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Herpes Breakthrough

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Ultrastructure and Assembly of Human Herpesvirus6 HHV6

Human herpesvirus-6 (HHV-6) is a ubiquitous member of the betaherpesvirus subfamily of the Herpesviridae family. The HHV-6 genome is arranged colinearly and codes for approximately 67 of proteins in common with human cytomegalovirus (HCMV), and 21 with all other herpesviruses. Sequence comparison shows that it is closely related to HHV-7 and HCMV. HHV-6 is a lymphotropic herpesvirus infecting up to 90 of the population and establishing latent or persistent infections for a lifetime (Salahuddin et al., 1986 Josephs et al., 1988 Levine et al., 1992 Krueger et al., 1998a). Clinical features of HHV-6 infection are described in Part II of this book. There are two variants of HHV-6, HHV-6A and HHV-6B with obvious gen-omic polymorphism within a variant (Ablashi et al., 1991, 1993 Schirmer et al., 1991). Both also vary in their tissue distribution in human and in their tissue culture cells for propagation (Lusso et al., 1988 Black et al., 1989 Ablashi et al., 1991 Di Luca et al., 1994). Some...

Cytomegalovirus Cell Tropism

Cell Tropism of Other 76 Abstract The human cytomegalovirus (HCMV) can infect a remarkably broad cell range within its host, including parenchymal cells and connective tissue cells of virtually any organ and various hematopoietic cell types. Epithelial cells, endothelial cells, fibroblasts and smooth muscle cells are the predominant targets for virus replication. The pathogenesis of acute HCMV infections is greatly influenced by this broad target cell range. Infection of epithelial cells presumably contributes to interhost transmission. Infection of endothelial cells and hematopoietic cells facilitates systemic spread within the host. Infection of ubiquitous cell types such as fibroblasts and smooth muscle cells provides the platform for efficient proliferation of the virus. T.E. Shenk and M.F. Stinski (eds.), Human Cytomegalovirus. Current Topics in Microbiology and Immunology 325. Springer-Verlag Berlin Heidelberg 2008

Functions of Human Cytomegalovirus Tegument Proteins Prior to Immediate Early Gene Expression

Abstract Proteins within the tegument layer of herpesviruses such as human cytomegalovirus (HCMV) are released into the cell upon entry when the viral envelope fuses with the cell membrane. These proteins are fully formed and active, and they mediate key events at the very start of the lytic infectious cycle, including the delivery of the viral genome to the nucleus and the initiation of viral gene expression. This review examines what is known about tegument protein function prior to the immediate early (IE) phase of the viral lytic replication cycle and identifies key questions that need to be answered to better understand how these proteins promote HCMV infection so that antiviral treatments that target these important viral regulators can be developed.

Characterization of HHV6specific antibodies

The determination of antibody isotype is an important issue in the general strategies of viral diagnosis. In most acute viral infections, IgM is the predominant antibody produced at the early phase of primary immune response, and its detection in a single serum specimen is sufficient to suggest that the infection is recent. However, in the case of herpesviruses, IgM may also be detected during viral reactivation from latency. The heterotypic reactivation of IgM, for instance during human cytomegalovirus (HCMV) and EBV infections is also possible and may obscure the interpretation of results. The presence of rheumatoid factor may induce false-positive results. The use of conjugated anti-human IgM antibody in IFA as well as ELISA does permit to detect HHV-6-specific IgM (Sutherland et al., 1991 Salonen et al., 2002) but the limitations mentioned above should be kept in mind. A first reaction step designed for the capture of IgM is known to improve assay specificity, and has been...

Functional Roles of the Human Cytomegalovirus Essential IE86 Protein

Abstract The IE86 protein of human cytomegalovirus (HCMV) is unique among viral and cellular proteins because it negatively autoregulates its own expression, activates the viral early and late promoters, and both activates and inhibits cellular promoters. It promotes cell cycle progression from Go G1 to G1 S and arrests cell cycle progression at the G1 S interface or at G2 M. The IE86 protein is essential because it creates a cellular environment favorable for viral replication. The multiple functions of the IE86 protein during the replication of HCMV are reviewed.

Interactions of Human Cytomegalovirus Proteins with the Nuclear Transport Machinery

Interaction of the Human Cytomegalovirus Protein pUL69 with the mRNA Abstract Accurate cellular localization is crucial for the effective function of most viral macromolecules and nuclear translocation is central to the function of herpesviral proteins that are involved in processes such as transcription and DNA replication. The passage of large molecules between the cytoplasm and nucleus, however, is restricted, and this restriction affords specific mechanisms that control nucleocytoplasmic exchange. In this review, we focus on two cytomegalovirus-encoded proteins, pUL69 and pUL84, that are able to shuttle between the nucleus and the cytoplasm. Both viral proteins use unconventional interactions with components of the cellular transport machinery pUL69 binds to the mRNA export factor UAP56, and this interaction is crucial for pUL69-mediated nuclear export of unspliced RNA pUL84 docks to importin-a proteins via an unusually large protein domain that contains functional leucine-rich...

General cellular pathology of HHV6 infection

In vitro studies show the immediate effects of HHV-6 binding to cells, infection of susceptible cells and intracellular replication (see also Chapter 2 Ultrastructure of HHV-6). Susceptible cells (e.g. HSB2, cord blood cells) show upon exposure to HHV-6 blastic transformation with or without giant cell formation, intranuclear inclusions, eventual mitoses and production of viral particles with cellular degeneration and apoptosis (Fig. 1 Biberfeld et al., 1987 Kramarsky and Sander, 1992 Kirn et al., 1997). Blastic transformation with giant cells can occur in cells upon virus contacts even without subsequent internalization and replication of viral particles (Boehmer, 1987). Typical Reed-Sternberg-type giant cells were induced by HHV-6 in established Hodgkin cell cultures without spontaneous giant cells (L428, L540, L591, HDLM2, KMH2) and without subsequent viral replication in these cells (Fig. 1 Krueger et al., 1991, 1992, 1995). Internalization of virus particles and their replication...

DRESS and HHV6 the first reports

Interestingly, all of the clinical and biological manifestations described in the DRESS are observed in some viral infection and especially HHV-6 infection. In 1993, Akashi et al. reported a severe infectious mononucleosis-like syndrome and primary HHV-6 infection in an adult (Akashi et al., 1993). A 43-year-old man was admitted with high fever, generalized exanthe-matic eruption followed by an exfoliative dermatitis, lymphadenopathy, atypical lymphocytes, hepatitis, and renal dysfunction. Lymphocyte population was mainly T-cell lymphocytes (52.6 CD8). CD19 and CD20 lymphocytes' levels were very low, 0.8 and 0.6 , respectively. The skin biopsy analysis demonstrated a diffuse infiltration with atypical lymphocytes in the dermis. HHV-6 infection was demonstrated by serial changes in titers of antibody against HHV-6 associated with an HHV-6 viremia. HHV-6 DNA was demonstrated in serum samples collected on days 10 and 13. We had the opportunity to report the...

HHV6 a helper virus for other herpesviruses in DRESS

HHV-6 reactivation may be associated in DRESS with other viral infections. Other herpesviruses such as Epstein-Barr virus, HHV-7, or CMV have been reported in association with HHV-6 reactivation (Suzuki et al., 1998 Aihara et al., 2001 Descamps et al., 2003c Mahe et al., 2004 Sekiguchi et al., 2005). We reported a case of severe allopurinol-induced DRESS with pancreatitis associated with EBV infection (Descamps et al., 2003c). An active EBV infection was demonstrated by the detection of EBV DNA in PBMC and a seroconversion in two consecutive sera. In two recent reports this HHV-6 and EBV coinfection was fatal (Mahe et al., 2004 Sekiguchi et al., 2005). Sequential reactivation of HHV could explain the observed flare-ups of this disease (Kano and Shiohara, 2004). Independently of the DRESS, this association of viral coinfection has been observed in transplant recipients (Desjardin et al., 2001). Moreover, sequential reactivation of herpesviruses has been demonstrated after bone marrow...

Herpes Simplex Virus Thymidine Kinase Gene Ganciclovir

One approach to the development of more effective therapies for prostate cancer is to initiate a cascade of molecular cellular events locally within the primary tumor that generate a localized and systemic antitumor immune response through the transfer of specific immunomodulatory genes. It has been considered that it might be possible to use specific genes to generate localized antitumor cytotoxicity as well as to initiate a systemic antitumor immune response. This strategy has evolved from purely cytotoxic-based gene therapies to more immunomodulatory gene therapies and various combinations to ultimately achieve the objective. Our initial gene therapy trials used the selected herpes simplex virus thymidine kinase (HSV-t ) gene delivered with a replication deficient adenoviral vector. HSV-t + ganciclovir (GCV) gene therapy has been shown to elicit widespread cytotoxic activities through direct and well-defined bystander activities and to elicit nonspecific and specific antitumor...

Pityriasis rosea and HHV6

Pityriasis rosea is a common, acute, self-limiting papulosquamous skin disorder. The initial skin lesion is called the herald patch,'' and typically appears on the trunk as a 2-3 cm oval scaly plaque with a central salmon-colored area and a darker erythematous peripheral zone. The disease normally resolves spontaneously within 4-8 weeks. The clinical and epidemiological features of this disease suggest a pathogenic role for an infectious agent. Drago et al. (1997) first suggested that reactivation of human herpesvirus 7 (HHV-7), which is the virus most similar to HHV-6, was linked to pityriasis rosea. An association between HHV-7 and the disease has been debated since then, and some investigators have suggested that HHV-6 is also linked to pityriasis rosea (Kosuge et al., 2000 Watanabe et al., 2002 Broccolo et al., 2005). HHV-6 latently infects peripheral blood mononuclear cells, and highly sensitive detection techniques such as nested PCR could falsely identify active HHV-6 infection...

