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

Abstract

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.

Keywords: AIDS-related malignancy; Kaposi's sarcoma; Kaposi's sarcoma-associated herpesvirus; candidate gene association; genetic susceptibility; human herpesvirus 8.

FIGURE 1

Summary figure depicting the reviewed genetic factors associated with KSHV infection and KS development. KSHV infects endothelial cells and following lytic infection, establishes latency from which reactivation events can occur; KS develops from latently infected endothelial cells (grey box). Gene names in green text indicate an association with decreased risk; red text an association with increased risk. Details of the single nucleotide polymorphism or haplotype involved in these associations are found in Table 1 or in text. *Various HLA haplotypes are either protective or increase risk of KS development as detailed in Table 1. Figure created with BioRender.com