Human cytomegalovirus (HCMV) stays asleep inside our cell

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Human cytomegalovirus (HCMV) may not be a household name as far as viruses go, but according to Xiaoping Zhu, professor and chair in Veterinary Medicine at UMD, half of the population walking around campus is likely to be a carrier.

Once contracted, it lays dormant in your body for the rest of your life and can flare up whenever your immune system is severely compromised, giving you flu-like symptoms.

This becomes a severe problem for people who already have weakened immune systems, for example the very young, old, pregnant women, organ transplant recipients, or HIV/AIDS patients.

More concerning, however, is that HCMV is the number one infectious cause of congenital birth defects in the world, including developmental disabilities and deafness.

But how can a protein be a major contributor in the development of birth defects, and also hold the potential to provide symptom relief from autoimmune diseases like lupus?

In a new paper published in Nature Communications, Zhu and his colleagues are helping to answer this question and uncover the mechanisms that will lead to multi-faceted prevention and treatment.

HCMV stays asleep inside our cells,” explains Zhu.

“Then one day, you get stressed, you have too much going on, and your immunity decreases allowing the virus to spring up again.”

This is the case with all strains of the herpes virus like HCMV, chickenpox, and herpes simplex.

HCMV can present similar symptoms to the flu virus. But unlike the flu, it persists in your body, and your immune system has to work harder than normal to combat the virus and keep it at bay.

It can also be passed through the placenta to a pregnant mother’s unborn child, not only affecting the child’s immune system, but also potentially causing birth defects.

“When the mother gets infected, the virus spreads from mother to baby and can cause mental disabilities, vision loss, and deafness.

People are aware of this concern with Zika virus for instance, but Zika doesn’t stay in your system for life like HCMV, and it isn’t present in 50 to 80 percent of the population globally depending on where you live,” says Zhu.

This makes the study of HCMV and the mechanisms that contribute to its persistence and transmission a high priority for the medical community, with National Institutes of Health (NIH) funding Zhu’s work.

The immune system has two arms of immunity, at the cellular and antibody levels, to specifically destroy bugs.

The mechanisms of the US11 protein that allow HCMV to evade white blood cells that kill viruses on the cellular level are well known, but in this latest publication from Zhu, he and his colleagues discuss a newly discovered function of the same protein that impairs antibody immunity.

Antibody immunity normally prevents viruses from entering and infecting uninfected cells and labels the infected cells to be destroyed by the white blood cells.

But US11 attacks a specific receptor that not only naturally bolsters your immunity, but also directs protective antibodies from the mother to be transferred to the fetus.

With this receptor impaired, HCMV may reduce transmission of these critical antibodies, resulting in vulnerability to all sorts of birth defects, and at the very least compromising the child’s immunity throughout their life.

“This is the first time that we discovered that this virus, or any pathogen, has this strategy to destroy this receptor function and reduce antibody functionality,” says Zhu.

“Antibodies are also used to treat diseases like AIDS, cancer, and make vaccines, and this mechanism makes that less effective. By understanding this function, we can hopefully figure out methods to block that mechanism in the future.”

Beyond prevention for birth defects and immune system dysfunction, Zhu sees another potential treatment benefit for this mechanism for patients struggling with autoimmune diseases.

“Humans have many autoimmune diseases, and in these cases like with lupus, it is actually our immune response that causes the disease, which is regulated by antibodies,” explains Zhu.

“In these patients, we are concerned with how to reduce autoimmune antibodies, because their overproduction causes damage on our own tissues and cells, swelling in the joints, and substantial pain.

Since this protein US11 can facilitate antibody degradation and suppress antibody function, it could be used in humans to treat autoimmune disease and target these disease-causing antibodies to indirectly benefit patients with immune diseases.”

This therapeutic prospect is being patented by UMD through Zhu and Xiaoyang Liu, who stress the importance of directly translating basic research like this into applied outcomes and treatment options, not just for humans, but for animals that are infected with similar viruses as well.

“Human and animal health research is interconnected,” says Zhu. “Similar knowledge can be used to promote animal and human health, and diseases pass directly from animals to humans and vice versa.”

With humans and animals standing to benefit from this work in many different ways, the applications of this discovery are widespread.

The full paper, entitled “Human cytomegalovirus evades antibody-mediated immunity through endoplasmic reticulum-associated degradation of the FcRn receptor,” is available through Nature Communications.


Cytomegalovirus (CMV) is a wide-spread virus, with manifestations ranging from asymptomatic to severe end-organ dysfunction in immunocompromised patients with congenital CMV disease. [1][2][3]

Human cytomegalovirus is a member of the viral family known as herpesviruses, Herpesviridae, or human herpesvirus-5 (HHV-5).

Human cytomegalovirus infections commonly are associated with the salivary glands. CMV infection may be asymptomatic in healthy people, but they can be life-threatening in an immunocompromised patient.

Congenital cytomegalovirus infection can cause morbidity and even death. After infection, CMV often remains latent, but it can reactivate at any time. Eventually, it causes mucoepidermoid carcinoma, and it may be responsible for prostate cancer.

CMV infects between 60% to 70% of adults in industrialized countries and close to 100% in emerging countries. Of all herpes viruses, CMV harbors the largest number of genes dedicated to evading innate and adaptive immunity in the host.

CMV represents a lifelong burden of antigenic T-cell surveillance and immune dysfunction. Congenital CMV is a leading infectious cause of deafness, learning disabilities, and intellectual disability.

Etiology

CMV is double-stranded DNA virus and is a member of the herpesviruses. Like other herpesviruses, after recovery of the initial infection, CMV remains dormant within the host. Viral reactivation occurs during compromise of the immune system with immunosuppression.

