Human Cytomegalovirus- An Overview

Human cytomegalovirus (HCMV) is a common virus that belongs to the herpesvirus family, also known as human herpesvirus-5 (HHV-5) . It is estimated that 50% to 80% of adults in the United States have been infected with HCMV by the age of 40 . Most people who are infected with HCMV do not have any symptoms or health problems, because their immune system can control the virus. However, HCMV can cause serious disease and complications in some people, especially those who have weakened immune systems, such as organ transplant recipients, cancer patients, HIV/AIDS patients, and newborns who are infected before or during birth .

HCMV is transmitted through direct contact with bodily fluids, such as saliva, urine, blood, breast milk, semen, and cervical secretions . The virus can also cross the placenta and infect the fetus during pregnancy . HCMV can remain latent in the body for life, meaning that it can stay dormant in certain cells without causing any symptoms. However, the virus can reactivate and cause disease when the immune system is suppressed or impaired by stress, illness, medication, or aging .

HCMV infection can affect various organs and systems in the body, such as the eyes, lungs, liver, brain, gastrointestinal tract, and blood cells . The signs and symptoms of HCMV infection depend on the age and immune status of the person infected. In healthy adults and children, HCMV infection may cause mild or no symptoms at all. Some people may experience a flu-like illness or a mononucleosis-like syndrome with fever, fatigue, sore throat, swollen glands, and muscle aches . In immunocompromised individuals, HCMV infection can cause severe and life-threatening complications, such as pneumonia, retinitis (inflammation of the retina that can lead to blindness), hepatitis (inflammation of the liver), colitis (inflammation of the colon), esophagitis (inflammation of the esophagus), encephalitis (inflammation of the brain), and sepsis (a systemic inflammatory response to infection) . In congenital HCMV infection, which occurs when a pregnant woman passes the virus to her fetus, the baby may be born with symptoms such as jaundice (yellowing of the skin and eyes), rash, low birth weight, microcephaly (small head size), seizures, hearing loss, mental retardation, and developmental delays .

The diagnosis of HCMV infection is based on clinical features and laboratory tests. The laboratory tests include virus isolation from body fluids or tissues using cell culture or animal inoculation; detection of viral antigens or nucleic acids using immunofluorescence assay (IFA), enzyme-linked immunosorbent assay (ELISA), polymerase chain reaction (PCR), or nucleic acid sequence-based amplification (NASBA); and detection of antibodies against HCMV using complement fixation test (CFT), ELISA, IFA, or radioimmunoassay (RIA) . The treatment of HCMV infection depends on the severity and type of disease. Antiviral drugs such as ganciclovir, foscarnet, cidofovir, and valganciclovir are used to inhibit viral replication and reduce viral load. However, these drugs are not curative and may have side effects and toxicity. Therefore, they are reserved for patients with severe or life-threatening disease or those at high risk of complications. Supportive care such as hydration, nutrition, oxygen therapy, blood transfusion, and pain management may also be needed. The prevention and control of HCMV infection include screening of blood donors and organ donors for HCMV antibodies; administration of immunoglobulin or antiviral prophylaxis to high-risk patients; hygiene measures such as hand washing and avoiding contact with bodily fluids; education and counseling of pregnant women about the risks of congenital HCMV infection; and development of vaccines against HCMV .

HCMV is a ubiquitous virus that can cause a wide spectrum of clinical manifestations in humans. It is important to recognize the risk factors, signs and symptoms, diagnosis methods, treatment options, and prevention strategies for HCMV infection in order to reduce morbidity and mortality associated with this virus.

Human cytomegalovirus (HCMV) is a member of the herpesvirus family that has a complex structure. The virus is composed of four main components: the capsid, the tegument, the envelope, and the genome.

