The effect of human cytomegalovirus on innate immune responses : Immune activation and evasion

Abstract: Human cytomegalovirus (HCMV) is a wide-spread virus infecting about 60-90 % of the healthy human population. After a primary infection, the virus establishes life-long latency in its host. Although HCMV seldom give any symptoms in immunocompetent individuals, it may cause severe disease in persons with a deficient immune system, such as AIDS patients, transplant recipients and fetuses. The infection is controlled mainly by virus-specific T cells and NK cells, but to co-exist with its host, HCMV has developed several mechanisms to influence the host immune response. Reactivation of HCMV is mediated by inflammation with activated immune cells and secretion of strong pro-inflammatory cytokines, and HCMV has been linked to several inflammatory diseases such as inflammatory bowel disease (IBD), systemic lupus erythematosus (SLE) and cardiovascular disease. In addition, HCMV has lately been detected in different tumors and is suggested to play a role in cancers such as prostate cancer, colon cancer and glioblastome multiforme (GBM). HCMV is believed to act as an onco-modulatoty virus, contributing to tumor cell growth and survival. In this thesis I wanted to further understand the mechanisms behind HCMV immune modulation and how these effects may contribute to the development of cancer. I describe that; (I) HCMV is able to partially stimulate PDC maturation and to induce a strong IFN-α secretion. HCMV activated PDCs stimulate B cell activation and proliferation but conversely depress T cell proliferation. This may enhance virally mediated immunosuppression and help HCMV escape immune recognition. (II) HCMV influence the PDC mediated activation of NK cells. HCMV infected PDCs reduce NK cell cytotoxicity, and instead facilitate the development of non-cytotoxic cytokine producing NK cells. NK cells are vital in the anti-viral immune response, and this may contribute to viral immune evasion as well as cytokine induced viral reactivation and replication. (III) Virally induced soluble molecules from in vitro infected cells are able to downregulate NK cell killing of target cells. Interestingly, HCMV positive glioblastoma cells demonstrated the same inhibition of NK cell cytotoxicity. This observation describes a mechanism by which HCMV hampers a vital NK cell function, which may led to reduced anti-viral and anti-tumor immune responses. (IV) Peripheral neutrophil activation correlates to tumor progression in patients with GBM and levels of several pro-and anti-inflammatry cytokines are altered compared to healthy individuals. HCMV is known to activate neutrophils and enhance secretion of cytokines important in inflammation, and HCMV may thereby contribute to the immune dysfunction often seen in these patients. In conclusion, the ability of HCMV to alter the host immune system is vital for virus latency and reactivation. Here I describe novel mechanisms that may contribute to HCMV immune evasion and to the development of cancer.