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      New Insights into the Viral Theory of Amyotrophic Lateral Sclerosis: Study on the Possible Role of Kaposi’s Sarcoma-Associated Virus/Human Herpesvirus 8

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          Abstract

          In the last few years, three new herpesviruses, HHV-6, -7 and -8, have been discovered, which share interesting biological characteristics for a possible role in the development of both neurological and lymphoproliferative diseases. In particular HHV-8, besides being strongly associated with Kaposi’s sarcoma, is related with several lymphoproliferative diseases. More recently, specific viral sequences belonging to HHV-8 have been detected in autoptic brain specimens from multiple sclerosis patients and controls, suggesting that, similarly to HHV-6, this novel herpesvirus is strongly neurotropic. HHV-8 is an unusual herpesvirus in that it is able to produce homologues of several human gene products, resulting in alterations in cell cycle, in apoptosis and cell-mediated immune responses. To verify a possible relationship between HHV-8 and the development of amyotrophic lateral sclerosis (ALS), we investigated the presence of signs of HHV-8 infection, by both nested polymerase chain reaction (nPCR) and indirect immune fluorescence analysis in ALS patients. Both PCR and serological data did not suggest a clear role of this virus in originating ALS. Nevertheless, new insights into the mechanisms by which viruses may interact with the host cell genome and with the human immune system make the viral hypothesis of ALS still worthy of further studies.

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          Association of human herpes virus 6 (HHV-6) with multiple sclerosis: increased IgM response to HHV-6 early antigen and detection of serum HHV-6 DNA.

          Viruses have long been suggested to be involved in the etiology of multiple sclerosis (MS). This suggestion is based on (1) epidemiological evidence of childhood exposure to infectious agents and increase in disease exacerbations with viral infection; (2) geographic association of disease susceptibility with evidence of MS clustering; (3) evidence that migration to and from high-risk areas influences the likelihood of developing MS; (4) abnormal immune responses to a variety of viruses; and (5) analogy with animal models and other human diseases in which viruses can cause diseases with long incubation periods, a relapsing-remitting course, and demyelination. Many of these studies involve the demonstration of increased antibody titers to a particular virus, whereas some describe isolation of virus from MS material. However, no virus to date has been definitively associated with this disease. Recently, human herpesvirus 6 (HHV-6), a newly described beta-herpes virus that shares homology with cytomegalovirus (CMV), has been reported to be present in active MS plaques. In order to extend these observations, we have demonstrated increased IgM serum antibody responses to HHV-6 early antigen (p41/38) in patients with relapsing-remitting MS (RRMS), compared with patients with chronic progressive MS (CPMS), patients with other neurologic disease (OND), patients with other autoimmune disease (OID), and normal controls. Given the ubiquitous nature of this virus and the challenging precedent of correlating antiviral antibodies with disease association, these antibody studies have been supported by the detection of HHV-6 DNA from samples of MS serum as a marker of active viral infection.
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            The role of Kaposi's sarcoma-associated herpesvirus (KSHV/HHV-8) in lymphoproliferative diseases.

            The Kaposi's sarcoma-associated herpesvirus (KSHV), also called human herpesvirus 8 (HHV-8), has been found to be present in a limited subset of lymphoproliferative disorders. Among these are the primary effusion lymphomas, formerly designated body cavity-based lymphomas, a rare type of malignant lymphoma which possesses an unusual set of clinical and biologic features, suggesting that they represent a distinct disease entity. This virus is also present in a large proportion of cases of multicentric Castleman's disease, particularly those associated with HIV-infection. In addition, KSHV has been implicated in the pathogenesis of multiple myeloma, where it has been identified in bone marrow adherent cells but not in the neoplastic myeloma plasma cell population. However, the latter finding remains controversial. The discovery of KSHV in a subset of malignant lymphomas has allowed the development of lymphoma cell lines which now serve as biological reagents for propagating the virus, as a substrate for serologic assays, and as a model system for pathobiologic studies. This review discusses the features of KSHV-associated lymphoproliferative disorders and the evidence supporting its role in the pathogenesis of these diseases. Copyright 1999 Academic Press.
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              Productive dual infection of human CD4+ T lymphocytes by HIV-1 and HHV-6.

              Although infection by HIV-1 has been implicated as the primary cause of AIDS and related disorders, cofactorial mechanisms may be involved in the pathogenesis of the disease. For example, several viruses commonly detected in AIDS patients and capable of transactivating the long terminal repeat of HIV-1, such as herpesviruses, papovaviruses, adenoviruses and HTLV-I have been suggested as potential cofactors. Another candidate is human herpesvirus-6 (HHV-6, originally designated human B-lymphotropic virus), which has not only been identified in most patients with AIDS by virus isolation, DNA amplification techniques and serological analysis, but is also predominantly tropic and cytopathic in vitro for CD4+ T lymphocytes. Here we demonstrate that HHV-6 and HIV-1 can productively co-infect individual human CD4+ T lymphocytes, resulting in accelerated HIV-1 expression and cellular death. We also present evidence that HHV-6 transactivates the HIV-1 long terminal repeat (LTR). These observations indicate that HHV-6 might contribute directly or indirectly to the depletion of CD4+ T cells in AIDS.
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                Author and article information

                Journal
                ENE
                Eur Neurol
                10.1159/issn.0014-3022
                European Neurology
                S. Karger AG
                0014-3022
                1421-9913
                2002
                February 2002
                15 February 2002
                : 47
                : 2
                : 108-112
                Affiliations
                aDepartment of Neurology and bCentre of Experimental Haematology, University of Modena, Italy
                Article
                47961 Eur Neurol 2002;47:108–112
                10.1159/000047961
                11844899
                2aa4a2e0-c450-4201-95e1-8023f9f179a7
                © 2002 S. Karger AG, Basel

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                History
                Page count
                Figures: 1, Tables: 1, References: 47, Pages: 5
                Categories
                Original Paper

                Geriatric medicine,Neurology,Cardiovascular Medicine,Neurosciences,Clinical Psychology & Psychiatry,Public health
                Amyotrophic lateral sclerosis,Polymerase chain reaction,Human herpesvirus 8

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