• Human cytomegalovirus

• Cytomegalovirus 7-transmembrane receptor homologues.

Human cytomegalovirus

Human cytomegalovirus (HCMV) is a highly prevalent betaherpesvirus that, in the absence of effective immune control, may cause serious disease. HCMV can transmit to the foetus across the placenta, which may result in abortion, congenital disease or longer term disability such as mental impairment, hearing or vision loss.  The risk of disease in the newborn is highest for mothers who contract HCMV infection for the first time during pregnancy.  Serious disease (which may be life-threatening) may also result if babies are infected shortly after birth.  CMV is the most common infectious cause of congenital abnormalities in Australia, with an estimated 200 or more babies affected each year (Rawlinson and Scott, 2003).  Other populations at risk from HCMV disease include transplant recipients and AIDS patients.  In addition to direct HCMV-associated diseases, such as pneumonitis, retinitis and cytomegalic inclusion disease of infants, HCMV infection has been found to increase the risk of chronic graft rejection and has been proposed as a predisposing factor for atherosclerosis.  There is no effective vaccine against HCMV.  Moreover, current antiviral chemotherapy suffers from problems associated with toxicity and rapid acquisition of drug resistance.  Further information concerning HCMV can be found at the following sites:

CDC fact sheets on HCMV;
CMV infection and children.

In common with other herpesviruses, HCMV establishes a lifelong infection, via establishment of a dormant state known as latency.  During latency the virus is effectively hidden from the host immune system.  The virus periodically reactivates from latency with the production of infectious virus which may be present in the blood and shed via bodily fluids, such as the saliva; this latency/reactivation cycle provides an effective long term survival strategy for the virus, enabling infection to be transmitted to new hosts.  HCMV and related viruses are notable for encoding a large number of genes which are involved in virus-host interactions, in particular the modulation of host immune responses.  It is likely that many of these functions have evolved to facilitate persistence of the virus in the face of pre-existing immunity.  HCMV primary infection and reactivation generally results in no overt disease, reflecting a balance between the immune control mechanisms of the host and the immunomodulatory functions of the virus.  However, in the immunodeficient (eg. AIDS patients or transplant recipients) or immunologically immature (e.g. newborn) host, such immunomodulatory functions may overwhelm the residual immunity and hence promote disease.

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Cytomegalovirus 7-transmembrane receptor homologues.
Nick Davis-Poynter, Helen Farrell

Cellular 7 transmembrane receptors (7TMR – also known as G protein-coupled receptors (GCR)) are a large superfamily of signalling molecules which respond to extracellular stimuli via triggering of G protein dependent intracellular signalling pathways.  Examples include rhodopsin (response to light), dopamine receptors (response to neurotransmitters) and chemokine receptors (response to immunomodulatory proteins).  They are grouped into several subfamilies and although they exhibit little sequence homology they share the same topology: an extracellular N-terminus, three extracellular loops, seven transmembrane-spanning helices (labelled I-VII below), three intracellular loops and an intracellular carboxyl terminus. A schematic view of 7TMR is depicted below:

Betaherpesviruses (such as HCMV) and gammaherpesviruses (such as Epstein-Barr virus (EBV)) are notable for encoding one or more genes that are homologous to cellular 7TMR.  Over the past few years, several of these viral 7TMRs have been characterized and found to share a number of features in common with their cellular counterparts, together with certain unusual properties.  Typically, the viral 7TMR show highest homology and functional similarity to cellular chemokine receptors, including in a number of cases demonstrated ability to bind cellular chemokines, with concomitant modulation of signalling activity.  Interestingly, several of the viral 7TMR have also been found to exhibit ligand independent signalling activity, suggesting that activation of signalling pathways in the absence of ligand may be important during the virus lifecycle.
HCMV encodes four viral 7TMR, designated US27, US28, UL33 and UL78.  Whereas US27 and US28 are characteristic of human and other primate CMVs, genes related to UL33 and UL78 have been found in all other betaherpesviruses characterized to date.  It is likely, therefore, that UL33 and UL78 were acquired by an ancient ancestor of the betaherpesviruses and have evolved to perform functions critical to the lifecycle of this virus family.
Studies of murine CMV (MCMV) and rat CMV (RCMV) have demonstrated the importance of UL33 and UL78 homologues to pathogenesis.  In both viruses, deletion of each of the viral 7TMR has been found to significantly reduce virus replication and/or dissemination within the host.  In this project we will focus on the MCMV homologue of UL33 (M33), to determine specific properties of M33 which are critical for its in vivo function and to evaluate the potential of M33 as a novel target for antiviral chemotherapy.  The specific hypotheses to be tested are:
(a)   M33 modifies the normal trafficking properties of infected cells in vivo;
(b)   The in vivo function of M33 requires constitutive signalling activity;
(c)   Inhibition of M33 signalling in vivo will disrupt the ability of MCMV to disseminate;
To test the above hypotheses, we will utilize MCMV recombinant viruses which have been engineered to express mutant forms of M33.  Mutations will include disruption of constitutive signaling or other specific properties of M33.  In addition, a modified M33 allowing targeted inhibition of M33 signalling activity by prototype ‘drugs’ will enable evaluation of the UL33 family of viral 7TMRs as targets for antiviral chemotherapy.

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