IHMF: The increasing importance of Cytomegalovirus Epstein Barr Virus and the Human Herpesvirus
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  The increasing importance of cytomegalovirus, Epstein-Barr virus and the human herpesviruses types 6, 7 and 8 View Monograph Download Monograph


Background Information
Herpesviruses – a continuing challenge

This monograph was written to summarize the discussions held at the 7th IHMF Workshop in 1995. During the past 6 years, knowledge of these viruses has increased and the aim of this brief update is to highlight some of the new developments.

 
Implications for transmission of cytomegalovirus

A few years ago, myeloid lineage cells were defined as a latent source of Cytomegalovirus (CMV), since the virus could be reactivated from latency in vitro in differentiated macrophages obtained from healthy donors.1 Reactivation was shown to be dependent on cellular differentiation and the production of inflammatory cytokines produced by allogeneically stimulated T cells.2 This finding has important clinical applications, since the immune-mediated process which involves the activation of T cells and the production of these cytokines may facilitate reactivation. In support of this hypothesis, activation of CMV in vivo frequently occurs following allogeneic organ and bone marrow transplantation as well as after bacterial infections.3 However, CMV has also been implicated as a triggering agent for the development of acute rejection, and prophylactics against the virus with valaciclovir may decrease the risk of acute rejection following transplantation.4

 
CMV pathogenesis back to top

The continuous work of defining in vivo relevant cell types for CMV has provided an increased knowledge of possible sources of virus. Dendritic cells have been shown to be fully permissive for virus infection,5 and endothelial cells have been suggested to be persistently infected with the virus.6 These findings suggest that virus infection of endothelial vessels may support shedding of virus for long periods of time. CMV has also been demonstrated in placenta trophoblasts,7 and primary virus infection during the first trimester of pregnancy has been implied to play a role in spontaneous abortions. Furthermore, congenital CMV infection remains the most important clinical infection among infants. New data also suggest that CMV infection in the fetus is an important cause of hearing loss,8 and that CMV infection is more frequently transmitted from seropositive mothers than previously thought. A new diagnostic tool has been developed in Italy, the CMV avidity test,9 which can be used for screening pregnant women. Clinical trials will determine the safety of therapy of CMV-infected pregnant women.

For many years, CMV has been suggested to be associated with suppressed immunological functions. Initially, this immunosuppressive state was observed in patients with acute CMV infection, who seemed to be more susceptible to other infections. This observation was initially supported by studies of the virus in mice that confirmed suppression of T and B cell functions in animals infected with murine CMV,10–12 and later by in vitro studies of human CMV.13–16 The CMV induced mechanisms of immunosuppression are still unclear today. Instead, multiple studies have focused interest on the specific mechanisms CMV has developed to avoid immune recognition by its host’s immune system.17 Such mechanisms include viral proteins that protect infected cells from recognition by T cells, NK cells as well as antibody/complement reactions, and that interfere with cytokine and chemokine production by infected cells. However, the role of these mechanisms in immunosuppression of CMV-infected patients is still unknown.

Another topic causing much interest today is that of herpesviruses as indirect aetiological agents for other diseases. CMV is considered a risk factor in the development of vascular diseases, and the CMV chemokine receptor homologue US28 has recently been shown to induce smooth-muscle cell migration,18 which is a hallmark in vasculopathies. In addition, the virus has an ability to affect cellular functions and has been linked to increased lipid uptake, oxidative stress and immune-mediated processes important for vascular disease development. Thus, the virus may play an important role in accelerating the development of atherosclerosis, transplant vascular sclerosis and restenosis, and illustrates that a herpesvirus carried by the host for a long period of time may turn out to be linked to one of the greatest health problems in the western world. This finding opens up new insights and invites future studies that may result in the development of new and novel strategies for prevention of vascular diseases. Most likely, CMV will also be linked to other medical conditions in the future.