Herpes Simplex Virus Thymidine Kinase

One specific molecular chemotherapy approach involves tumor cell transduction with the herpes simplex virus-thymidine kinase (HSV-tk) gene via a viral vector, followed by the systemic administration of the chemotherapy agent ganciclovir (GCV) (1). GCV is a prodrug that must be phosphorylated initially by the HSV-tk gene product to a monophosphate form and, subsequently, by the mammalian kinases to the cytotoxic triphosphate form. Once activated by this process, GCV functions as a purine analog that inhibits DNA polymerase thereby preventing DNA synthesis and inducing cell death (2,3). In addition, HSV-tk gene therapy mediates a bystander effect, whereby nontransduced neighboring cells are also killed. This bystander effect appears to result from the transfer of active GCV metabolites through intercellular gap junctions between the transduced cells and the neighboring cells (4,5). Gene therapy with HSV- tk coadministered with GCV has been shown to be effective in various tumor models...

Cytomegalovirus Infection

Cytomegalovirus (CMV) infection caused by platelet transfusions has been a substantial cause of morbidity and mortality in immunocompromised patients with cancer. Patients who receive allogeneic bone marrow progenitor cell transplantation are at risk for contracting the virus present in blood products because of cytotoxic preparative regimens, immunosupressive (cyclosporin and corticosteroid) therapy or graft-vs-host disease (GvHD) (14). Up to 60 of this patient population will become infected with CMV, and 50 will have CMV disease if no pre-emptive therapy is given. The risk of CMV infection ranges between 28 and 57 for patients receiving a bone marrow transplant and who are seronegative and receive standard blood products (15). Even with CMV-negative blood products, CMV seroconversion has been reported in 1-4 of CMV-negative donor-recipient transplant patients (16). A recent analysis of our own program identified CMV viremia in only 2.5 (1 of 39) of CMV-negative donor-recipient...

HHV6 infection can induce atypical lymphoproliferations

Atypical lymphoproliferations (APLs) constitute a heterogenous group of lesions that clinically mimic malignant lymphomas, but are lacking the criteria of mon-oclonality and malignant transformation. The incidence of APL seems to be increased in patients with immune disorders, and persistently active infection by lymphotropic viruses is frequently found in APLs. They can be defined as prema-lignant lymphoproliferations and may finally transform to malignant lymphomas. ''Type B reticulum cell sarcoma'' or the Moloney and Gross virus-induced lymph-oblastic lymphomas in mice represent similar polyclonal cell proliferations preceding virus-induced lymphomas. In humans, the majority of reported cases are associated with herpesvirus infections, namely EBV and or HHV-6. HHV-6 prevalence in lymph nodes from HD patients HHV-6 prevalence in lymph nodes from HD patients

Modulation of Host Cell Stress Responses by Human Cytomegalovirus

Abstract Human cytomegalovirus (HCMV) induces cellular stress responses during infection due to nutrient depletion, energy depletion, hypoxia and synthetic stress, e.g., endoplasmic reticulum (ER) stress. Cellular stress responses initiate processes that allow the cell to survive the stress some of these may be beneficial to HCMV replication while others are not. Several studies show that HCMV manipulates stress response signaling in order to maintain beneficial effects while inhibiting detrimental effects. The inhibition of translation is the most common effect of stress responses that would be detrimental to HCMV infection. This chapter will focus on the mechanisms by which cap-dependent translation is maintained during HCMV infection through alterations of the phosphatidylinositol-3' kinase (PI3K)-Akt-tuberous sclerosis complex (TSC)-mammalian target of rapamycin (mTOR) signaling pathway. The emerging picture is that HCMV affects this pathway in multiple ways, thus T. E. Shenk and...

HHV6 is found essentially in scleronodular HD in young adults

EBV, another herpesvirus frequently associated with HD, is not distributed equally among the different subtypes of EBV-positive HD 70 of mixed cellularity, > 95 of lymphocyte depleted, 10-40 of nodular sclerosis, and almost absent from lymphocyte-predominant HD subtypes. In addition, HD cases associated with EBV occurred most frequently in children or in elderly people. Previous epidemiological studies suggested multiple etiologies for HD and led to the hypothesis of an infectious viral non-EBV etiology for cases occurring in young adults. It was therefore interesting to look for the presence of HHV-6 sequences according to HD subtype. Torelli et al. (1992) described three HHV-6-positive HD, belonging to the nodular-sclerosis-lymphocyte-depletion subgroup, which occurred in young women (27-, 28- and 31-years old). Similarly, different authors obtained the highest prevalence and highest mean copy for the scleronodular subtype of HD (Table 1). In a large study conducted on 86 adult HD...

Control of Apoptosis by Human Cytomegalovirus

Abstract Caspase-dependent apoptosis has an important role in controlling viruses, and as a result, viruses often encode proteins that target this pathway. Caspase-dependent apoptosis can be activated from within the infected cell as an intrinsic response to replication-associated stresses or through death-inducing signals produced extrinsically by immune cells. Cytomegaloviruses (CMVs) encode a mitochondria-localized inhibitor of apoptosis, vMIA, and a viral inhibitor of caspase activation, vICA, the functional homologs of Bcl-2 related and c-FLIP proteins, respectively. Evidence from viral mutants deleting either vMIA or vICA suggests that each is necessary and sufficient to promote survival of infected cells undergoing caspase-dependent apoptosis. Additional proteins, including pUL38, IE1491aa, and IE2579aa, can prevent apoptosis induced by various stimuli, while viruses with deletions of UL38, M45, or m41 undergo apoptosis. The viral RNA, P2.7, binds mitochondrial respiratory...

Reactivation of Latent Herpes Viruses

The adaptive immune response is an important factor in the control of herpes viruses. These viruses, which include herpes simplex virus type 1 and type 2 (HSV-1 and HSV-2), varicella zoster virus (VZV), cytomegalovirus (CMV), and Epstein-Barr virus (EBV) are the most ubiquitous viruses with very high prevalence rates in healthy adults. For example, greater than 90 of adults are seropositive for HSV-1 and EBV and therefore latently infected with the virus (Henle and Henle 1982 Pebody et al, 2004 Peter and Ray 1998 Xu et al, 2002). The initial encounter with HSV-1 (i.e., the causative agent of cold sores) typically occurs in childhood with few clinical symptoms, whereas infection with EBV, which commonly occurs in young adults, leads to mononucleosis in approximately 40 of those infected (Henle and Henle 1982). However, after the primary infection has been resolved, the herpes viruses are able to establish lifelong latent infections in host tissue. The site of latency is virus specific,...

Local Delivery Of Herpes Simplex Virus Into Gliomas

Herpes simplex virus type I (HSV-1) is an enveloped, double-stranded, linear DNA virus with a genome of 152 kb which encodes more than 80 genes. About one half of the genes are essential for viral replication whereas the other (nonessential) genes encode proteins which support the viral life cycle within the host cell. The major advantages and disadvantages of HSV-1 for tumor oncolysis are illustrated in Table 1.

Cytomegalovirus Vaccine Development

Abstract Although infection with human cytomegalovirus (HCMV) is ubiquitous and usually asymptomatic, there are individuals at high risk for serious HCMV disease. These include solid organ and hematopoietic stem cell (HSC) transplant patients, individuals with HIV infection, and the fetus. Since immunity to HCMV ameliorates the severity of disease, there have been efforts made for over 30 years to develop vaccines for use in these high-risk settings. However, in spite of these efforts, no HCMV vaccine appears to be approaching imminent licensure. The T. E. Shenk and M. F. Stinski (eds.), Human Cytomegalovirus. Current Topics in Microbiology and Immunology 325. Springer-Verlag Berlin Heidelberg 2008

Human Herpesvirus6 Infection in Solid Organ and Stem Cell Transplant Recipients

Seroepidemiologic studies have shown that infection due to human herpesvirus-6 (HHV-6) is usually acquired during the first year of life the virus subsequently persists in the host. Seroprevalence in healthy adults exceeds 90 . Serology is unable to differentiate between the two subtypes and therefore it is possible that seropositive patients might get a new infection with the second subtype presumably most commonly subtype A. Most transplant patients will therefore be seropositive prior to transplantation. Previous HHV-6 infection has been documented in 87-91 of solid organ transplant (SOT) recipients by serologic assays (Dockrell et al., 1997 Ihira et al., 2001) and by the detection of HHV-6 DNA sequences in the peripheral blood mononuclear cells in 32 of the patients (Chapenko et al., 2001). Similar percentages have been noted in stem cell transplant (SCT) recipients. Yoshikawa documented pretransplant seropositivity in 100 of SCT recipients (Yoshikawa et al., 2002) while...

Manifestations of Human Cytomegalovirus Infection Proposed Mechanisms of Acute and Chronic Disease

Abstract Infections with human cytomegalovirus (HCMV) are a major cause of morbidity and mortality in humans with acquired or developmental deficits in innate and adaptive immunity. In the normal immunocompetent host, symptoms rarely accompany acute infections, although prolonged virus shedding is frequent. Virus persistence is established in all infected individuals and appears to be maintained by both a chronic productive infections as well as latency with restricted viral gene expression. The contributions of the each of these mechanisms to the persistence of this virus in the individual is unknown but frequent virus shedding into the saliva and genitourinary tract likely accounts for the near universal incidence of infection in most populations in the world. The pathogenesis of disease associated with acute HCMV infection is most readily attributable to lytic virus replication and end organ damage either secondary to virus replication and cell death or from host immunological...

Mutagenesis of the Cytomegalovirus Genome

Homology Arm Homologous Recombination

Abstract Bacterial artificial chromosomes (BACs) are DNA molecules assembled in vitro from defined constituents and are stably maintained as one large DNA fragment in Escherichia coli. Artificial chromosomes are useful for genome sequencing programs, for transduction of DNA segments into eukaryotic cells, and for functional characterization of genomic regions and entire viral genomes such as cytomegalovirus (CMV) genomes. CMV genomes in BACs are ready for the advanced tools of E. coli genetics. Homologous and site-specific recombination, or transposon-based approaches allow for the engineering of virtually any kind of genetic change. T.E. Shenk and M.F. Stinski (eds.), Human Cytomegalovirus. Current Topics in Microbiology and Immunology 325. Springer-Verlag Berlin Heidelberg 2008 Animal viruses use a small set of genes to profoundly affect functions of complex hosts. The goal of virus genetics is to understand virus-host interactions at the molecular level. Collection or construction...

