Affordable Access

Cytokine and Chemokine Responses in Human Herpesvirus 8 Infection of Monocyte Derived Dendritic Cells and B Lymphocytes

Authors

Abstract

Human herpesvirus-8 induces a wide range of inflammatory immune mediators known to contribute to its associated cancer, Kaposi’s Sarcoma (KS). Soluble immune mediators, such as cytokines, chemokines and growth factors produced during HHV-8 infection have been associated with tumor-cell proliferation, angiogenesis and vascular permeability. We sought to determine immune mediator production by two antigen presenting cells (APC) that are susceptible to HHV-8 infection, i.e., monocyte derived Dendritic cells (MDDC) and B lymphocytes. Dendritic cells abundantly express the HHV-8 receptor, type II C-type lectin, DC-specific ICAM-3 grabbing nonintegrin (DC-SIGN) resulting in viral entry, whereas only a small percentage of activated B cells express DC-SIGN in vitro. Despite this, HHV-8 infection of MDDC results in an abortive replicative cycle, whereas full-lytic cycle replication occurs in the B cells. I hypothesized that immune mediators produced by HHV-8 infected APC are unique between cell types and that HHV-8 infects a subset of B cells and initiates cytokine and chemokine production that contributes to HHV-8 replication, viral dissemination and initiation of KS and HHV-8 lymphomas. I used a cytometric bead array to determine cytokine and chemokine production in B cells and MDDC, as well as qRT-PCR, TCID50 assay and flow cytometry to determine HHV-8 replication in B cells. I identified significant differences in the quality and quantity of cytokine and chemokine profiles of HHV-8 infected APC. MDDC produced significant levels of MCP-1, MIP-1α, MIP-1β, RANTES, IP-10 and IL-10, while B cells produced significant levels of MIP-1α, MIP-1β, IL-6, TNF-α and IL-8. HHV-8 lytic replication in B cells resulted in polyfunctional immune mediator activity that may contribute to viral replication and proliferation of target cell populations in HHV-8 related cancers. The importance of this work was demonstrated by the detection of B cell-produced cytokines and chemokines in HHV-8/HIV co-infected individuals who developed KS. This is the first extensive, multiparameter, longitudinal study of HHV-8 infection of B cells and immune mediators in development of KS. This study provides novel targets for vaccine development and treatment options for KS, which could have great implications on Public Health.

There are no comments yet on this publication. Be the first to share your thoughts.