• The capsid is the innermost layer of the virus that contains the viral DNA genome. The capsid has an icosahedral symmetry with 162 capsomeres (150 hexons and 12 pentons) arranged in a T=16 lattice. The capsid has an average diameter of 100 nm and is surrounded by an amorphous protein layer called the tegument.
• The tegument is a proteinaceous matrix that fills the space between the capsid and the envelope. The tegument contains at least 25 different proteins that are involved in various functions such as viral entry, gene expression, immune evasion, and virion assembly. Some of the tegument proteins are also associated with the capsid or the envelope.
• The envelope is the outermost layer of the virus that consists of a lipid bilayer derived from the host cell membrane. The envelope contains various viral glycoproteins that mediate attachment and fusion with host cells. Some of the major envelope glycoproteins are gB, gH, gL, gM, and gN. These glycoproteins form complexes that interact with specific receptors on host cells and initiate viral entry.
• The genome is a linear double-stranded DNA molecule that consists of approximately 230 kb of nucleotides. The genome contains two unique regions (UL and US) flanked by inverted repeats (TRL, IRL, IRS, and TRS). The genome encodes about 150 open reading frames (ORFs) that produce viral proteins. Some of these proteins are essential for viral replication, while others are nonessential but contribute to viral pathogenesis and immune evasion.

The CMV genome consists of approximately 230kb of linear double-stranded DNA . The genome is monopartite and contains terminal and internal reiterated sequences . The genome is split into a unique long (UL) and a unique short (US) region, both flanked by inverted sequences . The UL region contains about 100 open reading frames (ORFs) and the US region contains about 50 ORFs. The inverted repeats allow for the possibility of genome rearrangements by inversion or deletion .

It has been found that 41 ORFs are essential and 117 are nonessential for CMV replication in cell culture. The essential ORFs are conserved among all HCMV isolates and the chimpanzee cytomegalovirus (CCMV) genome. The nonessential ORFs may have roles in modulating host immune responses, enhancing viral spread, or adapting to different cell types or hosts. Some of the nonessential ORFs are specific to HCMV and not found in CCMV or other herpesviruses.

The CMV genome encodes a variety of proteins that are involved in different stages of viral infection, such as:

• Viral glycoproteins that mediate attachment, entry, and egress of the virus. Examples are gB, gH, gL, gM, gN, gO, and gH/gL complexes .
• Tegument proteins that are packaged between the capsid and the envelope and have roles in viral assembly, transport, transcription, and modulation of host defenses. Examples are pp65, pp71, pp150, UL69, UL82, and UL97 .
• Capsid proteins that form the icosahedral structure that protects the viral DNA. Examples are MCP (major capsid protein), SCP (small capsid protein), and TRIP (triplex protein) .
• DNA replication proteins that synthesize new viral DNA in the nucleus. Examples are DNA polymerase, processivity factor (UL44), primase (UL70), helicase (UL105), and origin binding protein (UL9) .
• Transcription regulators that control the temporal expression of viral genes. Examples are IE1, IE2, UL36-38, UL112-113, and UL122-123 .
• Immune evasion proteins that interfere with host innate and adaptive immunity. Examples are US2-11, UL16, UL18, UL40, UL141-144, and MHC class I homologs .

The CMV genome is highly complex and dynamic, reflecting its adaptation to a wide range of host cells and tissues. Understanding the functions and interactions of its encoded proteins is essential for developing antiviral strategies against this ubiquitous pathogen.

Human cytomegalovirus (CMV) is a ubiquitous virus that can infect people of all ages and backgrounds. The prevalence of CMV infection varies widely depending on the geographic region, socioeconomic status, and exposure to risk factors .

CMV is transmitted through direct or indirect contact with body fluids of an infected person, such as saliva, urine, blood, tears, semen, vaginal fluids, and breast milk . The main routes of transmission are:

• Vertical transmission: This occurs when a pregnant woman passes the virus to her fetus through the placenta or during delivery, or when a nursing mother transmits the virus to her infant through breast milk. Congenital CMV infection is the most common viral infection of newborns and can cause serious complications such as hearing loss, vision impairment, neurological damage, and even death .
• Horizontal transmission: This occurs when CMV is spread from person to person through close contact with infected secretions. This can happen in various settings, such as households, childcare centers, schools, workplaces, sexual intercourse, organ transplantation, and blood transfusion. CMV can also be transmitted by touching contaminated surfaces or objects .
• Reactivation or reinfection: This occurs when a person who has been previously infected with CMV experiences a reactivation of latent virus in their body or gets infected with a different strain of the virus. Reactivation or reinfection can happen in immunocompromised individuals who have a weakened immune system due to HIV infection, cancer, organ transplantation, or other conditions. Reactivation or reinfection can also occur in immunocompetent individuals who are exposed to a new source of CMV .

