Epstein-Barr virus-recent advances

Epstein-Barr virus is a tumorigenic herpes virus that is ubiquitous in the adult population. The virus is generally spread to and between young children through salivary contact, and only causes clinical illness where primary infection is delayed until adolescence or beyond, when an intense immunopathological reaction leads to the symptoms of infectious mononucleosis in roughly 50% of cases. More than 90% of the world's population carry Epstein-Barr virus as a life-long, latent infection of B lymphocytes. Recent data show that by mimicking B-cell antigen-activation pathways the virus enters the long-lived memory B lymphocyte pool where it evades immune elimination by severely restricting its own gene expression. By influencing B-cell survival mechanisms Epstein-Barr virus may induce tumours such as B lymphoproliferative disease and Hodgkin's disease. Vaccines are being developed to prevent and/or treat these conditions, but an animal model is required to study pathogenesis before a rational vaccine strategy can be formulated.     

Epidemiology of cytomegalovirus infection after transplantation and immunosuppression.

Viral infections and clinical complications were studied during hemodialysis and after renal transplantation. Active cytomegalovirus infection developed in 96% of patients after renal transplantation; reactivation of herpes simplex, varicella-zoster, and Epstein-Barr viruses was found in 35%, 24%, and 0% of patients, respectively. Cytomegalovirus viremia developed in 42% of patients an average of two months after renal transplantation, lasted 1.75 (+/- 1.5) months (except in one patient with chronic viremia), and was followed by chronic viruria. Higher titers of infectious cytomegalovirus were found in the polymorphonuclear than in the mononuclear leukocyte fraction. Reactivation of a latent infection and, less likely, respiratory infection appear to be the most probable mechanisms of cytomegalovirus infection after renal transplantation. One to three months after transplant, cytomegalovirus infection may be related to fever, arthralgia, pneumonitis, and leukopenia; three to four months after transplant, the virus may be related to hepatitis; and 12-30 months after transplant, it may be related to retinitis in patients with chronic viremia. Although other causes of these complications are possible, herpes simplex virus, Epstein-Barr virus, varicella-zoster virus, measles virus, adenovirus, hepatitis B virus, and Toxoplasma gondii appear to be of lesser importance than cytomegalovirus in this respect.     

Herpes simplex virus infections of women and their offspring: implications for a developed society.

Herpes simplex virus infections of humans have been known since ancient times. Contemporary society has witnessed a series of devastating manifestations of herpes simplex virus infections--namely, genital herpes simplex virus infection and neonatal herpes simplex virus infection. With the evolution of society, particularly advances in birth control and increasing promiscuity, the seroprevalence of herpes simplex virus type 2 infections has increased worldwide, however, more so in developed societies. As a consequence, individuals of child-bearing age are at risk for either reactivation of herpes simplex virus at termination of gestation or acquisition of a new primary infection at that time. The consequences of vertical transmission of herpes simplex virus from mother to child, resulting in neonatal herpes simplex virus infection, can be devastating. Current efforts, which are directed toward the treatment of neonatal herpes, have established the value of drugs such as vidarabine and acyclovir. However, the real emphasis for future programs is the prevention of herpes simplex virus infections to avoid person-to-person transmission either horizontally or vertically. The development of vaccines directed against herpes simplex virus may be of value toward this end.     

Latent infection and the elusive cytomegalovirus

Herpesviruses characteristically establish latent infections in their hosts. In some instances, the tissue sites or even the specific cells that harbor dormant virus have been identified experimentally. However, the sites of cytomegalovirus (CMV) latency have been difficult to define experimentally in humans, even though epidemiologic evidence indicates that undetectable virus can be transferred from donor to recipient in transfused blood or a transplanted organ. Recently, DNA of human CMV has been found in peripheral blood leukocytes and in normal or malignant colonic tissue by hybridization methods. Studies in mice strongly implicate splenic B lymphocytes as cellular reservoirs of latent CMV; however, the virus may also persist in the salivary glands, the prostate, the testes, peripheral blood, and possibly macrophages. Whether latent CMV infection in these tissues is maintained in a single ubiquitous cell type (e.g., lymphocytes or macrophages) or in various cell types is not known. Definition of the sites and mechanisms involved in the maintenance of latent CMV is essential for a thorough understanding of the pathogenesis of CMV infection. Now that trials with live CMV vaccine have begun, further investigations of latent CMV infection in humans and in animal models are clearly needed.     

