Multifaceted evasion of the interferon response by cytomegalovirus.

Abstract

Human cytomegalovirus (HCMV), which infects the majority of the population worldwide, causes few, if any, symptoms in otherwise healthy people but is responsible for considerable morbidity and mortality in immunocompromised patients and in congenitally infected newborns. The evolutionary success of HCMV depends in part on its ability to evade host defense systems. Here we review recent progress in elucidating the remarkable assortment of mechanisms employed by HCMV and the related beta-herpesviruses, murine cytomegaloviruses (MCMV) and rhesus cytomegaloviruses (RhCMV), for counteracting the host interferon (IFN) response. Very early after infection, cellular membrane sensors such as the lymphotoxin beta receptor initiate the production of antiviral cytokines including type I IFNs. However, virion factors, such as pp65 (ppUL83) and viral proteins made soon after infection including the immediate early gene 2 protein (pUL122), repress this response by interfering with steps in the activation of IFN regulatory factor 3 and NF-kappaB. CMVs then exert a multi-pronged attack on downstream IFN signaling. HCMV infection results in decreased accumulation and phosphorylation of the IFN signaling kinases Jak1 and Stat2, and the MCMV protein pM27 mediates Stat2 down-regulation, blocking both type I and type II IFN signaling. The HCMV immediate early gene 1 protein (pUL123) interacts with Stat2 and inhibits transcriptional activation of IFN-regulated genes. Infection also causes reduction in the abundance of p48/IRF9, a component of the ISGF3 transcription factor complex. Furthermore, CMVs have multiple genes involved in blocking the function of IFN-induced effectors. For example, viral double-stranded RNA-binding proteins are required to prevent the shutoff of protein synthesis by protein kinase R, further demonstrating the vital importance of evading the IFN response at multiple levels during infection.

• Authors: Emily E Marshall, Adam P Geballe
• Journal: Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research (J Interferon Cytokine Res) Vol. 29 Issue 9 Pg. 609-19 (Sep 2009) ISSN: 1557-7465 [Electronic] United States
• PMID: 19708810 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Review)

Chemical References

• Interferon Regulatory Factors
• NF-kappa B
• Phosphoproteins
• Viral Matrix Proteins
• cytomegalovirus matrix protein 65kDa
• Interferons
• eIF-2 Kinase

Topics

• Cytomegalovirus (pathogenicity, physiology)
• Cytomegalovirus Infections (complications, genetics, immunology, virology)
• Humans
• Immunity, Innate
• Immunocompromised Host
• Infant, Newborn
• Interferon Regulatory Factors (genetics, immunology, metabolism)
• Interferons (immunology)
• NF-kappa B (genetics, metabolism)
• Phosphoproteins (immunology, metabolism)
• Signal Transduction
• Viral Matrix Proteins (immunology, metabolism)
• Virulence
• eIF-2 Kinase (biosynthesis, genetics)