The epidemiology of CMV infection is influenced by several factors, such as age, gender, ethnicity, lifestyle, and immune status. Some general patterns are:

• Age: CMV infection is more common in children and young adults than in older adults. In developed countries, about 50% to 80% of adults have been infected with CMV by the age of 40 years. In developing countries, the seroprevalence of CMV is higher and reaches 90% to 100% by early adulthood .
• Gender: Women are more likely than men to acquire CMV infection due to their higher exposure to children and their biological fluids. Women are also more likely to transmit CMV to their infants during pregnancy or breastfeeding .
• Ethnicity: CMV infection is more prevalent among non-white populations than among white populations. This may reflect differences in socioeconomic status, hygiene practices, cultural norms, and genetic susceptibility .
• Lifestyle: CMV infection is associated with certain behaviors that increase the risk of exposure to infected fluids, such as having multiple sexual partners, engaging in oral sex, sharing utensils or personal items, and working in healthcare settings .
• Immune status: CMV infection is more severe and more frequent in immunocompromised individuals than in immunocompetent individuals. Immunocompromised individuals are at risk of developing life-threatening complications from CMV infection, such as pneumonia, retinitis, colitis, hepatitis, encephalitis, and disseminated disease .

Human cytomegalovirus (HCMV) is a herpesvirus that replicates its linear double-stranded DNA genome in specialized replication compartments (RCs) in the host cell nucleus. The replication of HCMV DNA involves the following steps :

• Attachment to host cells is mediated by the fusion of the viral glycoproteins to host receptors which further mediates endocytosis of the virus into the host cell. The exact mechanism of entry may vary depending on the type of host cell, i.e., endocytosis versus plasma membrane fusion.
• After entry and uncoating, the capsid is transported to the nuclear pore where the viral DNA is released into the nucleus.
• Tegument proteins regulate host cell responses and initiate the temporal cascade of the expression of viral immediate-early (IE) genes, followed by delayed early (DE) genes, which initiate viral genome replication, and late (L) genes.
• Viral genome replication is initiated from a single origin of lytic replication (oriLyt) located within the UL region of the genome. The oriLyt contains binding sites for viral proteins such as UL84, UL44, UL57, and IE2 that are essential for replication initiation and elongation.
• The replication proceeds by a rolling circle mechanism that generates head-to-tail concatemers of viral DNA. The concatemers are then cleaved and packaged into preformed capsids in the nucleus.
• Late gene expression initiates capsid assembly in the nucleus, followed by nuclear egress to the cytosol. Capsids associate with tegument proteins in the cytosol and are trafficked to the viral assembly complex (AC) that contains components of the endoplasmic reticulum (ER), Golgi apparatus and endosomal machinery.
• The capsids further acquire tegument and viral envelope by budding into intracellular vesicles at the assembly complex. Assembly of the virus in nuclear viral factories and budding through the inner lamella of the nuclear membrane by the insertion of herpes glycoproteins, throughout the Golgi and final release by exocytosis at the plasma membrane.

The RCs are membrane-less organelles that originate as spherical structures and grow in size over time. They are composed of viral and cellular proteins that form a liquid-like phase separated from the surrounding nucleoplasm. The RCs are thought to provide a favorable environment for viral DNA synthesis, transcription, and processing, as well as to protect viral DNA from host defenses.

Human cytomegalovirus (HCMV) is a herpesvirus that infects and replicates in a wide variety of cells, including epithelial cells of the gland and mucosal tissue, smooth muscle cells, fibroblasts, macrophages, dendritic cells, hepatocytes, and vascular endothelial cells. This broad cell tropism facilitates systemic spread in the human body and inter-host spread.

Primary replication typically starts with replication in the mucosal epithelium as a result of direct contact with infectious secretions from an infected individual. A systemic phase of infection disseminates virus in the host via leukocyte associated viremia that may last for several months. In addition, HCMV undergoes latency in myeloid cells of the bone marrow, presumably leading to a life-long infection with sporadic reactivation .