A randomized double-blind placebo controlled trial of oral acyclovir in renal allograft recipients

Fifty renal transplant patients were randomized to receive either 800 mg acyclovir by mouth four times daily or identical placebo tablets for prophylaxis of herpes simplex infection. Patients were followed weekly to assess reactivation of herpes simplex, varicella zoster virus, Epstein-Barr virus or cytomegalovirus (CMV) infections. The patients received standard immunosuppressive regimens including cyclosporine A. Acyclovir suppressed secretion of herpes simplex virus in treated patients (P=0.001). Three episodes of mucocutaneous herpes simplex virus occurred in placebo recipients and one in a noncompliant acyclovir recipient. A clinically important difference in graft survival was demonstrated, but because of sample size failed to reach statistical significance (P=0.11). No reactivation of varicella zoster virus, Epstein-Barr virus or CMV infection was detected in either group. Toxicity was limited to central nervous irritability. The authors conclude that high dose oral acyclovir provides effective prophylaxis for prevention of herpes simplex virus infections in renal transplantation and may be associated with increased graft survival, perhaps from suppression of CMV infection.     

Correlation of pretransplant viral serology and complications of bone marrow transplantation

Latent herpes viruses such as herpes simplex virus, cytomegalovirus (CMV), and varicella zoster virus are often reactivated after bone marrow transplantation, giving rise to infections. In contrast, Epstein-Barr virus infections rarely occur. Significant mortality is induced especially by pneumonitis, most often caused by CMV. Immunosuppression and pancytopenia caused by CMV increase the risk of bacterial infections and invasive fungal infections. Herpes viruses may increase the risk of acute and chronic graft-versus-host disease (GVHD). Thus, immunity to several herpes viruses was associated with an increased risk of acute GVHD. Seropositivity for CMV in recipient and donor increased the risk of chronic GVHD. Herpes viruses were also associated with a decreased risk of leukemic relapse. CMV infection, asymptomatic CMV infection, and seropositivity for several herpes viruses were associated with a reduced incidence of relapse in different reports. In spite of this possible antileukemic effect, leukemia-free survival was unaffected by herpes virus immunity in recipients or donors.This study was supported by grants from the Children's Cancer Foundation (8403), the Swedish Medical Research Council (16X-05971), and the Swedish Cancer Foundation (0770-B91-04XAC).     

Immunization against genital herpes with a vaccine virus that has defects in productive and latent infection

An effective vaccine for genital herpes has been difficult to achieve because of the limited efficacy of subunit vaccines and the safety concerns about live viruses. As an alternative approach, mutant herpes simplex virus strains that are replication-defective can induce protective immunity. To increase the level of safety and to prove that replication was not needed for immunization, we constructed a mutant herpes simplex virus 2 strain containing two deletion mutations, each of which eliminated viral replication. The double-mutant virus induces protective immunity that can reduce acute viral shedding and latent infection in a mouse genital model, but importantly, the double-mutant virus shows a phenotypic defect in latent infection. This herpes vaccine strain, which is immunogenic but has defects in both productive and latent infection, provides a paradigm for the design of vaccines and vaccine vectors for other sexually transmitted diseases, such as AIDS.     

Generation of specific cytotoxic T cells with a fragment of the Epstein-Barr virus-encoded p63/latent membrane protein.

Human B lymphocytes, transformed by the herpesvirus Epstein-Barr virus, are known to express a characteristic antigen(s) recognized by the cellular immune response. This structure has been termed lymphocyte-determined membrane antigen. Because of the significance of this structure in controlling Epstein-Barr virus infection in vivo, the molecular nature of lymphocyte-determined membrane antigen has been long sought. In this paper, we show that a sequence of 10 amino acids (residues 43-53) from the Epstein-Barr virus-encoded membrane protein p63/latent membrane protein can induce Epstein-Barr virus-specific cytotoxic T cells and, therefore, bears at least one of the lymphocyte-determined membrane antigenic determinants.     

