Human cytomegalovirus


Human cytomegalovirus, also called human herpesvirus 5, is a species of virus in the genus Cytomegalovirus, which in turn is a member of the viral family known as Herpesviridae or herpesviruses. It is also commonly called CMV. Within Herpesviridae, HCMV belongs to the Betaherpesvirinae subfamily, which also includes cytomegaloviruses from other mammals. CMV is a double-stranded DNA virus.
Although they may be found throughout the body, HCMV infections are frequently associated with the salivary glands. HCMV infection is typically unnoticed in healthy people, but can be life-threatening for the immunocompromised, such as HIV-infected persons, organ transplant recipients, or newborn infants. Congenital cytomegalovirus infection can lead to significant morbidity and even death. After infection, HCMV remains latent within the body throughout life and can be reactivated at any time. Eventually, it may cause mucoepidermoid carcinoma and possibly other malignancies such as prostate cancer, breast cancer, ovarian cancer and glioblastoma.
HCMV is found in all geographic locations and all socioeconomic groups, and infects between 60% and 70% of adults in the first world and almost 100% in the third world. Of all herpes viruses, HCMV harbors the most genes dedicated to altering innate and adaptive host immunity and represents a lifelong burden of antigenic T cell surveillance and immune dysfunction. Commonly it is indicated by the presence of antibodies in the general population. Seroprevalence is age-dependent: 58.9% of individuals aged 6 and older are infected with CMV, while 90.8% of individuals aged 80 and older are positive for HCMV. HCMV is also the virus most frequently transmitted to a developing fetus. HCMV infection is more widespread in developing countries and in communities with lower socioeconomic status and represents the most significant viral cause of birth defects in industrialized countries. Congenital HCMV is the leading infectious cause of deafness, learning disabilities, and intellectual disability in children.
CMV also "seems to have a large impact on immune parameters in later life and may contribute to increased morbidity and eventual mortality."

Signs and symptoms

Human cytomegalovirus infection has a classic triad of symptoms: fever, peaking in the late afternoon or early evening; pharyngitis, usually exudative; and symmetrical adenopathy.

Virology

Transmission

The mode of HCMV transmission from person to person is unknown, but is presumed to occur through bodily fluids, including saliva, urine, blood, and tears. Cytomegalovirus is most commonly transmitted through kissing and sexual intercourse. It can also be transferred from an infected mother to her unborn child. Infection requires close, intimate contact with a person secreting the virus in their saliva, urine, or other bodily fluids. CMV can be transmitted sexually and via breast milk, and also occurs through receiving transplanted organs or blood transfusions. Although HCMV is not highly contagious, it has been shown to spread in households and among young children in day care centers.

Replication

HCMV replicates within infected endothelial cells at a slow rate, taking about five days in cell culture. It also infects fibroblasts, which requires expression of only a trimeric viral receptor complex, rather than the full pentameric complex that is required for infection of endothelial and epithelial cells. Like other herpesviruses, HCMV expresses genes in a temporally controlled manner. Immediate early genes are involved in the regulation of transcription, followed by early genes which are involved in viral DNA replication and further transcriptional regulation. Late genes are expressed during the remainder of infection up to viral egress and typically code for structural proteins. While HCMV encodes for its own functional DNA polymerase, the virus makes use of the host RNA polymerase for the transcription of all of its genes.
In disseminated cytomegalovirus infections, as may be seen in the context of an immunosuppressed host, the virus is readily transmitted between polymorphonuclear leukocytes and endothelial cells. Infected endothelial cells produce cytokines that attract PM-NLs, which then adhere to the endothelium by interactions between their CD18-containing cell surface integrins and the endothelial-expressed ICAM-1. Microfusions between the cells then take place in a manner dependent on expression of the viral gene locus UL128L.
Synthesis of the viral double-stranded DNA genome occurs at the host cell nucleus within specialized viral replication compartments.
Nearly 75% of the genes encoded by HCMV strain AD169 can be deleted and still result in the production of infectious virus. This suggests that the virus focuses on avoiding the host immune system for a timely entrance into latency.

At-risk populations

CMV infections are most significant in the perinatal period and in people who are immunocompromised.

