KSHV REGULATION OF INNATE CYTOKINE RESPONSES AND T CELL ACTIVATION

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Background The Kaposi's sarcoma-associated herpesvirus (KSHV) is the causative agent of Kaposi's sarcoma (KS). Existing data suggest that T cell responses are critical for the control of KS progression, and antigen-presenting cells (APC) provide important activation signals for generating these responses. Whether KSHV infection of APC impairs effective T cell responses thereby promoting KS progression is unknown. Our model systems show that KSHV impairs T cell activation through multiple KSHV-encoded mechanisms involving infection of APC, including alteration of cytokine production by APC. Therefore, we propose to use these systems, including primary cells from human patients, to identify mechanisms for KSHV regulation of APC function and T cell activation. Rationale KSHV is the most common cause of cancer, and specifically oral cancers, arising in HIV-infected patients. Oral KS is resistant to existing therapies and portends an ominous prognosis. A better understanding of how KSHV regulates T cell activation through the infection of APC may provide new opportunites for developing immune-based or anti-inflammatory strategies for the treatment or prevention of oral KS. Study design and outcome measures Using human and murine APC as targets of KSHV infection and gene transfer in cell culture, we will first identify specific KSHV-encoded genes involved in APC secretion of immunoinhibitory molecules, including IL-6, IL-10, and reactive nitrogen species (RNS). Next, using antigen-independent and antigen-dependent T cell activation assays, we will test interventional strategies for reducing IL-6, IL-10, and RNS secretion by KSHV-infected APC and restoring T cell activation in this environment.