Cytokine-Targeted Therapeutics for KSHV-Associated Disease

Abstract

Kaposi’s sarcoma-associated herpesvirus (KSHV) also known as human herpesvirus 8 (HHV-8), is linked to several human malignancies including Kaposi sarcoma (KS), primary effusion lymphoma (PEL), multicentric Castleman’s disease (MCD) and recently KSHV inflammatory cytokine syndrome (KICS). As with other diseases that have a significant inflammatory component, current therapy for KSHV-associated disease is associated with significant off-target effects. However, recent advances in our understanding of the pathogenesis of KSHV have produced new insight into the use of cytokines as potential therapeutic targets. Better understanding of the role of cytokines during KSHV infection and tumorigenesis may lead to new preventive or therapeutic strategies to limit KSHV spread and improve clinical outcomes. The cytokines that appear to be promising candidates as KSHV antiviral therapies include interleukins 6, 10, and 12 as well as interferons and tumor necrosis factor-family cytokines. This review explores our current understanding of the roles that cytokines play in promoting KSHV infection and tumorigenesis, and summarizes the current use of cytokines as therapeutic targets in KSHV-associated diseases.

Kaposi's sarcoma-associated herpesvirus at 27

“…1 ). New potential therapies based on altering cytokine signaling are being explored for these diseases, as recently reviewed in Alomari and Totonchy [ 16 ]. VEGF-A targeting antibodies have also shown some promise in in vivo models, especially antibody fragments that may have better penetration in tumors [ 17 ].…”

IL-21 signaling promotes the establishment of KSHV infection in human tonsil lymphocytes by increasing early targeting of plasma cells

“…This gap in our understanding dramatically affects our ability to find efficient strategies to decrease the transmission or influence host-level susceptibility to KSHV infection. One of the main factors that has been linked to KSHV-associated lymphoproliferations is cytokine dysregulation [10]. However, their contribution to the early stages of KSHV infection and whether the cytokine milieu in the oral cavity contributes to hostlevel susceptibility to KSHV infection is unclear.…”

“…infection. Approximately 5(10) 6 lymphocytes per condition were harvested into a 96-well round bottom plate at day 0 (baseline) or at 3 days post-infection at 1500 rpm for 5 minutes. Cells were resuspended in 100μl PBS containing zombie violet fixable viability stain (BL Cat# 423113) and incubated on ice for 15 minutes.…”

Molecular Virology of KSHV in the Lymphocyte Compartment—Insights From Patient Samples and De Novo Infection Models

“…In this review, we explore our current understanding of KSHV biology in B cells concentrating on studies which use de novo infection of human B cells, analysis of patient samples from KSHV lymphoproliferative disease, and relevant lymphoma cell lines. We have intentionally omitted discussion of KSHV manipulation of cytokine expression and signaling from this work as it is complex, and we have recently reviewed the topic comprehensively elsewhere (Alomari and Totonchy, 2020). Moreover, we have omitted discussion of humanized mouse models for KSHV infection as they have also been reviewed very recently (Münz, 2020).…”