UL84 and IE2

Since the initial elucidation of the trans-acting factors required for oriLyt-depend-ent DNA replication, the most complex interaction is that of UL84 and IE2. This interaction has become the focus of much of the research with respect to the characterization of a dual assignment for UL84 as a replication and regulatory factor for gene expression. UL84 was first described as the product of a 1,761-bp ORF encoding a 65-kDa protein (He et al. 1992). The mRNA transcript encoding UL84 can be...

MCMV as a Model System for CMV Interference with MHCI Expression

MCMV does not encode homologs of the HCMV VIPRs, but encodes its own VIPRs m04, m06, and m152 (see Fig. 2 recently reviewed in Reddehase et al. 2004 Pinto and Hill 2005). The gp34 protein encoded by m04 does not reduce MHC-I surface levels but forms a tight association in the ER and accompanies MHC-I to the cell surface (Kleijnen et al. 1997 Kavanagh et al. 2001) where it is able to inhibit cytotoxic T cell lysis by an unknown mechanism (Pinto and Hill 2005). The m06-encoded gp48 associates...

Modulation of Intracellular Signaling by CMV vGPCRs

Various CMV vGPCRs have been investigated for their putative role in the activation of signal transduction pathways. Attempts have been made to identify ligands that bind to these vGPCRs, as well as to identify the downstream intracellular signaling pathways. The most common signaling factors studied were 2. Increase of inositol phosphate (InsP) by phospholipase C (PLC) 3. Increase of cAMP by adenylyl cyclase (AC) and subsequent CREB-mediated gene transcription 4. NFk-B-mediated gene...

HCMV Vaccine What Is the Ideal Target Population Perinatal and Early Childhood HCMV Infection

One strategy for vaccine-mediated prevention of HCMV would be to target acquisition of primary infection in infancy and early childhood. Perinatal acquisition of HCMV may occur by one of three different routes exposure to HCMV in the birth canal during labor and delivery, transmission of HCMV by blood transfusion, or transmission by breast-feeding. In a prospective study in premature infants receiving breast milk containing HCMV, transmission was observed in 33 of 87 exposed infants, and...

The Establishment of HCMV Latency

One of the critical steps for establishing latency is likely to include the silencing of the viral MIEP such control of viral major IE gene expression is a credible mechanism by which all subsequent viral lytic gene expression will be regulated (Fig. 2). Thus, what regulates the MIEP The MIEP appears to be regulated by multiple cellular transcription factors and higher-order chromatin structure during both lytic (Meier and Stinski 1996 Nevels et al. 2004 Ioudinkova et al. 2006 Reeves et al....

References

Adamo JE, Schroer J, Shenk T (2004) Human cytomegalovirus TRS1 protein is required for efficient assembly of DNA-containing capsids. J Virol 78 10221-10229 Arnon TI, Achdout H, Levi O, Markel G, Saleh N, Katz G, Gazit R, Gonen-Gross T, Hanna J, Nahari E, Porgador A, Honigman A, Plachter B, Mevorach D, Wolf DG, Mandelboim O (2005) Inhibition of the NKp30 activating receptor by pp65 of human cytomegalovirus. Nat Immunol 6 515-523 AuCoin DP, Smith GB, Meiering CD, Mocarski ES (2006)...

Cell Tropism of Other Cytomegaloviruses

The tendency toward systemic dissemination resulting in infection of various organs is not unique to human CMV but has also been reported for animal CMVs. Apparently, a broad organ tropism is a hallmark of cytomegaloviruses, which is based on a similarly broad cell tropism. Under conditions of severe immunosuppression, murine CMV-infected cells were found in lung, liver, spleen, kidneys, adrenals, gastrointestinal tract, brain, salivary gland, and fibroblasts, epithelial cells, neuronal cells,...

Activation of Interferon Responses

The type I interferon response, consisting of interferon P and multiple forms of interferon a, is produced in response to viral infection and restricts replication at the earliest stages (reviewed in Stark et al. 1998). Interferon activation is accompanied by the induction of interferon-stimulated genes (ISGs), a subset of cellular genes that carry out many of the antiviral functions of interferon (reviewed in Theofilopoulos et al. 2005). The type I interferon response to virus infection can be...

Latent Viral Genome Load Defining the Risk of Recurrence

Epidemiologically, CMV infections can occur at any age, but frequently, CMVs are acquired by their respective hosts perinatally or during early childhood. Regardless of the time of virus acquisition, latency is eventually established. A CMV-specific immune status, i.e., the presence of CMV-specific memory CD4 and CD8 T cells as well as of antibodies, testifies for a resolved acute infection in the past, which may have been years or decades ago. Importantly, clinicians use CMV-antibody status to...

