Evidence for altered host genetic factors in KSHV infection and KSHV‐related disease development

Abstract

Summary Kaposi's sarcoma‐associated herpesvirus (KSHV) is the etiological agent of Kaposi's sarcoma (KS), the most common AIDS‐related malignancy. It also causes other rare, but certainly underreported, KSHV‐associated pathologies, namely primary effusion lymphoma, multicentric Castleman disease and KSHV inflammatory cytokine syndrome. Epidemiology and pathogenicity studies point to the potential for host genetic predisposition to KSHV infection and/or the subsequent development of KSHV‐associated pathologies partly explaining the peculiar geographic and population‐specific incidence of KSHV and associated pathologies and discrepancies in KSHV exposure and infection and KSHV infection and disease development. This review consolidates the current knowledge of host genetic factors involved in the KSHV‐driven pathogenesis. Studies reviewed here indicate a plausible connection between KSHV susceptibility and host genetic factors that affect either viral access to host cells via entry mechanisms or host innate immunity to viral infection. Subsequent to infection, KSHV‐associated pathogenesis, reviewed here primarily in the context of KS, is likely influenced by an orchestrated concert of innate immune system interactions, downstream inflammatory pathways and oncogenic mechanisms. The association studies reviewed here point to interesting candidate genes that may prove important in achieving a more nuanced understanding of the pathogenesis and therapeutic targeting of KSHV and associated diseases. Recent studies on host genetic factors suggest numerous candidate genes strongly associated with KSHV infection or subsequent disease development, particularly innate immune system mediators. Taken together, these contribute toward our understanding of the geographic prevalence and population susceptibility to KSHV and KSHV‐associated diseases.

Epidemiology of Kaposi’s Sarcoma

“…Chronic exposure of the skin to iron or alumino-silicate might induce localized immune dysfunction which might explain the topography of the lesions at the extremities of the body and its higher incidence in rural regions [77]. Additionally, some association with HLA [80] and other genetic factors with HHV8 infection susceptibility have been also postulated as predisposition factors for KS [81].…”

Kaposi's sarcoma-associated herpesvirus at 27

“…Thus far, targeted studies or studies of early-onset KS cases have predominantly been used to identify genetic determinants of KSHV susceptibility or KS and MCD development. These studies have identified several interesting candidate polymorphisms, reviewed more extensively Blumenthal et al [ 73 ]. In particular, polymorphism in specific HLA subtypes, in genes involved in regulation of immune responses like NFκB, TRIM31, LY6G6C, and in subtypes of the natural killer cell receptor KIR have been connected to susceptibility to KSHV infection or development of KS or MCD [ 73 ].…”

“…These studies have identified several interesting candidate polymorphisms, reviewed more extensively Blumenthal et al [ 73 ]. In particular, polymorphism in specific HLA subtypes, in genes involved in regulation of immune responses like NFκB, TRIM31, LY6G6C, and in subtypes of the natural killer cell receptor KIR have been connected to susceptibility to KSHV infection or development of KS or MCD [ 73 ]. A genetic association with both susceptibility to infection and disease development was also found for Ephrin A, a potential entry receptor for KSHV [ 73 , 74 ].…”

“…In particular, polymorphism in specific HLA subtypes, in genes involved in regulation of immune responses like NFκB, TRIM31, LY6G6C, and in subtypes of the natural killer cell receptor KIR have been connected to susceptibility to KSHV infection or development of KS or MCD [ 73 ]. A genetic association with both susceptibility to infection and disease development was also found for Ephrin A, a potential entry receptor for KSHV [ 73 , 74 ]. However, most of these associations were found in a single study and their wider importance as genetic determinants of KSHV infection and disease remains unknown.…”

Endoplasmic Reticulum-Shaping Atlastin Proteins Facilitate KSHV Replication

“…An intensive research effort led to important progress regarding KSHV epidemiology, diagnosis, and potential therapeutic and prophylactic strategies ( Gong et al., 2019 ; Holmes et al., 2020 ). The mechanisms involved in KSHV replication, host responses, and pathogenesis have also been extensively studied ( Blumenthal et al., 2020 ; Yu et al., 2020 ; Zhao et al., 2020 ). However, the role of cellular proteins, in particular those present in the endoplasmic reticulum (ER), where viral production occurs, remains only partly characterized.…”