 
Prevention, Treatment, and Vaccination against CMV back to top

Transfusion-associated transmission of CMV is today mainly avoided by leukocyte filtration of blood products, since a randomized trial19 showed a comparable transmission rate to seronegative blood products. However, whether recipients of bone marrow transplants and infants should receive filtered blood products remains controversial. CMV has been found in leukocytes from seronegative donors, and the possible use of PCR analysis to screen seronegative blood donors has been discussed.20 CMV seropositive bone marrow transplant patients have approximately a 75% risk of CMV reactivation, and without preventative action, 20–30% develop disease. The prognosis of treatment for established CMV disease is still not satisfactory. Thus, development of disease should be avoided by prophylaxis or pre-emptive therapy, which can reduce the risk by 50–90%. The gold-standard treatment for established CMV disease is still ganciclovir, which prevents CMV disease but does not seem to increase survival rates. This drug and valaciclovir4 may be used for prophylaxis in high-risk patients, and both foscarnet and ganciclovir can be used for pre-emptive therapy. Furthermore, the new drug cidofovir may turn out to be effective as second-line pre-emptive therapy after failure with other drugs,21 but needs to be further evaluated due to significant renal toxicity. The status of vaccine development is still not encouraging, but subunit vaccines targeting CMV mainly gB and attenuated towne strains are currently under investigation.

 
Epstein–Barr virus back to top

The number of tumours now linked to EBV is unexpectedly large, but the consistent finding of EBV in tissues from these malignancies are impressive and makes the involvement of EBV in etiology correspondingly strong. EBV has been associated with a variety of malignancies including B, T and NK cell lymphomas, Hodgkin’s disease (HD), nasopharyngeal and gastric carcinomas, and smooth-muscle tumours such as leiomyosarcoma.22-24 Some of these malignancies occur with increased frequency in immunocompromised patients (especially in patients with suppressed T-cell functions), while others have no apparent association with immune dysfunction. Patients receiving immunosuppressive therapy after solid organ or hematopoietic stem-cell transplantation are considered at risk for the development of EBV-associated lymphoproliferative disorders (EBV-LPDs). In patients with HIV infection, primary central nervous system (CNS) and immunoblastic lymphomas show similarities with post-transplant lymphoproliferative disease. EBV-LPDs affect bone marrow transplant patients and some solid-organ transplant patients with an incidence of up to 1% and 10%, respectively. Previous therapeutic approaches against this disease have been unsuccessful, but the use of adoptive T-cell therapy has shown encouraging results in the reduction of tumor mass; the method is not widely available, however.25 Furthermore, the recent demonstration of a crucial role for NK cells in cytokine-based therapy for EBV-LPDs has given new hope that may lead to more effective treatment for immunocompromised patients suffering from EBV-driven lymphomas. EBV-specific T-cell infusions have also been used as prophylaxis25 and can lower the EBV load.26

 
Human herpesvirus type 6 back to top


HHV-6 has now been shown to infect CD8+ and gamma-delta T cells, NK cells, epithelial cells, endothelial cells, fibroblasts, and a number of neuronal cells (as reviewed in 27. The receptor for both HHV-6A and 6B infections is CD46,28 which also serves as a receptor for the measles virus, and is involved in regulating the complement cascade. The salivary gland seems to support a chronic infectious site, and monocytes and bone marrow progenitor cells have been suggested as candidates for latency.29,30 Infections have an excellent prognosis and are, in addition to febrile illness and exanthema subitum, also associated with diarrhoea, respiratory tract symptoms, arthralgias, arthritis, hepatitis and encephalopathy.31 In transplant patients, infection has been associated both with bone marrow suppression,32 and with graft rejection in liver transplant patients.33 In addition, HHV-6 is associated with CMV disease in transplant patients, has been suggested to exacerbate CMV infection,34 and to serve as a co-factor in the development of AIDS.35 In vitro studies of HHV-6 suggest that both ganciclovir and foscarnet can be effective against HHV-6, but the effectiveness of these drugs for prophylaxis is at present unknown.