HHV6 therapy in CFS patients

CFS patients with active infection by HHV-6 (variants A or B) can be treated with antivirals or immune modulatory agents in order to relieve the symptoms of fatigue and minimize CNS complaints. Acyclovir has remained the gold standard of treatment for herpes viral infections in general. However, pilot studies using acyclovir and ganciclovir showed persistence of HHV-6 variant A in spinal fluid even after treatment (Peterson, unpublished studies). HHV-6 does not encode thymidine kinase, and thus is not highly sensitive to acyclovir and its analogs (Gomples et al., 1995). Non-guanosine derivatives, however, have been shown in vitro to be of greater efficacy against HHV-6 specifically. De Clercq et al. (2001) demonstrated increased efficacy of the non-guanosine compounds S2242, cidofovir, and foscarnet, both in T lymphoblast cells, and in fresh blood lymphocytes, though it should be noted that only foscarnet and cidofovir are commercially available. Cidofovir, the first nucleotide analog...

HHV6 Genome Similar and Different

Hhv6 Genome

Roseoloviruses, human herpesviruses 6 and 7 (HHV-6, HHV-7) are widespread T lymphotropic and neurotropic viruses causing mostly benign infections. However, particularly for HHV-6, during some primary as well as secondary reactivated infections, which can follow immune aberrations or deficiencies, there can be severe complications which can lead to fatalities. Thus, this is of relevance for immuno-suppressed HIV AIDS or transplantation patients, as well as increasingly, for those with neurological disease, including encephalitis and a link with multiple sclerosis (primarily HHV-6A). Understanding when and how this virus does or does not cause disease is key to developing effective treatments plus evaluating the impact of HHV-6 infections on worldwide populations. Studies on the virus genome provide a foundation for this exploration and can guide the way towards development of new anti-virals as well as possible novel treatments for immune-related pathologies using this well-adapted...

Discovery and Classification of Human Herpesvirus6 HHV6

Humanherpes Virus Gram Stain

AHHV-6 Foundation, 285 San Ysidro Road, Santa Barbara, CA 93108, USA bDepartment of Microbiology & Immunology, Georgetown University School of Medicine, Washington, DC, USA The discovery of herpesvirus-6 (HHV-6) dates back to early 1985 when Zaki Sal-ahuddin, in Dr. Robert Gallo's Laboratory of Tumor Cell Biology, was establishing long-term cultures from peripheral blood and splenic tissue of AIDS patients. He frequently found large syncytia that were distinct from HIV-1-induced syncytia. What he really saw in the peripheral blood mononuclear cells (PBMCs) of at least 6-8 patients with B-cell lymphoma were large, refractile cells (Fig. 1), always either single or, occasionally, two or more together. These cells began to disappear after a few days in culture, even in the presence of IL-2. The individuals with these cells were all AIDS patients with or without lymphoma. When these cells were stained with Giemsa, they were often multinucleated, or two large nuclei basically covered...

HHV6 association with CFS

White And Grey Matter Mri

One of the first reports of isolated post-infectious fatigue associated with encephalitis, lymph proliferation, and the presence of HHV-6 infection, was made by Buchwald et al. (1990). Daugherty et al. (1991) also reported a group of patients with profound fatigue lymphadenopathy and cognitive dysfunction associated with evidence of HHV-6 reactivation, although variant analysis was not available at that time. Early studies of CFS patients demonstrated an increase in serum IgG and IgM for HHV-6 in a large number of patients compared with control subjects. However, increases in antibodies to other viruses, particularly other herpesviruses, were also detected. Serological measurements of IgG and IgM titers have limited ability to suggest active infection, because most adults have been infected with HHV-6. These immunoglobulins might only indicate exposure, but not active or persistent infection. Studies using molecular analysis (in subsequent years) generally showed higher prevalence of...

Human Cytomegalovirus Modulation of Signal Transduction

Abstract An upregulation of cellular signaling pathways is observed in multiple cell types upon human cytomegalovirus (HCMV) infection, suggesting that a global feature of HCMV infection is the activation of the host cell. HCMV initiates and maintains cellular signaling through a multitiered process that is dependent on a series of events (1) the viral glycoprotein ligand interacts with its cognate receptor, (2) cellular enzymes and viral tegument proteins present in the incoming virion are released and (3) a variety of viral gene products are expressed. Viral-mediated cellular modification has differential outcomes depending on the cell type infected. In permissive cell types, such as diploid fibroblasts, the upregulation of cellular signaling pathways following infection can initiate the viral gene cascade and promote the efficient transcription of multiple viral gene classes. In other cell types, such as endothelial cells and monocytes macrophages, the upregulation of cellular...

Genital herpes

Herpes simplex virus First episode genital Acyclovir 400 mg PO tid x 7-10 d First episode proctitis Acyclovir 400 mg PO 5x d x 7-10 d Severe herpes infection Acyclovir 5 mg kg IV q8h x 5-7 d Acyclovir 400 mg PO tid or 800 mg PO bid x 5 d Prevention of recurrence Acyclovir 400 mg PO bid


HHV-6, a recently discovered DNA virus, causes exanthem subitum (roseola) in children. Two variants of HHV-6, A and B have been described. HHV-6B causes most human infections whereas no specific human disorder has been linked to HHV-6A. HHV-6 typically causes rash and fever in children but, in addition, this virus commonly enters the CNS during acute primary infections, occasionally resulting in meningitis or other neurological complications (4,113-115). HHV-6 has also been reported to cause encephalitis in immunosuppressed adults and has been linked in a few instances to encephalopathic and myelopathic disorders as well as to human demyelinating disease (116-122). Almost all children are infected early in life by this ubiquitous virus, with HHV-6 seropositivity being seen in 90 of all children by two years of age (113-115). Like other herpes family viruses, HHV-6 persists lifelong in brain and other tissues in most normal individuals, and as with other herpes viruses HHV-6 may be...

Herpes simplex

Herpes simplex infections are a frequent problem for HIV patients. With a significant immune deficiency (under 100 CD4 cells l), chronic courses of infection are possible. Two viruses should be distinguished. In severe cases, other organs may be affected. These include the esophagus (ulcers), CNS (encephalitis), eyes (keratoconjunctivitis, uveitis) and respiratory tract (pneu-monitis, bronchitis). In such cases and with persistence for a period of more than four weeks, herpes simplex infection is AIDS-defining.

Herpes zoster

Herpes zoster is the reactivation of an earlier infection with varicella virus, which subsequently resides lifelong in the spinal ganglia. Herpes zoster episodes occur even in HIV patients with relatively good immune status, and are also seen during immune reconstitution (Martinez 1998). With more advanced immunodeficiency, herpes zoster tends to become generalized. In addition to involvement of one or more dermatomes, dangerous involvement of the eye (affecting the ophthalmic branch of the trigeminal nerve, herpes zoster ophthalmicus, with corneal involvement) and ear (herpes zoster oticus) may occur. Most feared is involvement of the retina with necrotizing retinitis. The neurological complications include menin-goencephalitis, myelitis and also involvement of other cranial nerves (Brown 2001).

HHV6 and PML

After several reports had suggested an association of HHV-6 with MS, Mock et al. (1999) examined the possible association of HHV-6 with the demyelinative lesions of PML. In this study, a highly sensitive, two-step in situ PCR (ISPCR) procedure was used to amplify HHV-6 DNA from formalin-fixed paraffin-embedded archival brain tissues from normal, AIDS, and other neurological disease controls. A significantly higher frequency of infected cells was found in PML white matter compared to control tissues. Of interest, the HHV-6 genome was detected primarily within oligodendrocytes (Mock et al., 1999). Immunocytochemistry for HHV-6 antigens revealed active HHV-6 infection of the abnormal oligodendro-cytes within demyelinative PML lesions, but not in adjacent, unaffected tissue or control tissues, including brains from individuals with HIV-1 encephalopathy. The detection of active HHV-6 infection coupled with the collocation of JCV large T antigen and HHV-6 in swollen intralesional...


Cytomegalovirus (CMV) is a large DNA virus of the Herpes virus group. It is estimated that 50 to 80 of adults have prior evidence of CMV infection (58). The infection is usually subclinical when contracted by immunocompetent infants and adults and infrequently may lead to a mononucleosis-type syndrome. However, significant sequelae exist from in-utero infections as well as infections in immunocompromised patients.

Herpes Simplex Virus

The HSV 1716 (an HSV-1 mutant attenuated in its ability to replicate in neurons of the CNS) is another herpes-virus strain that has made its way from animal studies to early clinical trials. In addition to avirulence in SCID mice, efficacy studies showed antineoplastic effects against intracranially injected melanoma and human embryonal carcinoma (NT2) tumors (31-33). The virus was also found to be unable to replicate within neuronally differentiated counterparts of NT2 cells underscoring the selectivity of this virus for tumor cells (33). These results have lead to early trials to assess the safety and toxicity profiles of HSV1716 as an innovative anti-glioma agent in humans (34). As with G207, HSV1716 was well tolerated and an MTD could not be established as no patient exhibited signs of encephalitis postinjection even with the highest dose administered. Additionally, further studies have suggested that HSV 1716 replicates in at least some of the HGG treated with intratumoral...

Eukaryotic Expression Systems

Cytomegalovirus Promoter for Expression in Mammalian Cells The Cytomegalovirus Enhancer-Containing Promoter 214 Positive Regulation 216 Experimental Procedures 219 Effects Upstream of the Cytomegalovirus Enhancer 221 Effects Downstream of the Cytomegalovirus Promoter 222 Negative Regulation 223

Identification and Analysis of Dominant Negative Mutants

The function of nonessential genes is studied by gene deletion and by loss-of-function mutants. By ris-complementation assays functionally important sites of essential genes can be mapped. Unfortunately, a major target of genetics, the null phenotype of an essential gene is generally hard to come by. This requires the cumbersome establishment and optimization of a trans-complementation system for each gene under study. Here, we try to develop a systematic approach. Dominant negative (DN) mutants are special null mutants that induce the null phenotype even in the presence of the wt allele. DN mutants of cellular genes have been proven to be a valuable for genetic analysis of complex pathways (Herskowitz 1987). Knowledge of protein structure, protein functions or sequence motifs aid the design of DN mutants (Crowder and Kirkegaard 2005). Unfortunately, the information on the majority of herpesvirus proteins is too limited for knowledge based construction of DN mutants.

