 (LMP1), which up-regulates MHC-I. 17,18 This leads to cytotoxic T-cell (CTL)-mediated elimination of EBV latency III cells, promoting the transition to latency I-infected B cells. As with KSHV, immunosuppression disturbs the host-virus equilibrium leading to an increased incidence of EBV-associated tumors. 12 Several KSHV proteins regulate host innate or adaptive immune responses. 19 Among these there are 5 viral proteins that block the innate antiviral interferon (IFN) response, including orf45, 20 viral , 21 viral interferon regulatory factors (vIRFs) 1 and 2, [22][23][24][25][26][27] and the transactivator of the lytic cycle, RTA. 28 Furthermore 2 viral modulators of immune response (vMIRs) act as E3 ubiquitin ligases and down-regulate MHC-I. 29,30 vMIR2 also down-regulates ICAM-1 and CD86 by enhancing endocytosis, lysosomal targeting, and proteasome-mediated degradation 31,32 and increases endocytosis of CD1d, leading to the escape of infected cells from NKT cells. 33 The majority of these viral mechanisms are used during the lytic viral cycle, when most of these proteins are expressed and a vigorous host response occurs to curtail viral dissemination.Immune regulation during KSHV latency remains insufficiently characterized. However, the KSHV lytic and latent gene profiles are not mutually exclusive. Some lytic proteins, such as RTA and vMIR2, are expressed during the...