Contributors

Department of Cancer Biology and the Abramson Family Cancer Research Institute, University of Pennsylvania, 314 Biomedical Research Building, 421 Curie Blvd. Philadelphia, PA 19104-6142, USA, alwine mail.med.upenn.edu Department of Medical Microbiology, Cardiovascular Research Institute Maastricht (CARIM), University Hospital Maastricht, PO Box 5800, 6202 AZ, Maastricht, The Netherlands Departments of Pediatrics, Microbiology, and Neurobiology, University of Alabama School of Medicine,...

Tegumentation and Envelopment

The composition of the HCMV tegument and envelope, and the relationship of their acquisition to virus egress from the nucleus and cell, have recently been reviewed (Eickmann et al. 2006). The cartoon shown in Fig. 7 serves to summarize some of the steps involved. A general consensus of data supports an envelopment de-envelopment mechanism for nuclear egress of herpesviruses, followed by final envelopment through cytoplasmic membranes (Severi et al. 1988 Gibson 1993 Enquist et al. 1998...

IE1 Counteracts the Host Cells Silencing Mechanisms

The major immediate early transcript is differentially spliced to produce a number of proteins. The two major and best-investigated proteins, IE1 and IE2, have in common exons 2 and 3 but differ in the larger exon 4 (IE1) and exon 5 (HCMV IE2 and its MCMV homolog, IE3). These proteins act synergistically to activate early viral protein expression, but antagonistically to autoregulate the MIEP (Cherrington and Mocarski 1989 Pizzorno and Hayward 1990 Stenberg et al. 1990 Cherrington et al. 1991...

Delivery of the Genome to the Nucleus

Once in the cytoplasm, HCMV genome-containing capsids and some tegument proteins must make their way to the nucleus. Although a seemingly simple task, this journey is a difficult one due to the size of the viral particle and the density of the cytoplasm. HCMV overcomes these obstacles using strategies that are also employed by other viruses (Dohner et al. 2005 Greber and Way 2006), namely hijacking the intracellular transport machinery. Cells contain an organized network of microtubules (MTs)...

Nuclear RNA Export

Nuclear Export Signal

The identification of CRM1 as a protein export factor was initiated by the finding that nuclear export of unspliced HIV-1 RNA depends on binding of the viral protein Rev to CRM1 via a leucine-rich NES (Neville et al. 1997) (Fig. 2). Further studies demonstrated that although CRM1 mediates nuclear export of HIV-1 mRNA, it is not responsible for the export of bulk cellular mRNA (Cullen 2003). Instead, CRM1 acts as a RNA-export receptor for the export of rRNA, Usn RNAs and several specific mRNAs...

Healthcare Costs Associated with Congenital HCMV Infection A Compelling Argument for Vaccine Development

The economic burden on the healthcare system in caring for neurodevelopmental disability in early childhood caused by congenital HCMV infection is substantial. Congenital HCMV infection is the most common infectious cause of brain damage in children, and HCMV causes more hearing loss in children than did Haemophilus influenzae meningitis in the pre-Hib vaccine era (Pass 1996). The economic costs to society associated with congenital HCMV infection present a compelling argument for vaccine...

Formation of the Nucleocapsid

Capsid assembly is coordinated by the assembly protein precursor (pAP, pUL80.5, 38 kDa) and the genetically related protease precursor (pPR, pUL80a, 74 kDa), both of which are ultimately eliminated from the maturing particle. These proteins are encoded by 3'-coterminal in-frame genes, with the consequence that the car-boxyl approximately 60 of pPR is identical to pAP (Fig. 2). Two smaller proteins encoded by the same set of genes (pUL80.4 and pUL80.3) have unknown functions that are dispensable...

Mutagenesis of the Cytomegalovirus Genome

Homology Arm Homologous Recombination

CMV Genetics in Forward (Classical) Reverse CMV Genetics in Bacterial Artificial Cloning and Maintenance of CMV Genomes as Allelic Exchange by Shuttle Plasmid Allelic Exchange Using Linear Fragment Transposon Mutagenesis for Reverse and Forward Mutants, Revertants and the Mutation-Phenotype Genetic Analysis of Essential Comprehensive Mutational Analysis of Essential CMV Identification and Analysis of Dominant Negative Concluding Abstract Bacterial artificial chromosomes (BACs) are DNA molecules...

Downregulation of the NKG2D Ligand MICA by UL142

The HCMV MHC-class-I-like molecule UL142, which has a homolog in ChCMV but not in RhCMV Davison et al. 2003 Wills et al. 2005 , inhibits NK cell lysis by downregulating MIC-A Wills et al. 2005 Chalupny et al. 2006 . Interestingly, only the full-length alleles of MIC-A are targeted by the viral protein, whereas the MICA 008 allele, which has a truncated transmembrane region, is not affected by UL142 Zou et al. 2005 Chalupny et al. 2006 . MIC-A is the ligand of the activating NK cell receptor...