Lucky Day For Two Neuropathologists And More Luck On A Sabbatical

In addition to continuing electron microscopy now also on our second case of PML, I was forced to rapidly pursue library studies. Which journals and books was I to read in a field at the crossroads of virus and cancer research and cell biology It required a fast reorientation for a diagnostic neuropathologist. In September, I was able to resolve the nature of the nuclear inclusion bodies of the esophagitis case They consisted of herpes-type virions, well preserved in this autopsy tissue. In mid-November, I got a phone call from Dr. Lucien Rubinstein, of Stanford University. He had just received the ARNMD program with the listing of ''Papova Virus in Progressive Multifocal Leukoen-cephalopathy'' by Zu Rhein and Chou and wanted to inform me that he and Dr. Silverman had found similar virus particles in a recent case of PML (Sil-verman and Rubinstein, 1965). He offered to back us up in the meeting, with Dr. Zimmerman's consent.

Differential Diagnosis

Multiple diseases can present with findings similar to those seen with Adamantiades-Behget's disease and should be considered when a patient presents with recurrent oral or genital ulcers, inflammatory eye disease, or other manifestations of vasculitis. Included in the differential diagnosis are systemic lupus erythematosus (Chapter 1), seronegative spondyloarthropathies, inflammatory bowel disease (Crohn's or ulcerative colitis) (Chapter 20), herpes or other viral infections (Chapter 10), other forms of vasculitis (Chapter 8), and inflammatory skin diseases such as pemphigus vulgaris or pemphigoid lesions (Chapter 37). All patients presenting with oral and genital ulcerations should undergo testing for herpes simplex virus using culture or polymerase chain reaction methods, to ensure that viral infection is not present.

U48 and U82 gH and gL

Formation of the glycoprotein gH gL heterooligomer has important implications for understanding the pathology of HHV-6-associated disease because this complex is essential for infectivity and fusogenic cell-to-cell spread (Josephs et al., 1991 Liu et al., 1993a,b Qian et al., 1993 Anderson et al., 1996 Takeda et al., 1997 Anderson and Gompels, 1999). Definition of the HHV-6 gH domain involved in protein-protein interactions is addressed by targeting regions defined by conserved cysteines identified by alignment of gH amino acid sequences representative of all herpesvirus subfamilies. The N-terminus of HHV-6 gH includes a 230-amino-acid domain required for interaction with HHV-6 gL encompassing residues conserved specifically among betaherpesviruses. HCMV homologues, UL75 (gH) or UL115 (gL), can substitute for HHV-6 glycoproteins and participate in heterologous complex formation (Anderson et al., 1996). Furthermore, the region that governs this heterologous gL binding also maps to the...

Finding The Achilles Heel The y1345 Gene Controls Hsv1 Neurovirulence

The breakthrough in creating attenuated HSV-1 strains resulted from characterizing viruses containing engineered mutations in the y 4.5 genes. Embedded within a repetitive genome component (see Fig. 2A), the y 4.5 gene is expressed with Y1 late kinetics and is not required for growth in cultured monkey kidney cells. Strikingly, its impact on viral neurovirulence is greater than any single HSV-1 gene identified to date (11-13). Although the LD50 of many wt HSV-1 strains is less than 300 pfu following intracranial delivery, it is not possible to accurately measure the LD50 for y34.5 mutant viruses. Indeed, upwards of 106-107 pfu of y34.5 mutant viruses have been safely injected intracranially into mouse, non-human primate, and human brains (11-18). In studies designed to examine the efficacy with which y34.5 mutants were able to destroy human or murine gliomas implanted into mice, not only had the attenuation problem been solved, but the treated mice survived longer than their untreated...

Clinical Manifestations

Uveitis occurs in a wide variety of systemic diseases including those described herein and in other chapters of this book. Several associated diseases are of primary clinical interest, although individually they are relatively uncommon or even rare in the usual practice of a head and neck specialist. Sarcoidosis is a common cause of anterior, intermediate, and posterior uveitis, which is covered in more detail later in this chapter. Other diseases causing uveitis are described in other chapters of this book and include Behcet's disease, relapsing polychondritis, syphilis, Lyme disease, cat-scratch disease, tuberculosis, fungal infection, and infection with the human immunodeficiency virus, cytomegalovirus, and herpes viruses.

Introduction to Virus Entry

The ability of a virus to enter a host cell and deliver its genome for replication represents the essential, first step in the replication cycle of the virus. Human cytomegalovirus (HCMV), like most herpesviruses, enters cells via direct fusion of the viral envelope with the plasma membrane at neutral pH (Compton et al. 1992). However, in specific cell lines such as retinal pigment epithelial and endothelial cells, HCMV enters by receptor-mediated endocytosis, requiring low-pH (Bodaghi et al. 1999 Ryckman et al. 2006). Regardless, the HCMV entry process is highly complex, requiring multiple envelope glycoproteins, which interact with a series of cellular receptors.

Envelope and Membrane Fusion

The exact mechanism of the fusion step is not clear. Over the past several years, it has become increasingly apparent that amino acid heptad repeat (HR) motifs, which encode alpha-helical coiled-coils, are playing a role in the fusion process of HCMV. These coils are very well characterized in more simple viral fusogenic systems, such as with influenza, HIV, and Ebola viruses, but they are only beginning to be understood in the more complex herpesviruses (Weissenhorn et al. 1999). It is known that synthetic peptides from the HR region of HCMV gB and gH and p amino acid oligomers derived from the HR region of gB specifically inhibit HCMV entry (Lopper and Compton 2004 English et al. 2006). Additionally, the HR region of gB appears to be important because mutation of hydrophobic amino acid residues in this region results in a replication-deficient virus (M.K. Isaacson and T. Compton, unpublished results).

Infections in Human Populations

To be considered as this also affects how rapidly an infection may spread in the population. One more factor which may or may not be significant is the length of the prepatient period, the time between infection and symptoms becoming apparent, as the onset of symptoms may result in relative isolation from the rest of the population. Some infections, such as herpes simplex or hepatitis B (HBV), may be symptomatic in some individuals but to a greater or lesser degree asymptomatic in others with corresponding differences shown in infectivity, and the tendency to symptomatic vs. asymptomatic infection may vary according to age, as is shown very strongly in the case of hepatitis B (Medley et al., 2001). HBV is also a good example of an infection that may manifest itself as an initial asymptomatic infection or an acute primary infection (in this case lasting a few weeks) leading to recovery or to a persistent chronic infection which for HBV may last several decades or be effectively...

Alphavirus For The Transfection Of Tumor Cell Lines

Protein (GFP) and herpes simplex virus thymidine kinase (HSV-rfr) gene, which allowed parallel monitoring of the infection efficency by fluorescence (GFP) and tumor killing (HSV-rfr) after ganciclovir (GCV) administration (30). To simulate in vivo conditions, only low multiplicity of infection (MOI) was applied, which resulted in fairly modest GFP expression. However, the tumor killing was much better than anticipated because of the by-stander effect previously observed for HSV-rt treatment (31). These studies, however, made it clear that the delivery of the therapeutic gene is essential and approaches such as intratumoral injections or improved targeting for systemic delivery are essential.

Tropism for Dividing Cells in Cancer Gene Therapy

The selectivity of MuLV for dividing cells has been exploited in a phase III clinical trial that tested the efficacy of a suicide gene therapy approach to treating glioblastoma multiforma, a malignant brain tumor (77). The rationale of such gene therapies is to insert a gene capable of killing cells into the tumor while protecting the normal brain cells. The vector contains the herpes simplex thymidine kinase (TK) gene, which is able to phosphorylate the drug ganciclovir, resulting in a toxic derivative that is incorporated into DNA. The vector is produced in situ in the residual tumor and peritumor areas, following surgical resection of the tumor, by the injection of a mouse producer cell line that generates the retroviral particles. Although both tumor cells and healthy cells in the area of a growing brain tumor could potentially be transduced, only the tumor cells themselves and the vasculature supplying blood to the tumor are considered likely targets as they will be actively...

Glen N Barber PhD Contents

The ability of RNA viruses to efficiently reproduce in transformed cells was first recognized nearly 100 yr ago. However, it wasn't until the late 1990s that a resurrection of the interest in the ability of certain viruses to preferentially replicate in malignant cells and less so in normal cells occurred, the curiosity being to evaluate whether these agents could be useful in cancer therapy regimes. It was following these reports, demonstrating that DNA viruses such as adenovirus and herpes simplex virus (HSV) could act as antineoplastic agents, that similar encouraging investigations were conducted using RNA viruses such as reovirus and Newcastle Disease virus, vesicular stomatitis Virus (VSV), and measles virus (MV). Here we will review the use of RNA viruses as oncolytic agents in the treatment of malignant disease, focusing on the negative-stranded RNA virus, VSV. The general mechanisms by which oncolytic viruses such as VSV achieve their antitumor effectiveness and specificity...

Assessment of Virus Directly From Patients for GAG Dependence

Although some viruses, such as herpes simplex virus, appear to use HS in vivo, many others are selected for HS usage during passage in cell culture. Viruses with clear evidence for adaptation include Sindbis, dengue fever, foot and mouth disease, Ross River, tick borne encephalitis, and human immunodeficiency viruses (16,22,28,29,48-51). Sindbis virus is pathogenic for mice but grows poorly in cultured cells. Within a few passages in cultured cells, the virus grows to much higher titers but is no longer pathogenic in mice. This cell culture adapted virus binds heparin much better than the original mouse virus. When injected into mice intravenously, the heparin-binding virus is filtered out in the liver, in nonproductive associations (16,28). It seems likely that there is a strong selection against HS binding in such a blood-borne virus in the animal, and a strong selection for HS binding in cultured cells.

