Attenuation of The Host Innate Cytokine Response By The Human Cytomegalovirus Immediate-Early 2 Protein Ie86




Taylor, Roger Travis

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Human cytomegalovirus infects a majority of the human population and is a significant cause of life-long morbidity and mortality in neonates and patients with an impaired immune system. Human cytomegalovirus infection has a profound effect on host cell, and expression of new viral proteins interferes with the ability of the host response to effectively limit virus persistence and the initation of a latent infection. This aim of this dissertation was to identify how human cytomegalovirus attenuates the host innate immune response early during infection. Specifically, I have employed genetic and biochemical approaches to identify the HCMV immediate-early 2 protein, IE86, as an interferon beta antagonist. IE86 expression also blocks the expression of a number of proinflammatory chemokines, including RANTES, MIG and IL-8 during human cytomegalovirus infection. I have further demonstrated that IE86 mediates the attenuation of cytokine and chemokine expression by targeting the nuclear factor kappa B pathway early during infection. Using gel shift analysis I have demonstrated that IE86 blocks nuclear factor kappa B DNA binding to target promoters, including the interferon beta promoter. Since IE86 is one of the first viral proteins to be expressed during human cytomegalovirus infection, it can rapidly block cytokine and chemokine expression thereby suppressing the antiviral response and limiting the recruitment of effecter cells. The attenuation of the innate immune response by IE86 likely enhances virus replication and contributes to persistence within the host. This work addresses a number of unanswered questions about human cytomegalovirus's interactions with the host, and has identified a previously unrecognized mechanism employed by human cytomegalovirus to evade the host immune response. A better understanding of IE86's ability to attenuate cytokine expression may be key to designing novel antiviral therapy or development of an effective vaccine to prevent human cytomegalovirus infection and disease.

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