Pregnancy and congenital infection

HCMV is one of the vertically transmitted infections that lead to congenital abnormalities. Congenital HCMV infection occurs when the mother has a primary infection during pregnancy.
Up to 5 of every 1,000 live births are infected. Five percent develop multiple handicaps, and develop cytomegalic inclusion disease with nonspecific signs that resemble rubella. Another five percent later develop cerebral calcification.
However, infants born preterm and infected with HCMV after birth may experience cognitive and motor impairments later in life.

Immunocompromised adults

CMV infection or reactivation in people whose immune systems are compromised—for example, people who have received transplants or are significantly burned—causes illness and increases the risk of death.
HCMV infection involving the gastrointestinal tract represents a leading cause of morbidity and mortality among kidney transplant recipients. Signs and symptoms of the disease may be variable. Prompt anti-viral therapy administration and changes in immunosuppression are key factors for optimizing its management.
CMV reactivation is commonly seen in people with severe colitis.
Specific disease entities recognized in those people are
People without CMV infection who are given organ transplants from CMV-infected donors require prophylactic treatment with valganciclovir or ganciclovir, and regular serological monitoring to detect a rising CMV titre; if treated early, establishment of a potentially life-threatening infection can be prevented.

Immunocompetent adults

CMV infections can still be of clinical significance in adult immunocompetent populations.
The question of whether latent CMV infection has any negative effects on people who are otherwise healthy has been debated; as of 2016, the answer was not clear, but discussions had focused on whether latent CMV might increase the risk of some cardiovascular diseases and cancers.

Pathogenesis

Most healthy people who are infected with HCMV after birth have no symptoms. Some develop a syndrome similar to infectious mononucleosis or glandular fever, with prolonged fever, and a mild hepatitis. A sore throat is common. After infection, the virus remains latent in lymphocytes in the body for the rest of the person's life. Overt disease rarely occurs unless immunity is suppressed either by drugs, infection or old age. Initial HCMV infection, which often is asymptomatic, is followed by a prolonged, inapparent infection during which the virus resides in mononuclear cells without causing detectable damage or clinical illness.
Infectious CMV may be shed in the bodily fluids of any infected person, and can be found in urine, saliva, blood, tears, semen, and breast milk. The shedding of virus can occur intermittently, without any detectable signs or symptoms.
File:CMV placentitis2 mini.jpg|thumb|right|Micrograph of CMV placentitis. One cell in the image has the characteristic large nucleus with peri-nuclear clearing. Two cells have the characteristic viral inclusion bodies. H&E stain.
CMV infection can be demonstrated microscopically by the detection of intranuclear inclusion bodies. On H&E staining, the inclusion bodies stain dark pink and are called "owl's eye" inclusion bodies.
HCMV infection is important to certain high-risk groups. Major areas of risk of infection include pre-natal or postnatal infants and immunocompromised individuals, such as organ transplant recipients, persons with leukemia, or those infected with human immunodeficiency virus. In HIV infected persons, HCMV is considered an AIDS-defining infection, indicating that the T-cell count has dropped to low levels.
Lytically replicating viruses disrupt the cytoskeleton, causing massive cell enlargement, which is the source of the virus's name.
A study published in 2009 links infection with CMV to high blood pressure in mice, and suggests that the result of CMV infection of blood vessels' endothelium in humans is a major cause of atherosclerosis. Researchers also found that when the cells were infected with CMV, they created renin, a protein known to contribute to high blood pressure.
Human CMV causes cellular senescence, which could contribute to chronic inflammation. Human CMV is also linked to age-associated T cell dysfunction, contributing to immunosenescence. In persons infected with CMV about 10% of memory T cells are CMV-specific, but these may expand to as much as 30% in the elderly, 50% or more of CD8+ memory T-cells. COVID-19 symptom severity is associated with CMV, although the exact mechanism has not been elucidated.
CMV encodes a protein, UL16, which is involved in the immune evasion of NK cell responses. It binds to ligands ULBP1, ULBP2 and MICB of NK cell activating receptor NKG2D, which prevents their surface expression. These ligands are normally upregulated in times of cellular stress, such as in viral infection, and by preventing their upregulation, CMV can prevent its host cell from dying due to NK cells
A substantial portion of the immune system is involved in continuously controlling CMV, which drains the resources of the immune system. Death rates from infectious disease accelerate with age, and CMV infection correlates with reduced effectiveness of vaccination. Persons with the highest levels of CMV antibodies have a much higher risk of death from all causes compared with persons having few or no antibodies.