The Natural Immune Response to Htlvi Infection

Several successful viral vaccines have been devised that have prevented significant disease morbidity and mortality throughout the world. These include vaccines for polio, small pox, measles, and the world's first genetically engineered vaccine the recombinant hepatitis B virus vaccine. In all of these cases, the vaccines have been successful because they were designed to prevent only the appearance of disease and because the target viruses are intrinsically genetically stable. In contrast, there are many other viral infections for which vaccines have been only partially successful, such as for influenza viruses and herpes simplex virus, or are difficult to develop, as with HIV-1 and hepatitis C virus. With the latter viruses, issues such as high genetic variability, viral integration into the host genome, viral latency, the need for mucosal immunity, and or a requirement for long-lasting sterilizing immunity need to be addressed. HTLV-I vaccine prospects most closely resemble those...

Immune Reconstitution Syndrome An Unrecognized Consequence of Antiretroviral Therapy

The clinical manifestations of CNS-IRIS are diverse and depend on the presence or absence of, as well as the type of, opportunistic infections present. Several opportunistic infections play an established role in the development of CNS-IRIS, such as Mycobacterium species, Cryptococcus, JC virus, and Cytomegalovirus, each with diverse clinical symptoms and outcomes (28). Once CNS-IRIS is identified, treatments include the use of corticosteroids to suppress the immune system (24, 28). Preventive measures include careful screening for opportunistic infections prior to the onset of combined antiretroviral therapy and appropriate intervening therapy if necessary to reduce antigen presentation.

Model for Postfusion Preimmediate Early Events

This section describes an overly simplified model for postfusion, preimmediate early events during HCMV lytic infection of fully permissive fibroblasts (Fig. 1). The model is based on experiments with HCMV, data from other herpesviruses, and a certain amount of speculation on the part of the author. It is not meant as a comprehensive, definitive picture, but as a working model that needs to be refined and built upon.

Genetically Engineered VSV as a Gene Therapy Tool Against Cancer

Oncolytic studies indicated that wild type VSV exhibited considerable potential as an anticancer agent. However, the ability to modify VSV through genetic engineering obviously affords the prospect of creating new generations of custom-made VSV vectors that contain immunomodulatory and or suicide cassettes designed to increase their antitumor activity. In order to begin evaluating whether genetically engineered VSV carrying tumor-killing cassettes could be created and whether such viruses were more efficacious in tumor therapy than the wild-type VSV, we developed VSV vectors carrying, as models, the herpesvirus TK suicide cassette or the cytokine gene interleukin-4 (IL-4). The foreign genes were cloned as additional transcription units between the VSV G and L genes and all viruses were grown to exceptionally high titers (71,103). TK protein was synthesized to extremely high levels and was functional, being able to phosphorylate ganciclovirs (GCV). Recombinant viruses also retained...

Virus Encoded Proteins Are Developed through Targeted Evolution In Vivo

Large DNA viruses, in particular herpes- and poxviruses, have evolved a number of proteins that function as mimics of or as decoys for endogenous proteins of the host organism. Often the virus uses such proteins to evade key components of the immune system. The virus-encoded proteins are elegant examples of targeted evolution, where the virus has captured a gene from its host and through combinatorial chemistry varied its structure and thereby its function randomly through mutagenesis. Unlike biotech entrepreneurs, the virus has the advantage of being able to select the mutant protein with the optimal pharmacological property through in vivo screening in the intact organism. The virus with the most useful protein for example, the most potent or broad-spectrum antagonist will prevail. One example is the vMIP-II chemokine of human herpesvirus 8, which acts as an efficient blocker of a surprisingly large number of structurally different chemokine receptors. The chemokine system in...

Multiple Virus Encoded 7TM Receptors

More than 20 G-protein-coupled receptors have been identified in various herpes- and poxviruses (Table 1 and Fig. lA). Most of these receptors display key structural elements, that identify them as belonging to the family of chemokine receptors. In general, however, it is impossible to identify a specific endogeneous chemokine receptor as the original scaffold hijacked by the virus. The extensive subsequent mutational effort performed by the virus which has generated the desired pharmacological profile has at the same time significantly altered the primary structure of the receptor. Conceivably a multitude of more or less silent mutations have accompanied the functionally important substitutions that produced the useful property of the viral receptor. A few chemokine-like virus-encoded receptors nonetheless have been convincingly de-orphanized. That is, their endogenous chemokine ligand has been identified. The best examples are US28, a broad-spectrum CC and CX3C chemokine receptor...

Constitutive Signaling through Altered Pathways

ORF74, also named KSHV-GPCR (i.e., Kaposi's sarcoma-associated herpesvirus GPCR), is the prototype of a con-stitutively active, virus-encoded receptor. Multiple signal transduction pathways have been demonstrated for this receptor, involving a variety of G proteins, with Gq signaling dominating, in contrast to the Gi signaling of endogenous receptors. Small GTPases, kinases including MAP kinases, and many transcription factors are also involved in ORF74 signaling (Fig. 2). The receptor activates NFkB, for instance, via Gi o, Ga13 RhoA pathway, Gq, Py subunits, and P13-Ky. VEGF secretion, possibly regulated by a transcription factor (HIF-1a) controlled by MAP kinases, may mediate ORF74's ability to induce angiogenic lesions in vivo. The constitutive activity of other transcription factors (CREB and NFAT) downstream of ORF74 could be important for lytic replication of the virus, as both pathways have been shown to contribute to HHV8 reactivation. ORF74 also promotes cell survival...

Serologic assays Techniques

Indirect immunofluorescence antibody assays (IFA) were the first ones to be used for the detection of HHV-6 antibodies (Salahuddin et al., 1986 Linde et al., 1988 Lopez et al., 1988) and remain still widely employed. In these tests, HHV-6-infected cells are fixed on a glass slide, a serum dilution is added and a fluorochrome-conjugated anti-immunoglobulin antibody is then applied to detect the binding of serum antibodies to specific antigens. When illuminated with ultraviolet light, the number of fluorescent foci as well as the characteristic pattern of cell staining observed with the microscope constitute the main parameters to be taken into account for the result. The staining of uninfected cells with a counterstain partly quenching non-specific fluorescence is also important, in particular, to check that the ratio of infected to uninfected cells is in agreement with the known characteristics of cell preparation. Infected cells consist of primary cells such as cord blood mononuclear...

Molecular Chemotherapy With rAAV

Delivery of a gene-encoded toxin into cancer cells to achieve tumor eradication is usually performed by indirect killing through activation by a prodrug. This approach has focused mainly on delivery of the herpes simplex virus thymidine kinase (HSV-tk) gene. Expression of HSV- tk results in replicating tumor cells having enhanced sensitivity to nucleoside analogs, such as ganciclovir (GCV) or acyclovir. GCV is phosphory-lated initially by TK and subsequently by cellular factors to a triphosphate form that becomes incorporated into cellular DNA (81). This inhibits both DNA synthesis and RNA polymerase activity resulting in cell death (81).

Neuropathology in Untreated Pre Symptomatic HIVInfected Individuals

HIV-infected pre-symptomatic subjects rarely die before the onset of AIDS, since they generally have CD4 lymphocyte counts above 400 cells l and are not then vulnerable to the range of infections seen in the end stages. Drug abuse and overdoses, accidental or otherwise, are the usual reason for death in pre-AIDS and have provided opportunities to investigate CNS involvement in the pre-symptomatic phase of HIV infection (1, 2). Studies of a unique cohort of HIV-infected intravenous drug abusers in Edinburgh (UK), who were known to have acquired their infection in late 1983 early 1984, showed relatively minor changes in comparison with those seen in AIDS (1). Characteristic AIDS-related conditions, including HIVE and CNS opportunistic infections, such as toxoplasmosis, cytomegalovirus (CMV), varcella zoster virus (VZV) or Cryptococcus neoformans were found to be absent in pre-AIDS brains. Despite this, there is evidence of inflammation in the CNS of many of these subjects, in the form...

Primary infection characteristics and diagnostic considerations

Major issues in designing diagnostic tests for primary HHV-6 infection include (1) to provide a rapid assay for useful information in a short time, and (2) to distinguish between primary virus infection versus viral reactivation or latent infection (Table 1). Of particular concern is the fact that viral DNA is likely to be present in circulating peripheral blood mononuclear cells (PBMC) from all HHV-6-infected individuals, regardless of whether that infection was recent or not. Thus, one must rely on the unique features of primary infection to distinguish it from latency persistence or subclinical reactivation reinfection. The most important feature of primary infection is the high levels of viremia (Asano et al., 1991) so that infectious virus can readily be cultured from patients' PBMC and viral DNA is detected in cell-free plasma samples. In addition, quantitative PCR assays can reveal high cell-associated viral DNA loads in the PBMCs, in contrast to latent or persistent infection....

Inducible gene expression models

Resistance to tetracycline and is under the control of the protein TetR (Tet repressor) that binds to the tetO (operator) within the operon promoter to block transcription (Hillen et al., 1982 Hillen and Berens, 1994). The system that is widely used in mouse genetic models is bi-transgenic model that includes two genetic cassettes (Fig. 1). The so-called response cassette consists of the target gene linked to a hybrid promoter that contains tandem repeats of tetO and a minimal promoter to express the gene. Transcription of the target gene is controlled by tetracycline or its analogue, doxycy-cline (DOX) (Degenkolb et al., 1991). The most popular versions of the tet system employ a TetR derivative that has been modified to serve as a transcriptional activator by fusing TetR with the herpes simplex virus protein VP16 (16) (Fig. 1). This chimeric protein, known as tTA (tet Tran-scriptional Activator), binds to the tetO tandem repeats (tetracycline response elements) and activates...

Miscellaneous Applications

Another application for Ad-mediated gene delivery is modulation of the receptor repertoire expressed on the surface of infected cells. Lieber et al. (1995) used an Ad vector to deliver the am-photrophic retrovirus receptor (RAM) cDNA to cells that are normally resistant to infection with the amphotropic retroviral vectors commonly used in gene therapy work. Following Ad infection, target cells were markedly more infectible with a recombinant retrovirus. An Ad recombinant was used to express human CD4 on the surface of a number of CD4-negative cell lines (Yasukawa et al., 1997). In several of these lines, CD4 expression allowed infection by the herpesvirus HHV-7, confirming the role of CD4 in HHV-7 entry.