HCMV infection is generally asymptomatic in healthy individuals. However, in immunocompromised individuals, such as organ transplant recipients or human immunodeficiency virus carriers, HCMV poses a life-threatening risk. HCMV is also recognized as the leading infectious cause of congenital neurological disease by transmission through the placenta from the mother to the child .

The pathogenesis of HCMV infection and disease is influenced by several factors, including the viral strain, the host immune status, the route and dose of infection, and the presence of co-infections. HCMV has evolved multiple strategies to evade and modulate host immune responses, such as interfering with antigen presentation, cytokine signaling, complement activation, natural killer cell function, and apoptosis .

HCMV also encodes several homologs of cellular proteins that can mimic or manipulate host functions, such as chemokines, cytokines, receptors, and enzymes. Furthermore, HCMV can establish latency and reactivation cycles that allow the virus to persist and reactivate under conditions of immunosuppression or inflammation.

The mechanisms by which HCMV causes end organ disease are not fully understood, but they may involve direct cytopathic effects of viral replication, indirect effects of viral proteins or cytokines on host cells, immunopathological reactions mediated by inflammatory cells or antibodies, or a combination of these factors .

Some of the common manifestations of HCMV disease include retinitis, pneumonitis, hepatitis, esophagitis, colitis, encephalitis, and congenital defects . The severity and outcome of these conditions depend on the extent of viral replication, the degree of tissue damage, and the availability and efficacy of antiviral therapy .

Most people who are infected with CMV who are otherwise healthy experience few if any symptoms. When first infected, some adults may have symptoms similar to infectious mononucleosis, including:

• Fatigue
• Fever
• Sore throat
• Muscle aches

However, in people with suppressed immune systems, CMV infection can attack different organs of the body and may cause :

• Blurred vision and blindness (CMV retinitis)
• Lung infection (pneumonia)
• Painful swallowing (esophagitis)
• Diarrhea (colitis)
• Inflammation of the liver (hepatitis)
• Inflammation of the brain (encephalitis), which may cause behavioral changes, seizures, or coma.

Infants with CMV infection at birth (congenital CMV) have no symptoms at birth, however, up to 20% of those without symptoms at birth will go on to develop deafness. Only about 10% of infants with congenital CMV show signs and symptoms of the infection or develop complications. Signs and symptoms of CMV at birth may include :

• Deafness
• Yellow skin and eyes (jaundice)
• Skin rash or purple skin splotches
• Premature birth
• Low birth weight
• Pneumonia
• Enlarged liver and spleen
• Abnormally small head (microcephaly)
• Seizures

The effects of congenital CMV infection include:

• CNS abnormalities – microcephaly, mental retardation, spasticity, epilepsy, periventricular calcification
• Choroidoretinitis and optic atrophy
• Sensorineural deafness
• Hepatosplenomegaly and jaundice which is due to hepatitis
• Pneumonitis
• Myocarditis
• Thrombocytopenic purpura
• Hemolytic anemia
• Late sequelae – damage to the enamel forming organ of the teeth resulting in yellow discoloration of the teeth and brittleness.

Laboratory diagnosis of human cytomegalovirus (HCMV) infection is important for people who are at risk of serious complications, such as immunocompromised individuals, organ transplant recipients, pregnant women, and newborns. There are various methods to detect HCMV infection, depending on the type of specimen, the purpose of testing, and the availability of resources.

Blood tests

Blood tests are the most common way to test adults for HCMV infection. Blood tests can detect antibodies (IgG and IgM) or viral DNA (by polymerase chain reaction, PCR) in the blood.

• Antibody tests measure the immune response to HCMV infection. A positive test for HCMV IgG indicates that a person was infected with HCMV at some time during their life, but does not indicate when the infection occurred. A positive test for HCMV IgM indicates that a person has a recent or active infection, but it can also be present during reactivation of latent infection. Therefore, IgM testing alone is not sufficient to diagnose primary infection. IgG avidity tests measure the binding strength between IgG antibodies and the virus, and can help distinguish a primary infection from a past infection. Low avidity indicates a recent infection, while high avidity indicates a past infection.
• PCR tests detect the presence of HCMV DNA in the blood, and can be either qualitative or quantitative. Qualitative PCR tests indicate whether HCMV DNA is present or absent, while quantitative PCR tests measure the amount of viral DNA in the blood. PCR tests are more sensitive and specific than antibody tests, and can be used to diagnose active or reactivated infection, monitor viral load, assess response to treatment, and identify congenital infection in newborns.