Activation of latent murine cytomegalovirus in vivo and in vitro: a pathogenetic role for acute infection

Many cytomegalovirus (CMV) infections result from activation of virus previously latent in the host. Murine models of latent CMV infection have been developed in which latent virus can be activated in vivo by immunosuppression or by coculture of splenic lymphocytes in vitro. In the present study, latent murine CMV (MCMV) could be activated from lymphocytes of mice regardless of genetic strain, age at time of virus inoculation, or use of syngeneic or allogeneic fibroblasts for coculture. After intraperitoneal inoculation, virulent virus was activated from lymphocytes more often than attenuated MCMV (69% vs. 20% of lymphocyte cocultures were positive, respectively). Latent MCMV was not detected in lymphocytes after subcutaneous inoculation of weanling mice but could be activated from mice infected subcutaneously as newborns. The absence of latent infection in the lymphocytes of the mice that had been inoculated as weanlings was due to lack of virus replication in the spleen during acute infection.     

Facial herpes zoster complicated by varicella zoster virus (VZV) encephalitis: The diagnostic significance of atypical lymphocytes in cerebrospinal fluid (CSF)

Background

In general, viral infections of the central nervous system (CNS) manifest as encephalitis and, less commonly, as meningoencephalitis or aseptic meningitis. Varicella zoster virus (VZV) is an uncommon cause of encephalitis.

Methods

Herpes zoster (shingles) is a cutaneous reactivation of previous chickenpox infection due to VZV. Herpes zoster may be dermatomal (ie, <3 dermatomes) or disseminated (ie, >3 dermatomes). Decreased cell-mediated immunity from stress, steroids, or immunosuppressive drugs often precede dermatomal/disseminated herpes zoster. With herpes zoster, the closer the dermatomal involvement is to the CNS (ie, head/neck shingles), the more likely a patient will have symptomatic CNS involvement (eg, encephalitis). Except for the association of the herpes zoster rash and the simultaneous/subsequent encephalitis, there are few clinical features that distinguish VZV encephalitis from that due to other viruses. The cerebrospinal fluid (CSF) profile of VZV encephalitis is usually clinically indistinguishable from that due to of other causes of viral encephalitis. In VZV meningoencephalitis or encephalitis, the CSF typically shows a modest lymphocytic pleocytosis with normal CSF glucose levels, variably elevated CSF protein levels, and normal CSF lactic acid levels. Atypical lymphocytes are rare in the CSF with VZV encephalitis.

Results

We present the case of a 75-year-old woman who developed VZV encephalitis after having herpes zoster on her forehead. Except for facial herpes zoster, there were no clinically distinguishing features to determine the cause of her encephalitis. Her CSF had 800 white blood cells/high power field with 26% lymphocytes (17% atypical lymphocytes). The patient’s CSF glucose and CSF lactate dehydrogenase levels were normal, and her CSF protein was elevated. The CSF lactic acid was minimally elevated secondary to red blood cells in the CSF. Electroencephalogram showed general background slowing bilaterally, typical of viral encephalitis. The absence of unilateral focal frontotemporal/parietal lobe focus on electroencephalogram argued against the diagnosis of herpes simplex encephalitis. CSF atypical lymphocytes provided the key clue to the etiology of her encephalitis. CSF atypical lymphocytes are not uncommon in Epstein-Barr virus or cytomegalovirus encephalitis. Less commonly, atypical lymphocytes may be present in the CSF with enteroviruses, West Nile encephalitis, and Japanese encephalitis. VZV is a rare cause of atypical lymphocytes in the CSF but was the clue to the diagnosis before CSF polymerase chain reaction results for VZV were available. Her CSF polymerase chain reaction was negative for Mycobacterium tuberculosis, herpes simplex virus, human herpesvirus-6, cytomegalovirus, enteroviruses, and West Nile virus, but was positive for VZV. She made an uneventful recovery with acyclovir.