Regional Connectivity

Moving from connections between individual neurons to connections between brain regions, the most widespread and valuable method delivering detailed information about directed long distance connections is neuroanatomical tract tracing (for reviews see Sawchenko and Swanson 1981 Kobbert et al., 2000 Wouterlood et al. 2002). The general approach comprises now a vast range of substances with the common feature that they are taken up by neurons and spread along their projections, where the label then can be visualized. Some substances are directly inserted intracellularly and therefore suitable for tracing of individual neurons. Most of the tracer substances, however, are applied extracellularly to the living tissue by pressure injection, iontophoresis or mechanical insertion. Most of them are actively incorporated through the neuronal membrane and transported in the cytoplasm to reveal the distant location of cell bodies (fast retrograde transport) or axonal terminals (fast and slow...

Use of Heterologous Promoters

Many different promoters have been inserted into Ad vectors and in most cases have retained their activity. Widely used viral promoters include the long terminal repeat of RSV, the SV40 early promoter, and the cytomegalovirus (CMV) major immediate-early promoter. The CMV promoter provides very strong expression of a transgene in many cell types, at least in the short term (Jiang et al., 1996 Guo et al., 1996), and has become perhaps the most widely used promoter in adenoviral vectors. Bartlett et al. (1996) have reported that the constitutively active U1 small nuclear RNA promoter, which is transcribed in essentially all cell types, has activity similar to CMV and is active when placed into an El-deleted Ad vector. A number of groups have sought to target adenovirus-based gene expression to tumor cells. Hepatoma cells often express elevated levels of a-fetoprotein (AFP) relative to normal liver. A recombinant Ad carrying AFP promoter and enhancer sequences driving the herpes simplex...

Neuropathological Findings in the PostHAART

The incidence of most of the major CNS complications that were observed prior to the introduction of HAART has fallen. Table 1 shows the changes in the Edinburgh cohort since the introduction of HAART. There has been a marked decline in the incidence of CMV and of toxoplasmosis. The US Multicenter AIDS Cohort Study (MACS) has also shown a significant decrease in the incidence of cryptococcal meningitis and CNS lymphoma, with a non-significant decrease in toxoplasmosis. The incidence of PML dropped only marginally (69). Some studies have reported an actual increase in HIVE or more severe forms of HIV-related brain disease in HAART-treated individuals (70-73). Gray et al. have shown that in the French cohort there is a decreased incidence of cerebral toxoplasmosis and CMV encephalitis, with the incidence of PML and PCNSL unchanged (72). Gray et al. also report an increase in varicella zoster encephalitis and herpes simplex encephalitis, both previously rare neurological complications of...

The epidemiology of roseola from historical observations

The epidemiologic picture of human herpesvirus 6 (HHV6) has continually evolved over its known life span of 2 decades. Still, it remains more of a collage than a completed portrait, for HHV6 has multiple characters. It is a covert companion of life, and yet a mimicker of many maladies. Although HHV6 was named relatively recently, this virus probably has long been recognized as an exanthematous disease of childhood. In papers and texts from the 1800s, an acute infection of young children with rash was given such sobriquets as roseola infantilis, exanthem criticum, exanthem subitum, the rash of roses, and prophetically, the sixth exanthematous disease of childhood. These old descriptions suggest that even in ages past infections likely from HHV6 were common, geographically widespread, and occurred in young children, primarily infants. Kempe and co-workers (1950) subsequently also attempted unsuccessfully to isolate the virus. They did, however, show that the infectious agent was present...

Viral Encoded transActing Factors Required for Lytic Replication

Table 1 lists the ORFs identified from the initial cotransfection replication assay performed in human fibroblasts. Six of these genes identified are common to all herpesviruses and are designated the core replication proteins, which comprise a DNA polymerase, polymerase accessory protein, single-stranded DNA binding protein, helicase, primase and primase associated factor. Interestingly, efficient ori-Lyt-dependent DNA replication can occur when core proteins from one herpesvi-rus, for example EBV, is used with a different herpesvirus species oriLyt, for example HCMV, in the cotransfection replication assay (Sarisky and Hay ward 1996 Xu et al. 2004b). In all cases, the only additional factor that is needed is the initiator protein unique to each herpesvirus. This fact suggests that a set of core enzymes can carry out DNA synthesis on a primed oriLyt substrate independent of the mechanism of initiation. It also suggests that the initial events in DNA synthesis can be performed...

Viral and Cellular Encoded UL84 Binding Partners

The interaction of UL84 with UL44 (Pol accessory protein) is very interesting in that the initiator protein for herpes simplex virus type 1 (HSV-1), UL9, also interacts with its Pol accessory protein (Trego and Parris 2003). It is postulated that UL42 increases the ability of UL9 to load on DNA (Trego et al. 2005), a scenario that is also plausible for UL84 with respect to its interaction with UL44. The finding that UL44 interacts with UL84 opens up the possibility that UL44 may have a

Risk factors for coronary heart disease CHD the role of oxidative stress

Cigarette smoking, hypertension, diabetes mellitus, genetic alterations, elevated plasma homocysteine concentrations, infectious microorganisms, such as herpes viruses or Chlamidia pneumoniae, have proinflammatory actions, increasing the formation of hydrogen peroxide and free radicals such as superoxide anion and hydroxyl radicals in plasma. These substances reduce the formation of nitric oxide (NO) by endothelium. Nitric oxide is a free radical with an unpaired electron in its highest orbital. This is why it behaves as a potential antioxidant agent by virtue of its ability to reduce other molecules. In vitro experiments support this concept inasmuch as NO is able to inhibit lipid peroxidation. However, NO is rapidly inactivated by the peroxide anion (O2_) to form peroxynitrite (NO3 ) which is a potent oxidant. Therefore, in the presence of O2 , NO behaves as a potent pro-oxidant. This is the mechanism that accounts for the low-density lipoprotein (LDL) oxidation that occurs when NO...

Vectors with Modified Tropism

Many vectors use the CMV immediate early promoter enhancer, which was chosen on the basis that it directs a high level of transgene expression and is expressed in most tissues studied. However, often expression in a specific tissue or cell type is more desirable and expression in other tissues might be toxic. Therefore, the promoters of genes specific to a cell type have sometimes been used for specific applications (118-120). For example, carcinoembryonic antigen and alpha-fetoprotein (AFP) are tumor-specific antigens that are not expressed by normal cells. When a therapeutic gene is expressed from an Ad vector with an AFP promoter, expression should be confined to specific tumor cells expressing AFP and not normal cells. Kaneko et al. (118) showed this theory to be correct and further demonstrated that the expected selectivity is maintained in vivo. In this context, the vector Av1AFPTK1 expressing thymidine kinase from herpes simplex virus (HSV-TK) from the AFP promoter can prevent...

RNAi In Clinical Cancer Therapy

In concept, diseases such as cancer, which are characterized by overexpression or aberrant activation of specific oncogenes, are suitable candidates for nucleic acid-based gene-silencing therapies. Several nucleic acid drugs that are based on ODNs were under clinical trials and Vitravene (sodium fomivirsen) has been used for the treatment of cytomegalovirus (CMV) infection of the eye in clinics (2,3,5). Several ribozyme-based phase I II clinical trials are in early-phase of clinical evaluation for patients with breast cancer, colon cancer, and hepatitis (3). The problems of toxicity and poor clinical efficacy with antisense and ribosome molecules remain to be solved even after more than a decade of drug development attempts. Although the term RNAi was coined just 6 yr ago (23) and the application of siRNAs in mammalian cells was started only three years ago (27,28), RNAi is rapidly taking center stage of the development of nucleic acid-based therapeutics. siRNA-based biotechnology...

Interaction of the HCMV pUL84 with Importina Proteins

The second cytomegalovirus protein for which we detected a nonconventional interaction with components of nuclear transport pathways is the gene product of the open reading frame UL84. The open reading frame UL84 of HCMV encodes a multifunctional protein with nuclear localization that appears to be absolutely essential for viral replication (Xu et al. 2002, 2004a Lischka et al. 2003a He et al. 1992 Yu et al. 2003) (see also the chapter by G. Pari, this volume). Initially, pUL84 was identified as a direct binding partner of the regulatory protein IE2-p86, which is the major transcription-activating protein of HCMV (Spector and Tevethia 1994). Studies concerning the functional consequence of the pUL84-IE2 interaction revealed on the one hand that this interaction downregulates the transactivation activity of IE2 on some early promoters (Gebert et al. 1997). On the other hand, it has been reported that this pUL84-IE2 complex is required for the activation of a bidirectional promoter...

Clinical features

Fever, weight loss, diarrhoea, skin changes, CNS manifestations. Haematological abnormalities include thrombocy-topaenia, leucopaenia, neutropaenia, hypergammaglob-ulinaemia and anaemia. Infections may start to occur with organisms such as herpes simplex or zoster, Pneumococcus and Salmonella. When the CD4 count falls below 0.2 X 109 l, the patient becomes susceptible to a wide spectrum of opportunistic infections (Streptococcus pneumoniae, Haemophilus influenzae, Pneumocystis carinii, toxoplasmosis, Mycobacterium tuberculosis, atypical mycobacteria, histoplasmosis, Cryptococcus, cryptosporidiosis, fungal infections, Jamestown Canyon (JC) virus infection and CMV infections), malignancies (Kaposi's sarcoma and non-Hodgkin's lymphoma) and CNS disease such as dementia may develop. This stage of infection is classified by the Centre for Disease Control (CDC) as fully developed acquired immunodeficiency syndrome (AIDS). Many staging systems for HIV have been proposed and exist. Mostly...