Other body fluids and tissues

Other body fluids and tissues can also be tested for HCMV infection, depending on the clinical situation and the suspected site of infection. These include urine, saliva, cerebrospinal fluid (CSF), amniotic fluid, tissue biopsy, sputum, bronchoalveolar lavage (BAL), and semen.

• Urine and saliva tests are used to diagnose congenital HCMV infection in newborns within three weeks of birth. These specimens are collected by swabbing the mouth or bladder of the baby, and tested by PCR for HCMV DNA. A positive result indicates that the baby was infected before or during birth. A negative result does not rule out congenital infection, as some babies may have low or intermittent viral shedding.
• CSF test is used to diagnose HCMV infection of the central nervous system (CNS), such as encephalitis or meningitis. CSF is collected by a spinal tap (lumbar puncture), and tested by PCR for HCMV DNA. A positive result indicates that HCMV has invaded the CNS and may cause neurological damage.
• Amniotic fluid test is used to diagnose intrauterine HCMV infection in pregnant women who have symptoms of HCMV infection or who have a history of exposure to HCMV. Amniotic fluid is collected by amniocentesis, and tested by PCR for HCMV DNA. A positive result indicates that the fetus has been infected by HCMV and may develop congenital abnormalities.
• Tissue biopsy test is used to diagnose HCMV infection of specific organs or tissues, such as liver, lung, kidney, eye, or gastrointestinal tract. Tissue samples are obtained by surgery or biopsy, and tested by PCR for HCMV DNA or by immunohistochemistry (IHC) for HCMV antigens. A positive result indicates that HCMV has caused tissue damage or inflammation.
• Sputum and BAL tests are used to diagnose HCMV pneumonia in immunocompromised patients who have respiratory symptoms. Sputum is collected by coughing up phlegm from the lungs, while BAL is collected by inserting a tube into the lungs and washing them with saline. Both specimens are tested by PCR for HCMV DNA or by IHC for HCMV antigens. A positive result indicates that HCMV has infected the lungs and may cause respiratory failure.
• Semen test is used to diagnose HCMV infection of the male reproductive system, which may affect fertility or sexual transmission. Semen is collected by masturbation or ejaculation, and tested by PCR for HCMV DNA. A positive result indicates that HCMV has infected the semen and may be transmitted to sexual partners.

The treatment of human cytomegalovirus (HCMV) infection depends on the type and severity of the disease, the immune status of the patient, and the potential side effects of the antiviral drugs. The main goals of treatment are to reduce viral replication, prevent organ damage, and improve survival and quality of life.

Antiviral medications

The most common type of treatment for HCMV infection is antiviral medications, which can slow down or inhibit the reproduction of the virus, but cannot eliminate it completely. Antiviral medications are usually given intravenously or orally, depending on the drug and the condition of the patient. The duration of treatment may vary from several weeks to several months, depending on the response and the risk of recurrence.

The main antiviral drugs used for HCMV infection are:

• Ganciclovir: This is a nucleoside analogue that inhibits DNA synthesis in HCMV by interfering with its DNA polymerase enzyme. It is effective against both primary and recurrent HCMV infections, and is the drug of choice for life-threatening or sight-threatening disease . It can be given intravenously or orally (as valganciclovir). The main side effects are bone marrow suppression, renal toxicity, and neurological toxicity .
• Foscarnet: This is a pyrophosphate analogue that inhibits DNA polymerase and RNA polymerase of HCMV by binding to their active sites. It is effective against ganciclovir-resistant strains of HCMV, and is used as a second-line drug for severe disease . It can only be given intravenously. The main side effects are renal toxicity, electrolyte imbalance, and seizures .
• Cidofovir: This is a nucleotide analogue that inhibits DNA synthesis in HCMV by incorporating into its DNA chain and terminating it. It is effective against ganciclovir-resistant strains of HCMV, and is used as a second-line drug for severe disease . It can only be given intravenously. The main side effects are renal toxicity, neutropenia, and ocular toxicity .
• Letermovir: This is a novel antiviral drug that inhibits the terminase complex of HCMV, which is essential for viral DNA cleavage and packaging. It is effective against ganciclovir-resistant strains of HCMV, and is used for prophylaxis in hematopoietic stem cell transplant recipients. It can be given intravenously or orally. The main side effects are gastrointestinal disturbances, headache, and fatigue.

