Mechanisms of Cell Signaling by the Human Cytomegalovirus US27 Gene Product

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DESCRIPTION (provided by applicant): Human cytomegalovirus (HCMV) is a widespread pathogen that has devised numerous mechanisms for evading the host immune system. One such strategy involves molecular mimicry, the expression of proteins that functionally resemble host proteins. The US27 gene product is a predicted G-protein coupled receptor with homology to human chemokine receptors. The specific goals of this research application are to investigate the impact of this receptor on cell growth and survival, identify ligands that bind US27, and characterize downstream signaling events with the aim of understanding how this virally encoded receptor exploits cell signaling for the advantage of the virus. We hypothesize that US27 functions to alter communication between immune cells during virus infection by interfering with normal chemokine signaling. This is based on the observations the US27 gene product contains many features common to cellular chemokine receptors and the finding that US27 is expressed in HCMV infected cells and present in the envelope of infectious virions. While the US27 gene is non-essential for lytic replication in vitro, this may indicate a role in other aspects of HCMV infection in vivo, such as immune modulation, pathogenesis, or dissemination. The proposed study will provide a thorough characterization of this viral GPCR. We will a) examine the ability of US27 to induce cell cycle arrest or trigger apoptosis, b) identify US27 ligands using receptor chimeras to screen a library of human chemokines, and c) elucidate cell signaling pathways employed by US27. The results of these studies will provide a better understanding of the molecular action of US27, leading to future studies that may clarify the role of this protein in virus infection and provide a potential target for novel anti-viral therapeutics. PUBLIC HEALTH RELEVANCE: Opportunistic pathogens like human cytomegalovirus (HCMV) can cause serious disease in individuals with compromised immune systems, such as transplant recipients, AIDS patients, or newborn infants. HCMV infects 70-90% of the general population, causing pneumonitis, retinitis, and congenital defects, and it has also been implicated in the acceleration of cardiovascular disease. By studying the molecular interactions between this pathogen and its human host, novel antiviral drug targets may be identified, potentially leading to decreased human mortality and disease.