Lymphatic and hematopoietic system see also chapters 14 and

In chronic persistent HHV-6 infection, viral DNA load and cellular changes show certain cyclic changes, suggesting some fluctuation in viral replication (Krueger et al., 2001). In about 6 , heterophile-negative infectious mononucleosis is caused by HHV-6A or B infection (Steeper et al., 1990 Horwitz et al., 1992 Akashi et al., 1993). More frequent is the reactivation of latent HHV-6 in patients with classical EBV-induced infectious mononucleosis resulting in a more protracted course of the disease with elevated liver enzymes (Bertram et al., 1991). Occasionally caused by HHV-6, preferentially variant B, are angioimmunoblastic lymphadenopathy (Luppi et al., 1993 Daibata et al., 1997), hemophagocytic syndromes (Sugita et al., 1995 Tanaka et al., 2000) and Langerhans cell histiocytosis (Leahy et al., 1993). HHV-6 (preferentially subtype A) and or increased viral DNA loads were found in certain malignant lymphomas, including subtypes of Hodgkin's disease (Krueger et al., 1989 Torelli et...

Partially Attenuated Live Vaccines and Sero Immunization

Harvard, began to work with this material 17 . Theiler was cognizant of the achievements of Pasteur and Roux, 50 years before, in the isolation of rabies virus by intracerebral inoculation, first of dogs and subsequently of monkeys, guinea pigs and rabbits. He also credited the work of Andervont, who in 1929 had shown that mice were susceptible to herpes simplex encephalitis after intracerebral inoculation 18 .1 Theiler inoculated a small number of adult Swiss mice by intracranial route with liver suspension from a monkey infected with the French strain. All the animals died of encephalitis, without signs of liver damage. Brain tissue from the mice passed to a rhesus monkey caused typical fatal yellow fever. In 1930, Theiler reported in Science the development of a convenient small animal model for the isolation and study of yellow fever virus 19 . 1 In fact the first studies showing mice to be susceptible to herpes virus were done earlier by G. Blanc and J. Camio-Petros (Recherches...

Other organs and tissues see also chapters 13 and

Other diseases described in association with active HHV-6 infection were interstitial pneumonitis (Cone et al., 1993 Know et al., 1995) and fulminant hepatic failure with HHV-6 present in liver tissue and in portal vein endothelium (Aita et al., 2001 Ishikawa et al., 2002). Some recipients of stem cell transplants, which suffered from severe posttransplant diarrhea showed HHV-6B DNA and antigens in their peripheral blood cells and in intestinal epithelia (Amo et al., 2003). Finally, it is important to notice that HHV-6 can apparently activate other viral infections, e.g. those induced by EBV, CMV, HIV-1, measles, apparently also papillomavirus and parvovirus. HHV-6 may thus contribute to the pathologic effects of these viruses (Lusso et al., 1992, 1995 Flamand et al., 1993 al-Kaldi et al., 1994 Chen et al., 1994 Ablashi et al., 1995 Como et al., 1998 Singh et al., 1998). Dual active infections appear especially frequently with other herpesviruses (CMV, EBV, HHV-7) as well as with...

Multiple Myeloma 21 Epidemiology

The role for an underlying viral etiology is controversial. In 1997, DNA sequences belonging to human herpesvirus-8 (HHV8 ) were identified in bone marrow dendritic cells and bone marrow biopsy sections of MM patients, analyzed by polymerase chain reaction (PCR) assay and in situ hybridization.14,15 Subsequent studies have yielded conflicting data however, the preponderance of evidence from molecular and seroepidemiological studies suggests there is no definitive association between HHV8 infection and MM.16,17

Richard H Pin md Maura Reinblatt md Yuman Fong md and William R Jarnagin md

The use of viruses to treat human malignancy is not a new concept but has only recently evolved into a clinically viable therapy. Spurred by advances in molecular biology that have allowed relatively easy manipulation of the viral genome, a number of different viruses have been evaluated and shown to have promise as anticancer agents. Of these, herpes simplex virus (HSV) has been perhaps the most intensively investigated. Several strains of replication competent oncolytic HSV have been developed, some of which have been used in clinical trials. Continuing research efforts are aimed at manipulating the viral genome to more specifically target tumor cells, to further enhance efficacy while maintaining safety, and to assess the role of oncolytic HSV in combination with chemotherapy and radiation therapy. Key Words Herpes simplex virus (HSV) oncolytic viral therapy.

Mucosal Cell Mediated Immunity Cytotoxic T Lymphocytes

Cytotoxic T lymphocytes (CTL) represent another immune effector mechanism that may be capable of protecting the mucosal surfaces of the host against HIV infection.15 Although mucosal CTL were not measured, systemic HIV-specific CTL were detected in uninfected children born to HIV-infected mothers.3334 However, virus-specific CTL have been detected in the cervix and vagina of HIV-infected women and SIV-infected rhesus macaques, respectively.1611 These results support the conclusion that the appropriate HIV vaccines may be able to induce HIV-specific CTL that home to and reside in the mucosal tissues of the host and protect against mucosally transmitted HIV. Results from other virus models suggest that mucosal CTL will be beneficial for protection against mucosally acquired HIV infection. For example, herpes simplex virus (HSV)-specific CTL induced by vaginal inoculation with an attenuated HSV-2 protected mice against a lethal HSV-2 vaginal infection.18 Additional studies are required...

Viral Oncolytic Therapy

Herpesviruses are effective against a broad spectrum of human tumors. G207 is a mutant HSV with deletions in both copies of y 4.5, and a mutation in UL39 (Table 1). This attenuated virus was first described in the treatment of malignant gliomas, and further research has demonstrated its efficacy in treating a wide range of tumors types, including breast, bladder, colon, gallbladder, stomach, liver, pancreas, and the oro-digestive tract (10,12-17). In these studies, G207 has been able to effectively kill cancer cells in vitro and reduce experimental animal tumor burdens in vivo. Furthermore, G207 has demonstrated preclinical safety in BALB c mice and Aotus monkeys. In BALB c mice, doses of 1 x 107 plaque-forming units (pfu) of G207 injected intrace-rebrally did not produce any adverse effects (18). Likewise, a dose of 1 x 109 pfu in Aotus monkeys did not result in any pathology (19). Clinical safety has been further confirmed in a phase I clinical trial of patients with malignant...

Typical Transcriptional Activator

Although a typical activator contains both an activation domain and a DNA binding domain, sometimes these two domains can reside on separate proteins. For example, the herpes simplex virus (HSV) activator VP 16 dos not bind to DNA, but rather, it is brought to DNA by interacting with other DNA-binding proteins (Triezenberg et al, 1988). The activation domain of VP 16 can also activate transcription when directly linked to a DNA binding domain (Sadowski et al., 1988). This finding demonstrated that an activation domain can be brought to DNA by distinct, but interchangeable, means, either directly binding to DNA (through its linked DNA binding domain) or interacting with other DNA-binding proteins. This concept was further demonstrated by the creation of an artificial composite activator (Ma and Ptashne, 1988). The yeast repressor protein GAL80 inhibits the activation function of GAL4 by interacting with and masking its activation domain (Johnston et al, 1987 Lue et al, 1987 Ma and...

Evolution of CMV vCK Genes

To date, three vCK genes have been identified in the HCMV genome (Fig. 2), the CC chemokine-like gene UL128, and the CXC chemokine-like genes UL146 and UL147. To some extent, these genes are conserved among primate CMVs (Table 1). UL128-like genes are also present on the genomes of murine CMV (MCMV) and rat CMV (RCMV), as well as on the genome of human herpesvirus type 6 (HHV-6) (Table 1). The rodent CMV and HHV-6 species lack UL146- and UL147-like genes. Similar to the UL33- and UL78-like genes, the UL128-like chemokine genes are likely to have been acquired by betaherpesviruses at least 110 My ago. The conservation of this gene family suggests an essential role for these genes in the survival of betaherpesviruses in vivo. This notion is supported by the observation that the UL128 sequences from different clinical HCMV isolates are highly conserved (Baldanti et al. 2006). Paradoxically, the UL128 gene appears to be functional in laboratory strain HCMV AD169, whereas in the clinical,...

Other Clinical and Preclinical In Situ Cytokine Gene Therapy Approaches

Delivery of the granulocyte-macrophage colony-stimulating factor (GM-CSF) gene in either a herpesvirus vector (83) or a canarypox vector (84) has been explored in preclinical models. The GM-CSF gene was combined with IFN-a gene for liposomal delivery in a bladder cancer model (85).

Chemokine Receptors Encoded by CMVs Evolution of CMV vGPCR Genes

Both vGPCR and vCK genes have been identified within the genomes of beta- and gammaherpesviruses, but not within those of alphaherpesviruses. There is no apparent evolutionary relationship for these genes between the beta- and gamma-herpesvirus subfamilies. Yet, within the betaherpesvirus subfamily, both vGPCR and vCK genes appear to be conserved among murine and primate CMV species, as well as the HHV-6 and human herpesvirus type 7 (HHV-7). The HCMV genome contains four vGPCR genes, UL33, UL78, US27 and US28 (Fig. 2) (Murphy et al. 2003a). These genes are conserved among all known primate CMVs (Table 2). Table 2 Cytomegalovirus chemokine receptor-like genes Table 2 Cytomegalovirus chemokine receptor-like genes

The Role of Tissue Culture in Vaccine Development

As early as 1928, Maitland and Maitland had shown that vaccinia could be grown in a system consisting of kidney tissue fragments nurtured by a mixture of serum and organic salts. Their observations led to a proliferation of attempts to exploit tissue culture techniques for virus growth. Until then, nearly all work had been conducted in laboratory animals (rodents or nonhuman primates). Over the succeeding years, a large roster of investigators manipulated tissue culture systems in a variety of ways to grow viruses as varied as ectromelia, equine encephalitis, herpes simplex, influenza, Japanese encephalitis, mumps, rabies, vaccinia, yellow fever and others. Although individual successes were reported, they were rarely sufficiently simple to be repeated easily in the laboratories of other investigators, or to be maintained for lengthy periods of time. It was also difficult to prove that virus had multiplied rather than merely persisted in the varied culture systems. To avoid the...

