Human cytomegalovirus (CMV, herpesvirus 5) is a member of the herpesvirus family. This group of viruses includes herpes simplex virus types 1 and 2, varicella-zoster virus, and Epstein-Barr virus. CMV is a large enveloped virus; its double-stranded DNA genome codes for over 200 proteins. Viral proteins are regulatory and structural. Among structural proteins, glycoproteins and phosphoproteins are described.
CMV, similarly to other herpes viruses, shares a characteristic ability to remain dormant within the body for life. After initial infection, which may cause few symptoms, CMV becomes latent, residing in cells without causing detectable damage or clinical illness. Severe impairment of the body’s immune system by medication or disease may allow the virus to reactivate from the latent or dormant state and become symptomatic.
CMV infects most humans without harm. However infection with CMV causes serious, life-threatening disease in two circumstances: (1) in immunosuppressed adults and (2) in congenital infections of developing fetuses. In immunocompromised patients (organ transplant recipients, patients with lymphoid cancers, and HIV-infected patients) CMV is a major cause of disease and death. The common manifestations of disease in those patients are pneumonia, retinitis, and gastrointestinal diseases.
Congenital CMV (CCMV) infection is mostly (86% of all cases) asymptomatic. Symptoms, if they develop, include jaundice, pneumonia, a rash, an enlarged liver and spleen, low birth weight, seizures, small head. Mortality of children under symptomatic CCMV is around 20%. Around a half of symptomatic infants and around 12% of asymptomatic ones later develop physical or mental problems. These can include hearing loss, visual impairment or blindness, learning difficulties, epilepsy.
Although the virus is not highly contagious, it can be transmitted through different bodily fluids, including: saliva, semen, blood, urine, vaginal fluids, breast milk. The most popular routes of CMV transmission to children include: mother-to-child via breastfeeding, parents- or siblings-to-child via close contact, or child-to-child via close contact in out-of-home settings such as day care centers. Infection of CMV seronegative pregnant women occurs mostly through exposure to the urine and saliva of existing small children.
Although it is estimated that the majority of congenital infections occur among women who were CMV seropositive prior to conception, it is primary infection, which poses the greatest risk for the fetus. A recurrent or reactivated infection is much less likely to result in serious fetal injury. The risk of serious fetal injury is greatest when maternal infection develops in the first trimester or early in the second trimester.
CMV is widespread in human populations, and around a half of adult humans in developed countries are CMV carriers. Congenital CMV-related disabilities are as common among newborns and children as other better known diseases such as Down syndrome and fetal alcohol syndrome. Around 1% of children in developed countries are born with congenital CMV syndrome, and around 0,2% of all children in these countries develop long-term consequences.
Cytomegalovirus infection leads to the generation of a very strong humoral and cellular immune response that is maintained for life and appears necessary to control viral replication. Existing antibodies effectively limit viral spread during reactivation; one of important consequences is low level of clinically significant congenital CMV in seropositives. In pregnant women, the level of IgM antibodies increases soon after infection, reaches its peak after 3 weeks, and then decreases. IgM antibodies are usually detected only following primary infection and generally persist for less than 4 months. IgG antibodies are non-detectable until approximately the third week after infection; the level of IgG begins to rise and reaches a maximum 3 months after infection. IgG antibodies persist in organism for life.
Viral glycoproteins and phosphoproteins represent dominant antigens for the humoral response. Structural glycoproteins are mainly localized in the viral envelope. Glycoprotein B (gB), the most abundant envelope protein of CMV that is responsible for fusion of the virion with the infected cell, is the predominant target of the humoral immune response in natural infections.
Viral structural phosphoproteins are mainly localized in the viral tegument and/or in the capsid. Among phosphoproteins, tegument protein pp150 is the most immunogenic. High antibody titres to this protein have repeatedly been found irrespective of the stage of infection in nearly 100% of CMV seropositive subjects. Among non-structural proteins, p52 (accessory protein of viral DNA polymerase) was proved to be immunogenic. In this study, IgM antibodies to p52 were preferentially present during primary CMV infection and therefore these antibodies could reportedly represent a very important marker of acute primary infection.
The synthesis of antibodies against different CMV proteins is differentiated in time. The IgG response against surface glycoproteins is delayed by 50-100 days in comparison with response against phosphoproteins.
The available methods for diagnostics of CMV detect either virus itself/its nucleic acid or antibodies elicited by CMV. Cell culture remains the gold standard for diagnosis of CMV allowing to detect virus in such samples as urine, blood, saliva etc. A disadvantage of cell culture is a relatively long period of analysis - most cultures should be held up for 3 weeks or longer to ensure cytopathic effects to develop. Serological analysis is useful in following main cases:
1) in organ transplant recipients and women planning pregnancy-to determine susceptibility or resistance to primary infection (by the level of IgG);
2) in organ transplant donors- to diagnose possible carrier state (by the level of IgG);
3) in pregnant women-to provide possible serological evidence of recent infection and, if positive, to differentiate between primary and reinfection (by the level of IgG/IgM and by the avidity of IgG).
Detection of CMV-specific IgM cannot be regarded as absolute proof of primary CMV infection for several reasons. Firstly, about 25% of patients with primary CMV infection still have detectable IgM 4 months after infection, with IgM sometimes persisting for over a year. Secondly, IgM antibody may reappear during reactivation of a latent infection or reinfection. False-positive IgM results may also occur due to non-specific IgM reactivity. False-negatives due to the lack of CMV-specific IgM are also possible. Taking into account the special importance to reliably diagnose primary CMV infection in pregnant women, the serological testing of suspected primary CMV infection in this category of patients should include the measurement of not only the level of IgM, but also the avidity of IgG.
Since the 1980s the IgG avidity assays, which measure antibody maturity, have been shown to reliably detect recent primary CMV infection. Under primary infection, IgG of low avidity is detectable for 3 to 4 months postinfection, with avidity values then moving into the intermediate range for 1 to 2 months, and reaching high levels. Thus, a high-avidity result during the first trimester is a strong indicator that infection occurred more than 5 months earlier, before conception. However, a low-avidity result during the third trimester strongly suggests that infection occurred within the prior 4 months, already after conception.
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