Epidemiology

Approximately 59% of the population older than six years old has been exposed to CMV, with an increase in the population’s seroprevalence with increasing age. Infection can occur as a primary infection, reinfection, or reactivation.

Transmission of CMV can occur in numerous ways: via blood products (transfusions, organ transplantation), breastfeeding, viral shedding in close-contact settings, perinatally, and sexual transmission. Reactivation is seen in patients who become immunocompromised and is associated with elevated morbidity and mortality.  [4][5]

  • Primary infection: infection in seronegative patients; may be asymptomatic
  • Recurrent infection: Reinfection or reactivation of CMV in seropositive patients
  • CMV infection: Presence of CMV in body fluids (urine, blood) or tissue
  • CMV disease: CMV infection with associated non-specific signs and symptoms and/or end-organ involvement

Pathophysiology

Once CMV is transmitted, and the primary infection clears, the virus remains dormant in myeloid cells. Vital replication and reactivation are contained primarily by cytotoxic T-cell immunity. However, when reactivation occurs, virions are released into the bloodstream and other body fluids, leading to the presence of symptoms, predominantly in immunocompromised patients.[6][7]

Histopathology

CMV replicates within endothelial cells at a slow rate. Like other herpesviruses, CMV expresses genes in a temporally controlled manner.

  • Early genes within 0 to 4 hours after infection are involved in the regulation of transcription.
  • Early genes within 4 to 48 hours after infection are involved in viral DNA replication and further transcriptional regulation.
  • Late genes are expressed during the rest of infection up to viral egress and code for structural proteins.
  • While CMV encodes for functional DNA polymerase, the virus makes use of the host RNA polymerase for the transcription of its genes.

Synthesis of the viral double-stranded DNA genome occurs in the host cell nucleus within specialized viral replication compartments.

History and Physical

Primary CMV infection usually has an asymptomatic or subclinical course. Mononucleosis is the most prevalent presentation of CMV in patients with an intact immune system, characterized by fever, rash, and leukocytosis.

In the typical presentation of Epstein-Barr Virus (EBV) mononucleosis, the principal causal organisms include pharyngeal exudate and presence of heterophile antibodies, characteristics which are frequently absent in CMV mononucleosis.

Other manifestations include anemia, abnormal liver function tests, thrombocytopenia, positive rheumatoid factor, and positive antinuclear antibody levels. Organ involvement is uncommon in immunocompetent hosts.

However, CMV is an important opportunistic pathogen in patients with a suppressed immune system, for example, from HIV, solid organ transplant, and bone marrow transplant. This can present with specific organ diseases, such as hepatitis, pneumonitis, and colitis.

In patients with a depressed immune system, CMV is more aggressive. Specific disease entities include:

  • CMV hepatitis which may lead to fulminant liver failure
  • Cytomegalovirus retinitis characterized by a “pizza pie appearance” on ophthalmic exam
  • CMV esophagitis
  • Cytomegalovirus colitis
  • CMV pneumonitis
  • Polyradiculopathy
  • Transverse myelitis
  • Subacute encephalitis

Evaluation

A definitive diagnosis is rarely required in immunocompetent patients. The diagnosis of CMV cannot be made solely based on clinical examination.

Laboratory viral identification is the preferred initial test in patients who have suspected CMV infection. Although a histopathological diagnosis is a gold standard for diagnosis (by identification of CMV inclusion bodies), quantitative PCR assays are the preferred method for viral detection.

In immunocompromised patients, the viral load can be undetectable in some cases.

For this reason, a negative PCR does not exclude CMV infection. Serological testing provides essential information regarding serostatus before organ transplantation for risk-stratification of CMV infection. However, it is not recommended for diagnosis of acute infection.[8][9]

Although the risks are low, CMV assays are part of the standard screening for non-directed blood donation in many countries. CMV-negative donations are earmarked for transfusion to infants or immunocompromised patients. Some blood donation centers maintain donor lists whose blood is CMV negative for special cases.

Testing for CMV resistance is now common in transplant centers. Resistance to ganciclovir has been noted in many transplant patients and makes treatment difficult. Resistance to CMV should be suspected in any transplant patient who fails to respond to therapeutic doses of ganciclovir or is rapidly declining in health.

Treatment / Management

Several antiviral agents have been approved for the treatment of CMV (cidofovir, foscarnet, ganciclovir, valganciclovir).[1][2][5]

  • Immunocompetent patients present with minimal or no symptoms and are self-limited and do not require specific therapy other than symptomatic management. However, antiviral therapy should be considered in severe cases of CMV mononucleosis, CMV infection and CMV disease in immunocompromised patients.
  • The use of antiviral therapy is not without risk. Toxicity is common with the use of these agents and must be weighed against the benefits of initiating treatment.

Patients without CMV infection who receive organ transplants from CMV-infected donors should receive prophylactic treatment with valganciclovir or ganciclovir, and regular serological monitoring; if treated, early establishment of a potentially life-threatening infection can be avoided.

Differential Diagnosis

  • HIV
  • Human Herpesvirus 6 infection
  • Viral hepatitis
  • Epstein Barr virus
  • Infectious mononucleosis

Prognosis

The prognosis for most patients with CMV is good as long as they do not have a state of immunosuppression. Recovery is usually complete with treatment. However, fatigue may persist for several months.

CMV pneumonia in marrow transplant patients can carry a high mortality if the treatment is delayed.


More information:Nature Communications (2019). DOI: 10.1038/s41467-019-10865-y

Journal information: Nature Communications
Provided by University of Maryland

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