Supportive care

In addition to antiviral medications, patients with HCMV infection may require supportive care to manage their symptoms and complications. Supportive care may include:

• Fluids and electrolytes: Patients with dehydration, diarrhea, or renal impairment may need intravenous fluids and electrolyte replacement to maintain hydration and acid-base balance.
• Blood transfusions: Patients with anemia or thrombocytopenia may need blood transfusions to restore their blood counts and prevent bleeding complications.
• Immunoglobulins: Patients with congenital HCMV infection or severe immunosuppression may benefit from intravenous immunoglobulins (IVIG), which contain antibodies against HCMV and other pathogens. IVIG may reduce viral load, enhance immune response, and prevent or treat organ damage .
• Analgesics and anti-inflammatory drugs: Patients with fever, pain, or inflammation may need analgesics (such as acetaminophen or ibuprofen) or anti-inflammatory drugs (such as corticosteroids) to relieve their discomfort and reduce tissue damage.
• Antibiotics: Patients with bacterial co-infections or secondary infections may need antibiotics to treat their infections and prevent sepsis.

Prevention and control

The prevention and control of HCMV infection depend on reducing the risk of exposure and transmission of the virus, as well as enhancing the immune response against it. The preventive measures may include:

• Screening of donors and recipients: Blood donors and organ transplant donors and recipients should be screened for HCMV antibodies to identify their infection status and risk of transmission. CMV-negative recipients should receive CMV-negative blood products or organs whenever possible .
• Prophylaxis in high-risk groups: High-risk groups such as organ transplant recipients, hematopoietic stem cell transplant recipients, HIV-infected patients, or pregnant women should receive prophylaxis with antiviral drugs (such as ganciclovir, valganciclovir, or letermovir) or immunoglobulins to prevent primary or recurrent HCMV infection or disease .
• Hygiene measures: People who are infected with or exposed to HCMV should practice good hygiene measures such as washing hands frequently, avoiding contact with body fluids (such as saliva, urine, or breast milk), using condoms during sexual intercourse, and cleaning surfaces and objects that may be contaminated with the virus .
• Vaccination: There is currently no licensed vaccine for HCMV infection, but several candidates are under development. Vaccination may offer protection against primary or recurrent infection or disease in high-risk groups such as pregnant women, infants, or immunocompromised patients.

There is no vaccine or specific antiviral drug to prevent or treat CMV infection in healthy individuals. However, there are some general measures that can reduce the risk of transmission and infection, especially for pregnant women, immunocompromised people, and organ transplant recipients.

• Wash hands often with soap and water, especially after changing diapers, feeding children, wiping children`s noses, or touching toys or other objects that may have been contaminated with saliva or urine.
• Avoid kissing young children on the mouth or cheek. Instead, kiss them on the forehead or hug them.
• Avoid sharing food, drinks, utensils, toothbrushes, or other items that may have saliva on them.
• Use condoms during sexual contact to prevent the spread of CMV through semen or vaginal fluids.
• Clean and disinfect surfaces that may have been contaminated with body fluids.
• Wear disposable gloves when handling body fluids or tissues that may contain CMV, such as blood, urine, saliva, or biopsy samples. Dispose of the gloves after use and wash hands thoroughly.
• For pregnant women who work in childcare settings or healthcare facilities, consider wearing a mask and gown when caring for young children or patients who may have CMV infection. Alternatively, request a temporary reassignment to work with older children or adults who are less likely to have CMV infection.
• For organ transplant recipients, follow the instructions of the transplant team regarding CMV prevention and treatment. They may prescribe antiviral drugs to prevent CMV disease or to treat it if it occurs. They may also monitor the CMV viral load in the blood regularly to detect early signs of infection or reactivation.
• For immunocompromised people, such as those with HIV/AIDS or cancer, consult with the healthcare provider about the risk of CMV infection and the possible options for prevention and treatment. They may also benefit from antiviral drugs or immune-based therapies to control CMV infection.

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