Human Cytomegalovirus & Disease

Human Cytomegalovirus (Human Herpesvirus 5) General: Enveloped Double Stranded DNA virus of the herpesviridae family. It is a Beta Herpesvirus.  Large genome (approx 235kbp) Cytomegalovirus is the most important pathogen in the immunocompromised host. It is therefore important as a potential infection of transplantation (organ or bone marrow) patients following surgery (who are given immunocompromising drugs to facilitate organ integration) as it can cause transplant rejection  Mainly affects adults but neonatal infection does occur due to congenital inheritance of the virus Can affect almost every cell in the body, thus resulting in: Encephalitis  Retinitis  Pneumonia  Hepatitis Gastroenteritis (affects oesophageal and large intestinal epithelial cells) Transmission: Bodily fluids: Blood, saliva, genital secretions, urine Transplanted organs  Mechanism of Action: Binds to cell via Glycoproteins gB and gH/gL gH/gL assembles with a third glycoprotein, gO, forming a trimer of glycoproteins linked together by disulphide bonds  Replicates inside the cell via a rolling circle replicative cycle (nick at ori Lyt section of genome, polymerase generates complementary strand which is then cleaved) CMV has a very fast replication time similar to that of HIV (doubling time ~ 1 day) They also encode their own polymerases (do not use host machinery) The genetic material of CMV is episomal (outwith the human chromosomes) during latency in monocytic cells - they are not integrated into the host genome. The stimuli for reactivation of the viruses is poorly understood. During primary infection, the epithelial cells of the alimentary tract are typically infected.  The virus breaks down the cytoskeleton which maintains the cell's structure This leads to enlarged cells containing viral inclusion bodies giving it the typical 'Owl's Eye' appearance seen on histology  CMV also infects monocytes during primary infection, thus establishing a latent infection, meaning  can persist in its natural host following primary infection meaning once you have CMV you have it for life  Latency: CMV exists in a latent state within primitive bone-marrow-resident CD34+ cells and CD33+ myeloid progenitor cells which go on to differentiate into Monocytes and dendritic cells in the blood.  The CMV exists extra-chromosomally as its own episome with its own encoded polymerases CMV directly increases the amount of cells which differentiate into memory cells thus perpetuating the latent reservoir of CMV infected cells  Immune Evasion of CMV: CMV proteins US2, US, US6 and US11 (Unique Short glycoproteins) stop MHC-1 molecules from reaching the cell surface, thus preventing their recognition by CD8+ T cells  Endolysosome prevents recognition of molecules that would otherwise be presented to CD4+ T cells   Symptoms:  Usually occur 1-4 months following infection Symptoms include: Fever Malaise Resp symptoms: cough, SOB GI symptoms: dysphagia, abdo pain, N&V, diarrhoea Liver symptoms: jaundice Retinal symptoms: Scotomas, blurred vision Neural symptoms: Altered mental state, potentially seizures  Diagnosis: PCR is the main mode of diagnosis using bodily fluid samples for the identification of viral DNA Immunoflorescence assays to detect antibodies in blood Increased IgM = acute infection Increased IgG = past infection  Histological analysis for the Owl's Eye appearance of infected cells. The Owl's Eye appearance is produced by the formation of viral inclusion bodies in cells that has become enlarged due to viral infection   Neonatal Infection: Most common congenital infection causing intra-uterine growth restriction, newborn morbidity and late sequelae (condition which is the consequence of a previous disease) which mainly presents as hearing loss at around 3-4 years of age Mainly occurs in South America (Brazil, Chile) and India Detection of CMV in saliva can be found in neonates within 3 weeks of birth and indicates intra-uterine infection (as incubation time of CMV is >3 weeks) Retrospective diagnosis is also possoble by using the blood test spot on the Guthrie card (from the heel prick test taken just following birth). Helpful for, say, someone in their teens with early onset hearing loss to establish a cause Congenitally infected neonates are given Valganciclovir for 6 months ONLY when the baby has moderate-severe disease due to the potential side effects of the drug Transplant Patients: CMV serostatus (do they have IgG antibodies which would indicate that they are infected with CMV) is established before transplantation. Treatment (preferably using Ganciclovir) should be given for 2 to 3 weeks prior to transplant and should be continued for an additional 7 days after the first negative result for viraemia following surgery Link between CMV and Cardiovascular Disease: Those who are infected with CMV have a higher risk of cardiovascular disease (such as coronary artery disease) It has been shown in recent studies that viral spread within the vascular wall brings about activation of the immune system in atherosclerotic plaques thus bringing about endothelial dysfunction which worsens cardiovascular condition Link between CMV and HIV: Can cause disseminated or localised end-organ disease in HIV-infected patients with advanced immunosuppression. Retinitis is the most common clinical manifestation of CMV end-organ disease in HIV-infected patients.  

Antivirals Aciclovir: Not very potent against CMV  Requires the addition of three phosphate groups in order to become added, and one of these phosphates MUST be added by a viral enzyme, therefore Aciclovir is only active inside cells which are virally infected  Aciclovir replaces Guanine in the growing viral polymerase chain of the replicating virus. It does not have a 3' hydroxyl group and thus chain termination ensues as replication cannot continue, bringing about a non-functional virus.    Ganciclovir: Main anti-viral treatment against CMV Guanosine analogue - competitive inhibitor of the DNA polymerase generated by CMV Ganciclovir is phosphorylated by the CMV UL97 gene, thus only works in cells affected by CMV.  Ganciclovir is administered intravenously (Valganciclovir is the oral equivelant) Requires monitoring of patients on this treatment as it can cause neutropenia and thrombocytopenia  Mechanism of action: Binds to growing chain and derails the polymerase, causing it to fall off the developing strand thus not completing it.    Foscarnet: Second line therapy for CMV infection Selectively inhibits the pyrophosphate binding site on viral DNA polymerases at a low level that does not affect non-viral polymerases