Conclusion

CSF atypical lymphocytes, if present, are an important diagnostic clue in some causes of viral encephalitis. The most common cause of nonseasonal viral encephalitis is herpes simplex virus, which is not associated with CSF atypical lymphocytes. Patients with Epstein-Barr virus, cytomegalovirus, West Nile encephalitis, and enteroviruses usually have extra-CNS signs and symptoms which should suggest the cause of the patient’s encephalitis. CSF atypical lymphocytes limit the differential diagnostic possibilities in patients with viral encephalitis and may be the key clue to the diagnosis, as in the case presented.     

Simultaneous infection with multiple herpesviruses.

Active dual infection with Epstein-Barr virus (EBV) and cytomegalovirus (CMV) was observed in four otherwise healthy persons with mononucleosis syndromes. A secondary serologic response to EBV occurred in three patients as determined by the presence of antibodies to EBV-induced nuclear antigen (EBNA) early in the illness. All four patients lacked heterophil antibodies; in the one case tested, immunoglobulin M (IgM) antibodies specific for EBV viral capsid antigen (VCA) were absent as well. The Guillain-Barré syndrome occurred in one patient, who also had active infection with herpes simplex virus 1 (HSV-1). In a fifth patient, herpes zoster developed complicating heterophil-positive infectious mononucleosis due to primary infection with EBV.These five cases demonstrate that mononucleosis syndromes may occur in association with dual or multiple herpesvirus infections and that reactivation of EBV may be common during heterophil-negative mononucleosis. Reactivation of latent virus is most likely related to depressed cellular immunity due to a primary infection with another herpesvirus. An alternate hypothesis is that viral DNA polymerase induced by infection with one herpesvirus might simultaneously permit the productive replication of a second herpesvirus previously latent within the same cell. Thus, reactivation may result from molecular interactions between viruses at the cellular level.The possibility of multiple infections must be considered whenever determining the specific viral etiology of heterophil-negative mononucleosis.     

Viral pneumonia in recipients of solid organ transplants

Viral pulmonary infections are a major cause of morbidity and mortality in solid organ transplant recipients. The herpes viruses-cytomegalovirus, herpes simplex virus, varicella zoster virus, and Epstein-Barr virus--cause most of the viral infections in this population. Respiratory syncytial virus, adenovirus, and human immunodeficiency virus also cause pneumonitis in the transplant recipient. Differences in the clinical and laboratory presentation of pneumonitis due to the various viral agents can provide clues to the etiology. However, definitive diagnosis requires laboratory identification of the virus or appropriate serologic changes. With cytomegalovirus, herpes simplex virus, Epstein-Barr virus, and adenovirus, one must take care to distinguish between asymptomatic shedding of the virus and disease produced by the virus. Advances in diagnostic techniques such as rapid antigen detection, nucleic acid hybridization, and gene amplification may allow an earlier diagnosis of viral pneumonia. Advances in risk reduction with appropriate pairing of donors and recipients, improved immunosuppressive regimens, vaccination, and prophylactic administration of antiviral agents may reduce the incidence of viral infection. Finally, advances in anti-viral therapy have made possible the successful treatment of pneumonia due to some of the viral agents.     

Fatal disseminated adenovirus infection in a renal transplant recipient.

A 61 year old woman died of diffuse interstitial adenovirus pneumonia 55 days after receiving a cadaveric renal allograft. The adenovirus was serologically distinct from the 33 known human adenovirus serotypes and appears to represent a new human adenovirus. Pathologic and virological findings indicate that the pneumonia was only one manifestation of a disseminated infection, the source of which may have been a latent adenovirus infection preexisting in the donor kidney. The establishment of the etiologic diagnosis in this case, which was complicated by the presence of oculocutaneous and esophageal herpes simplex virus infection as well as focal pulmonary aspergillosis, required coordinated histopathologic and virological investigation. Our findings demonstrate that severe viral infections in transplant recipients are not caused exclusively by members of the herpesvirus group.     

Activation of latent Lyme borreliosis concurrent with a herpes simplex virus type 1 infection

The case is reported of a 26-y-old woman with latent Lyme borreliosis that was concurrently activated with a herpes simplex virus type 1 infection. Immune suppression by stress may have caused activation of both infections.     

