The envelopment of human cytomegalovirus (HCMV) is complex and requires the incorporation of a large number of viral glycoproteins in the viral envelope surrounding the tegumented particle. Envelope glycoproteins conserved between different herpesviruses, including gB, gH, gL, gM, and gN have been shown to be essential for the production of infectious virions. In contrast to several well studied 1-herpesviruses, both glycoprotein components of the gM/gN complex of HCMV are essential for assembly of infectious virus and interestingly, gM represents the most abundant envelope glycoprotein. Recent findings have indicated that mutations in the cytoplasmic tail of gM that alter its intracellular trafficking to the cytoplasmic assembly compartment (AC) resulted in a replication impaired phenotype of the mutant virus. In addition, mutations in a single amino acid in the cytoplasmic tail of gN resulted in a severely replication impaired virus. In both cases, the phenotype of the mutant viruses was associated with a significant decrease in the assembly of enveloped particles in the infected cell suggesting that either altered trafficking of the gM/gN complex to the AC or altered function of the complex once in the AC resulted in the loss of envelopment of the tegumented particle during this final step in virus assembly. In this application we will explore the role of the gM/gN complex in HCMV envelope assembly by (1) elucidating intrinsic signals in the gM/gN complex required for intracellular trafficking to the AC, (2) defining cellular components of vesicular trafficking required for the localization of gM/gN to the AC, and (3) characterizing viral protein interactions with gM/gN that contribute to the envelopment of the tegumented particle. Our overall goal is to investigate the hypothesis that the gM/gN complex plays a central role in the biogenesis of the HCMV envelope. Findings from these studies could offer new avenues for the development of antiviral agents for the treatment of medically important infections associated with HCMV. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
2R01AI050189-06
Application #
7388353
Study Section
Special Emphasis Panel (ZRG1-IDM-M (04))
Program Officer
Beisel, Christopher E
Project Start
2001-05-01
Project End
2012-11-30
Budget Start
2007-12-15
Budget End
2008-11-30
Support Year
6
Fiscal Year
2008
Total Cost
$326,250
Indirect Cost
Name
University of Alabama Birmingham
Department
Pediatrics
Type
Schools of Medicine
DUNS #
063690705
City
Birmingham
State
AL
Country
United States
Zip Code
35294
Smith, Phillip D; Shimamura, Masako; Musgrove, Lois C et al. (2014) Cytomegalovirus enhances macrophage TLR expression and MyD88-mediated signal transduction to potentiate inducible inflammatory responses. J Immunol 193:5604-12
Hook, Lauren; Hancock, Meaghan; Landais, Igor et al. (2014) Cytomegalovirus microRNAs. Curr Opin Virol 7:40-6
Hook, Lauren M; Grey, Finn; Grabski, Robert et al. (2014) Cytomegalovirus miRNAs target secretory pathway genes to facilitate formation of the virion assembly compartment and reduce cytokine secretion. Cell Host Microbe 15:363-73
Kropff, Barbara; Burkhardt, Christiane; Schott, Juliane et al. (2012) Glycoprotein N of human cytomegalovirus protects the virus from neutralizing antibodies. PLoS Pathog 8:e1002999
Indran, Sabarish V; Britt, William J (2011) A role for the small GTPase Rab6 in assembly of human cytomegalovirus. J Virol 85:5213-9
Krzyzaniak, Magdalena A; Mach, Michael; Britt, William J (2009) HCMV-encoded glycoprotein M (UL100) interacts with Rab11 effector protein FIP4. Traffic 10:1439-57
Krzyzaniak, Magdalena; Mach, Michael; Britt, William J (2007) The cytoplasmic tail of glycoprotein M (gpUL100) expresses trafficking signals required for human cytomegalovirus assembly and replication. J Virol 81:10316-28
Mach, Michael; Osinski, Karolina; Kropff, Barbara et al. (2007) The carboxy-terminal domain of glycoprotein N of human cytomegalovirus is required for virion morphogenesis. J Virol 81:5212-24
Seo, Jun-Young; Britt, William J (2007) Cytoplasmic envelopment of human cytomegalovirus requires the postlocalization function of tegument protein pp28 within the assembly compartment. J Virol 81:6536-47
Mach, Michael; Kropff, Barbara; Kryzaniak, Magdalena et al. (2005) Complex formation by glycoproteins M and N of human cytomegalovirus: structural and functional aspects. J Virol 79:2160-70

Showing the most recent 10 out of 11 publications