Christopher Parsons, MD
Project 7: KSHV Regulation of Innate Cytokine Responses and T Cell Activation (Start date 8/1/08)
Oral cavity involvement by Kaposi's sarcoma (KS), the most common HIV-associated cancer, occurs in as many as half of all cases and is associated with higher mortality. KS is caused by the Kaposi's sarcoma-associated herpesvirus (KSHV), and reduced KSHV-specific T cell responses pose an increased risk for KS. The goal of our research is to identify KSHV-associated mechanisms responsible for reducing T cell recognition and killing of KSHV-infected cells in order to develop interventional strategies for restoring KSHV-specific immunity and controlling KS pathogenesis.
Kaposi's sarcoma (KS) is the most common cancer, and one of the most common oral lesions, encountered in the setting of HIV infection. The incidence of oral KS has not declined appreciably with highly active antiretroviral therapy for HIV infection, and involvement of the oral cavity portends a poor outcome for KS patients. KS is caused by a γ-herpesvirus known as the Kaposi's sarcoma-associated herpesvirus (KSHV), and activation of KSHV-specific T cell responses is important for the control of KS. Antigenpresenting cells (APC), most notably dendritic cells and macrophages, provide initial signals for T cell activation during viral infection, in part through their production of proinflammatory cytokines. KSHV infects both dendritic cells and macrophages, but whether KSHV regulates APC production of cytokines to reduce anti-viral T cell activation is unknown. We have found that KSHV infection of human myeloid dendritic cells (DC) reduces DC proinflammatory cytokine release while increasing release of the predominant regulatory cytokine, interleukin-10 (IL-10). We also found that KSHVinfected DC block release of proinflammatory (Th1) cytokines by autologous T cells. Finally, using a murine APC culture model amenable to gene transfer studies, we have shown that KSHV-encoded microRNAs (miRNA) induce macrophage production of IL-10 and reduce macrophage activation of T cell proliferation. Based on these results, we hypothesize that KSHV infection reduces APC activation of antiviral T cell responses through the coordinated regulation of cytokine expression during infection of APC. To address this hypothesis, we propose the following aims to be completed during the COBRE award period: Specific Aim 1: To identify KSHV-encoded mechanisms regulating human DC cytokine expression and autologous T cell activation; Specific Aim 2: to determine the mechanism(s) for KSHV microRNA regulation of APC cytokine responses and T cell proliferation; and Specific Aim 3: To determine whether KSHV-induced APC expression of IL-10 impairs T cell activation and virus-specific T cell targeting of KSHV-infected cells. The proposed studies will strengthen future R-01 applications by pinpointing specific KSHV-associated mechanisms for APC cytokine regulation and characterizing functional studies for determining how KSHV regulates T cell recognition of KSHV-infected cells relevant to KS. Future applications will propose to use these tools to evaluate strategies for overcoming KSHV regulation of APC cytokine responses and restoring KSHV-specific T cell immunity, thereby providing new directions for the treatment and prevention of oral KS.