Donald R. Carrigan

Adenovirus Infections in Immunocompromised Patients

Adenovirus infections have been reported in as many as one-fifth of bone marrow transplant (BMT) recipients and patients with acquired immunodeficiency syndrome (AIDS), and in a lesser, though still prominent, proportion of organ transplant recipients. The relative contributions of primary infections versus reactivations from latency in immunocompromised patients remain unclear. Compared with adult BMT recipients, pediatric BMT recipients appear to be infected by adenovirus more frequently and earlier in the post-transplant period. The diagnosis of adenovirus infection is complicated by the existence of > 40 viral serotypes, although certain subgroups are more likely to be involved in certain patient populations. Adenoviruses are responsible for a broad range of clinical diseases that may be associated with high mortality, including pneumonia, hepatitis, encephalitis, hemorrhagic cystitis, and gastroenteritis. The clinical and histopathologic features of adenovirus disease may resemble those of cytomegalovirus disease, potentially complicating the diagnosis. Risk factors for clinical adenovirus disease include the number of sites from which the virus is cultured and, in BMT recipients, the presence of moderate to severe acute graft-versus-host disease.

IMMUNOPATHOLOGY AND VIRAL REACTIVATION : A GENERAL THEORY OF SCHIZOPHRENIA

A theory is proposed that explains a broad range of clinical manifestations in schizophrenia. It is a heuristic device for organizing research in the neuroimmunology and virology of schizophrenia. This approach is different from other immune and viral theories of schizophrenia and defines testable hypotheses for further theory refinement or rejection. Defective alpha-interferon (alFN) regulation resulting in excessive effect is postulated to cause schizophrenia. The role of alFN in the regulation of development and its induction within the brain by the reactivation of viruses that are commonly present in the normal central nervous system (CNS) are the primary pathophysiological mechanisms. Biological properties of alFN include neural excitation, opiate and adrenocorticotropic hormone activity, and inhibition of cellular proliferation and differentiation. Psychosis results from in situ viral stimulation of alFN production in the CNS of a vulnerable host having defective regulation of either sensitivity or production. Negative symptoms result from alFN effects on CNS development and the behavioral toxicity of alFN. Biological developmental abnormalities, gender differences in severity, and decline in psychotic symptoms with age are discussed in the context of the theory. Research strategies and specific testable hypotheses are presented.

Human herpesvirus 6 (HHV-6)-associated dysfunction of blood monocytes

HHV-6 is a recently described member of the herpesvirus family. HHV-6-associated marrow failure and interstitial pneumonitis where macrophages are the primary infected cell type have been described in marrow transplant patients (Carrigan, 1991; Drobyski et al., 1993). In recent studies we have shown that exposure of normal human marrow to HHV-6GS (a type A strain) or several type B strains resulted in suppression of growth factor induced outgrowth of macrophages by > 90% (Burd and Carrigan, 1993). Additional experiments using HHV-6GS to characterize the effects of the virus on peripheral blood monocytes showed that the respiratory burst capacity of these cells as determined by luminol-enhanced chemiluminescence using phorbol myristate acetate as a trigger was decreased by 83% +/- 13% in a series of 5 experiments. The decreased respiratory burst was evident as early as 15 min after exposure to virus. Experiments in which cells were separated on a fluorescence activated cell sorter prior to respiratory burst assay showed that the response was mediated solely by peripheral blood monocytes. The respiratory burst response of virus-exposed cells to opsonized zymosan was not affected, indicating that the virus may selectively interfere with the protein kinase C pathway of cellular activation. Ultracentrifugation of stock material to remove infectious virus showed that the suppressive factor was associated with the supernatant fraction. These findings suggest that HHV-6 infection may be associated with a defect in one of the major monocyte activation pathways, and this could be of importance with respect to persistent infection by HHV-6 in immune compromised patients.

Chapter 21 Human herpesvirus-6 and bone marrow transplantation

Publisher Summary Marrow transplantation is being increasingly used for the treatment of a variety of diseases, including aplastic anemia, leukemia, and breast cancer. This chapter discusses a series of studies concerning the role of HHV-6 as a pathogen in marrow transplant patients. Human herpesvirus-6 (HHV-6) is a cause of severe interstitial pneumonitis, either directly, or in concert with other respiratory pathogens, in marrow transplants patients. In addition, a series of clinical and experimental observations have implicated HHV-6 marrow infection as an important cause of poor graft function in marrow transplant recipients. Serological and virological evaluation of marrow transplant patients has shown that HHV-6 reactivations are common in seropositive patients after marrow transplantation. Post-transplant HHV-6 primary infections occur and these infections frequently have peripheral and CNS clinical manifestations. This chapter also discusses that HHV-6 is an important pathogen in marrow transplant patients, and the two most common serious clinical manifestations of HHV-6 infection appear to be interstitial pneumonitis and poor marrow function.