The association of HHV-6 with multiple sclerosis (the relapsing–remitting form in particular), especially the HHV-6A strain which has greater neurotropism,36 is still interesting in this setting. However, this association remains controversial at this stage. Furthermore, the oncogenic role of HHV-6 suggested for cancers such as Hodgkin’s disease, and non-Hodgkin’s lymphoma, the Rosai-Dorfman disease, and cervical carcinomas needs to be further characterized.

 
Human herpesvirus type 7 back to top

Today, diagnosis of HHV-7 infection is made on the basis of detection of viral antigen, DNA and HHV-7 specific antibodies are used in the context of clinical symptoms. Due to the cross-reactivity to other viruses (especially HHV-6), there is still a need for the development of standardized routine assays for HHV-7. HHV-7 has now been associated not only with exanthema subitum, but also with neurological manifestations such as hemiplegia, seizures, epilepsy, encephalitis, and febrile convulsions, hepatitis, pityriasis rosea and transplant complications37 (and as reviewed in38). However, reports describing primary infections, which also include leukopenia, diarrhoea, mild lymphoadenopathy and sore throat are rare. Most interestingly, HHV-7 has been isolated from 100% of peripheral blood lymphocyte (PBL) samples obtained from patients with active pityrisasis rosea, but not from control patients.39 In transplant patients, HHV-7 reactivation seems to precede the development of symptomatic CMV disease, and has therefore been implied in exacerbation of disease. Due to the undefined circumstances that warrant specific treatment for HHV-7, no specific drug of choice is recommended today. In vitro, HHV-7 has been shown to be insensitive to the thymidine kinase-dependent drug aciclovir, but is sensitive to cidofovir.40 HHV-7 is less sensitive to ganciclovir than either CMV or HHV-6, but the DNA polymerase inhibitor phosphonophormic acid seems to be effective both in vitro and in vivo.41 However, further in vivo studies are required to evaluate these drugs in the clinical situation.

 
Cellular tropism of HHV-7 and implications for HIV back to top

HHV-7 was initially thought to have a strict cell tropism, but the virus has been detected in paraffin embedded lung, skin, mammary gland, tonsil, liver, kidney and ileum tissues, and not in tissue samples from the large intestine, brain and spleen.42 Most commonly, the virus infects and establishes latency in T cells but can also persistently infect salivary glands.43 HHV-7 is shed in the saliva of 75–96% of adults, which is the most likely route of transmission (as reviewed in 38). The virus has also been detected in the cellular fraction of breast milk of nursing mothers, which implies a new route of transmission.44 Since the CD4 molecule serves as a receptor for both HIV and HHV-7,45 the possible interactions of these viruses in the development of AIDS is currently under further investigation. Interestingly, HHV-7 infection of CD4 positive macrophages has been shown to reduce the average level of HIV infection by 91%46, and a reciprocal interference between HHV-7 and HIV has been observed in peripheral blood lymphocytes (PBLs).47

 
Human herpesvirus type 8 back to top

Since characteristic clinical symptoms of a primary HHV-8 infection have not yet been reported, many studies still focus on the role of HHV-8 in Kaposi´s sarcoma (KS). HHV-8 does possess the machinery expected for a tumor virus and may indeed cause KS lesions, but can also appear as a consequence rather than a cause of the disease. The seroprevalence of HHV-8 is 0–10% in the USA, is a little higher in the Mediterranean countries, and reaches 50% in some African populations (as reviewed in48). Women are less commonly infected than men, and infection in children is extremely rare. HHV-8 has been detected in 40% of homosexual men, which is dramatically higher than in the general population.49 Sexual transmission appears to be the most common route of transmission, and HHV-8 is shed in semen. In contrast, transmission via blood products seems to be uncommon. The virus can also be found in saliva of seropositive individuals, but whether the virus is transmitted orally is currently not clear. In the clinical transplant setting, both HHV-8 infection and KS may occur (0.1–1%) as a complication50 and the virus has been associated with bone marrow failure. The immune status of the infected individual seems to be important to control the infection, since 68% of HHV-8 infected individuals were slow to develop tumours.51

 
References back to top

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Cecilia Soderberg-Naucler
Karolinski Institute
14186 Huddinge
Sweden

 

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