HIV Infection and Clinical Spectrum of Associated Vasculitides

Various infections have been causative in the pathogenesis of systemic vasculitides, and HIV infection is not spared. In an immunocompromised host, cytomegalovirus, Epstein-Barr virus, varicella zoster virus, herpes simplex virus, hepatitis B and hepatitis C virus, and mycobacteria, along with HIV infection can cause vasculitis. Herein we emphasize the spectrum of vasculitides, their pathogenesis, presentation, course, and therapy in the HIV-infected population. Every spectrum and size of the blood vessel involvement have been seen in HIV-associated vasculitides. We review each spectrum in detail and describe our experience with polyarteritis nodosa, the most common presentation occurring in HIV-infected patients. We also discuss the differences in HIV, hepatitis B, and hepatitis C- related polyarteritis nodosa in detail.     

Epstein-Barr-virus-induced interstitial lung disease

PURPOSE OF REVIEW: We describe a patient in whom Epstein-Barr virus infection appears to have caused an unusual interstitial lung disease with multisystem involvement resembling sarcoidosis and interstitial lung disease. We have reviewed the relevant literature about the relation of Epstein-Barr virus and interstitial lung disease. RECENT FINDINGS: Epstein-Barr virus replication within type II alveolar cells was shown to occur in adult cryptogenic fibrosing alveolitis. Latent membrane protein 1 is one of the Epstein-Barr-virus-associated proteins and is expressed on the surface of Epstein-Barr-virus-infected cells in the latent and replicating phases. Latent membrane protein 1 was positive in the cuboidal epithelial cells of the lungs from some patients with idiopathic pulmonary fibrosis, and that its positivity correlated with poor prognosis. Epstein-Barr virus was also found in the lungs of children with lymphocytic interstitial pneumonia, AIDS and Langerhans cell histiocytosis. Epstein-Barr virus DNA was not detectable in patients with sarcoidosis. There was also lack of evidence for a role of Epstein-Barr virus in the increase of lung cancer in idiopathic pulmonary fibrosis. SUMMARY: Using monoclonal antibodies against viral antigen Epstein-Barr virus was shown to replicate within type II alveolar cells of adult idiopathic pulmonary fibrosis patients. Latent membrane protein 1positivity indicates poor prognosis; Epstein-Barr virus positivity did not increase the incidence of lung cancer in these patients. Epstein-Barr virus was also associated with lymphocytic interstitial pneumonia, AIDS and Langerhans cell histiocytosis but not with sarcoidosis.     

Therapeutic options for herpes simplex infections

Herpes simplex viruses are responsible for a number of disease states in infected individuals. Capable of establishing latent infection, herpes simplex can reactivate, causing pain, discomfort, and psychosocial consequences. Because no cure is available, treatment modalities for herpes simplex infection are required, from both personal and public health standpoints. To date, therapy has centered around the use of antiviral drugs to control infection and suppress recurrences. To expand the scope of available treatments, efforts have focused on the development of vaccines against herpes simplex virus and new agents such as immune response modifiers. Recent data suggest that these new agents are promising in their therapeutic potential.     

Herpesvirus infections of the central nervous system

In recent years, advances in the diagnosis and treatment of herpes simplex encephalitis (HSE) have been achieved due to the prevalence of antiviral drugs and the introduction of the polymerase chain reaction (PCR) to test the cerebrospinal fluid. The several clinical forms of herpes simplex virus type 1 (HSV-1) infections of the central nervous system (CNS), including acute disseminated encephalomyelitis and brainstem encephalitis, have been clarified. However, fatal, prolonged, or relapsed cases are still observed, and early detection and appropriate treatment is necessary to lead to a good prognosis for these intractable HSE cases. In adult HSV-2 infections, meningitis and myelitis associated with genital herpes are common. In the past, HSV-2 myelitis has been reported as a form of fatal necrotizing myelopathy; however, using PCR and magnetic resonance imaging studies, mild surviving cases are increasingly likely to be identified. Meanwhile, various CNS syndromes resulting from the herpes group viruses, including varicella-zoster virus and Epstein-Barr virus have also been reported. These herpesviruses have several characteristics in common, e.g., they exist in the latent state and they occur in both mucocutaneous and CNS infections. Adult HSV-1 and -2 infections of the CNS are discussed together with other herpes group virus infections of the CNS.