A Virus-Associated Immunopathological Theory of Schizophrenia

Schizophrenia is a clinical syndrome which is increasingly considered to be a neurological disease with behavioral symptoms that primarily manifest as dysfunction of frontal and limbic brain areas. Hypotheses of the etiology or etiologies of schizophrenia have tended to be limited to intrinsic central nervous system (CNS) processes, such as neurotransmitter dysregulation or neuroanatomical models. These models have a correspondingly limited predictive validity. An alternate and potentially more useful perspective of the disease would be one that takes into account its pleomorphic nature. Schizophrenia has a broad spectrum of associated findings suggesting involvement of developmental processes and a pathophysiology that may be systemic in nature. Viral hypotheses have been one way that the issue of pleomorphism has been addressed.

Human herpesvirus-6-associated malignant lymphoma in a bone marrow transplant recipient

BACKGROUNDnHuman herpesvirus-6 (HHV-6), the sixth member of the herpesvirus family, can infect and replicate in human hematopoetic cell lines and can cause various illnesses in humans. HHV-6 has been suggested to be linked to various lymhoproliferative disorders. In vitro studies have demonstrated the oncogenic potential of HHV-6. The role of HHV-6 in human lymphomas needs to be examined.nnnOBJECTIVEnTo determine the involvement of HHV-6 in an immunoblastic lymphoma which developed in a bone marrow transplant patient, who had HHV-6 viremia.nnnSTUDY DESIGNnParaffin-embedded lymphoma tissues were examined for the presence of HHV-6 by immunohistochemistry, PCR and in-situ hybridization. This is a case report investigation.nnnRESULTSnAn acute myelogenous leukemia patient received an allogeneic bone marrow transplant. He developed human herpesvirus-6 (HHV-6) viremia approximately 6 weeks after transplantation and HHV-6 was concurrently isolated from his bone marrow. Soon afterward, a large cell immunoblastic lymphoma was diagnosed. Complications of this tumor subsequently resulted in the patients death. Periaortic lymph nodes and tumor cells infiltrating the liver and kidneys showed the presence of HHV-6 by immunohistochemistry and polymerase chain reaction (PCR). Southern blot analysis of the PCR amplified DNAs confirmed the presence of transforming pZVH14 DNA sequences of HHV-6 in the tumor tissues. Lymph nodes of 6 immunologically intact individuals were negative for HHV-6 by immunohistochemistry and PCR analysis. Tumor tissues were negative for EBV DNA by in situ hybridization with DNA probes specific for the EBV EBER RNAs.nnnCONCLUSIONnOur data suggest that HHV-6 may be involved in the pathogenesis of some immunoblastic lymphomas.

Pathogenicity of Human Herpesvirus-6

Human herpesvirus-6 (HHV-6) is a recently discovered lymphotropic virus. Serologic evidence indicates a high incidence of HHV-6 antibody in almost all areas of the world, and most children are infected by 2 years of age. HHV-6 can productively infect CD4+ lymphocytes, but CD4 does not appear to be used by the virus as its primary receptor. The virus can also infect monocytes, macro-phages, epithelial cells, and cells of other lineages. Virus transmission probably occurs horizontally, as the virus is secreted in the saliva of healthy individuals, and is unlikely to be transmitted through the placenta. HHV-6 has been identified as the etiologic agent of exanthem subitum. It can cause interstitial pneumonitis in bone marrow transplant patients, in whom it is associated with suppression of bone marrow function. HHV-6 can also cause infectious mononucleosis, lymphadenitis, liver dysfunction, and is associated with various lymphoprolifera-tive disorders and the chronic fatigue syndrome. It has been proposed that the virus plays a role in the pathogenesis of AIDS. HHV-6 is suggested to be an oncogenic virus because of its lymphoproliferative linkage and because HHV-6 DNA can transform murine fibroblast and human epidermal keratinocyte cell lines. These transformed cells are tumorigenic in nude mice. Primary HHV-6 infection may establish latent infection in monocytes or macrophages, and the virus can be reactivated from a latent state in immunocompromised patients and in individuals with various malignant and nonmalignant diseases.