Adapterbased Targeting

The first in vitro demonstration of Ad targeting via the adapter modality resulted in CAR-independent, folate receptor-mediated cellular uptake of the virion by cancer cells over-expressing this receptor (39). This was accomplished using a bispecific conjugate consisting of a neutralizing Fab chemically linked to folate. A similar targeting adapter consisting of the same Fab fused to FGF2 was used to target Ad vectors to FGF receptor-positive Kaposi's sarcoma and ovarian cancer substrates (40-42). Upon intraperitoneal injection of Ad-Fab-FGF2 coding for herpes simplex virus type I thymidine kinase (HSV-TK) into tumor-bearing mice, survival was prolonged (43). Importantly, decreased hepatic toxicity was demonstrated (44,45). Other Fab-ligand conjugates have been targeted against epithelial cell adhesion molecule, tumor-associated glycoprotein 72, EGFR, CD-40, and others (32,46-52).

Mechanisms Driving Gut Versus Peripheral Homing

Naive T cells have the capacity to acquire any set of homing receptors on activation. However, the site of antigen entry exerts a strong influence on the traffic pattern that lymphocytes acquire. For example, pathogens entering through the skin, such as herpes simplex virus, preferentially generate lymphocytes with skin-homing receptors (Gonzalez et al. 2005 Kantele et al. 2003 Koelle et al. 2002, 2005). On the other hand, oral vaccination induces higher levels of a407 on effector memory T cells (Kantele et al. 1999b Lundin et al. 2002 Rojas et al. 2003 Rott et al. 1997) and B cells (Gonzalez et al. 2003 Kantele et al. 1997,1999a, 2005 Quiding-Jarbrink et al. 1997 Youngman et al. 2002) than parenteral administration of the same antigen. Importantly, among memory B and CD8 T cells, only a407+ (but not a4p7Neg) cells carried protection against intestinal rotavirus infection on adoptive transfer (Rose et al. 1998 Williams et al. 1998). In agreement with these observations, it has been...

Stable Gene Transfer Vectors

In lentiviral vectors, have been generated by deleting promoter and enhancer sequences from the U3 region of the 3' LTR (23-25). Following reverse transcription, this modification is duplicated to form the 5' U3 region. Thus, promoter and enhancer functions are effectively removed from both proviral LTRs. SIN vectors are a major improvement in safety, as they reduce the capacity for recombination or rescue from exogenous virus, and deletion of the 3' U3 sequences may reduce the frequency of insertional activation. Transgene expression in SIN vectors is achieved by the insertion of an internal promoter, a range of which have been evaluated for HSC gene therapy, including the ubiquitous cytomegalovirus (CMV), elongation factor 1a (EF-1a), and phosphoglycer-ate kinase (PGK) promoters (17,26). Vector comparisons utilizing the green fluoores-cent protein (GFP) reporter indicate that the EF-1a promoter provides the most robust multilineage hematopoietic expression levels (26). Additional...

Pneumonitis in immunosuppressed patients

HHV-6 is a common latent resident in the normal lung (Cone et al., 1996), and even viral reactivation does not necessarily cause disease in immunologically competent persons. HHV-6 can be demonstrated in some 33 of bronchial lavages in healthy volunteers (Nagate et al., 2001). It may become pathogenic, though, if certain immune deficiency permits the persistent activity and replication of the virus quite similar to other ''opportunistic'' viruses such as Epstein-Barr virus (Purtilo et al., There are large numbers of publications reporting severe and even lethal HHV-6-associated interstitial pneumonias in immunocompromised patients. These patients were preferentially various organ transplant recipients, or they suffered from HIV infection, immune deficiency or autoimmune disorders (Carrigan et al., 1991 Cone et al., 1993, 1994, 1995, 1996 Pitala et al., 1993 Knox and Carrigan, 1994 Buchbinder et al., 2000 Nagate et al., 2001 Totani et al., 2001 Michaelides et al., 2002 Taplitz and...

Special entities of lymphoma

There is a characteristic close association with the herpes virus HHV-8, which can be detected in the malignant cells, and which provides a relatively typical gene expression profile (Simonelli 2005, Fan 2005). Recently, a solitary variant has been reported, which is neither morphologically nor immunophenotypically distinguishable from the classical PEL types (Chadburn 2004). The response to CHOP is usually poor and poorer than that of centroblastic NHL (Simonelli 2003). Case studies with complete remission on HAART alone have been described (Boulanger 2001, Hocqueloux 2001). We have, however, seen two PEL patients who have also died of progression despite CHOP and HAART after only a few months.

FIGURE 19 Aphthous ulcers Source Courtesy of the International AIDS SocietyUSA From Refs 3 4

KS has been strongly associated with human herpes virus Type 8 (HHV8), also known as KS-associated herpes virus, believed to be transmitted orally. Recurrent Aphthous Ulcers. Aphthous ulcers of unknown etiology are relatively common in HIV disease, becoming more severe with worsening immunosuppression. Contrary to those found in the general population, aphthous ulcers (canker sores) are often large and not of the minor (herpetiform) type in HIV-infected persons. They can persist for weeks or even months, causing severe pain and disability with resultant malnutrition, which further complicates the problem. Empiric therapy with high-dose acyclovir usually fails. Most often, biopsy and cultures are performed to exclude specific treatable causes such as fungal or viral infection (especially CMV). In most cases, no etiologic agent is found (3). Topical treatment with steroid paste (Lidex) can sometimes be useful, but large lesions require more aggressive management, and oral thalidomide...

Immune Suppression and Inflammation

Respiratory tract, (2) loss of microvilli in the gastointestinal tract, (3) loss of mucin and goblet cells in the respiratory, gastrointestinal, and genitourinary tracts, (4) squamous metaplasia with abnormal keratinization in the respiratory tract, (5) alterations in antigen-specific secretory immunoglobulin (Ig)A concentrations, (6) impairment of alveolar monocyte macrophage function, and (7) decreased integrity of the gut. In early studies of vitamin A deficiency in autopsy studies of humans and experimental animals, the findings included widespread pathological alterations in the respiratory, gastrointestinal, and genitourinary tracts (87,368,369). During vitamin A deficiency, there is loss of mucin and goblet cells from the conjunctiva and squamous metaplasia of the conjunctiva and cornea (285,370) and impaired wound healing (298). Vitamin A is involved in the expression of both mucins (248,371) and keratins (249,372,373). Lactoferrin, an iron-binding glycoprotein involved in...

Peptide Binding Versus Adjuvanticity

The Van Eden laboratory has proposed that some HSP can play an important role in regulating immune responses by inducing a regulatory phenotype in T-lymphocytes which helps to control potentially damaging autoimmune responses (Wendling et al., 2000). The potentiation of immune responses to chaperoned peptides may reflect a balance between the generation of IL-10 secreting regulatory T-cells specific for HSP epitopes versus effector cells specific for the chaperoned peptide (van Eden et al., 2003). In a previous study, a role for Mycobacterial Hsp70 in the DC mediated cross-presentation of viral peptides derived from Influenza A (Inf A) and human Cytomegalovirus (huCMV) was shown to be dependent on the induction of an intracellular calcium signaling cascade within the DC, and not on the direct stimulation of the cells to produce cytokines and chemokines. However, the provision of a second signal mediated by effector T-cell DC interactions, greatly augmented the HSP effect on the DC...

Electrical Stimulation Of The Spinal Cord And Peripheral Nerves

In additional studies involving neuropathic pain, Harke et al. found that SCS relieved pain in 23 of 28 patients with postherpetic neuralgia and 4 of 4 with acute herpes zoster (24). Katayama et al. found that deep brain stimulation led to pain control in 6 of 10 patients with phantom limb pain, whereas SCS was only efficacious in 6 of 19 patients (25).

Vaccination of contacts

Whenever HIV patients are susceptible to vaccine-preventable infections, particular care should be taken to vaccinate close contacts, who, after gaining protective immunity, will not transmit the disease. However, if contacts are vaccinated with certain live vaccines (e.g. oral polio vaccine), the HIV patient is at risk of acquiring vaccine-associated illness. Thus, oral polio vaccination of contact persons is con-traindicated and the inactivated vaccine should be used. Secondary transmission of MMR or varicella following vaccination is very unlikely only if contacts develop vaccine-associated varicella, the HIV patient should receive acyclovir prophylaxis.

The Risks Posed by Prenatal and Perinatal Infection

Maternal illness continues to be one of the more significant challenges to the maintenance of pregnancy and to fetal well-being (McGregor et al, 1995). In addition to concerns about miscarriage and premature delivery, many bacteria and viruses can pose a grave threat to the fetus if they are able to infect placental tissues or transfer across the placenta. Rubella, syphilis, and toxoplasma are among the pathogens that were once prominent health hazards. Even the common herpes viruses, such as cytomegalovirus, which are normally benign when restricted to the maternal compartment, can have devastating effects on brain development if they reach the fetal compartment or if there is exposure during delivery or the early postpartum period (Barry et al, 2006 Revello and Gerna, 2002).

Targeting Genetic Vaccines

One of the most commonly used mammalian promoters in genetic vaccines is the cytomegalovirus promoter (pCMV). This is an extremely strong viral promoter that is capable of mediating high levels of antigen expression in many cell types. However, some of the expression products in a genetic vaccine, such as the immunomodulating

Reactivation transplantation Solid organ transplant

In 1992, Yoshikawa first published that 14 of kidney transplant recipients developed HHV-6 viremia in the first 2-4 weeks posttransplant and 55 showed an increase in anti-HHV-6 antibody titer in the first 3 months (Yoshikawa et al., 1992). Since then, Singh and Carrigan (1996), Singh and Patterson (2000), Ljung-man (2002), and Lautenschlager et al. (2000) have reported HHV-6 as an emerging pathogen in solid organ transplantation. HHV-6 is expressed in the early weeks posttransplant, often exacerbating the severity of other diseases in the transplant recipient (Des Jardin et al., 1998, 2001 Dockrell et al., 1997, 1999), including cytomegalovirus (CMV) (Humar et al., 2000 Boeckh and Garret, 2003). of morbidity and mortality (Tolkoff-Rubin and Rubin, 1998). Serologically CMV-negative patients receiving an organ from a CMV-positive donor are at greatest risk, although use of potent immunosuppressives like anti-lymphocyte globulin, steroids, and mycophenolate mofetil as well as a history...

Indinavirassociated nephropathy

When evaluating the triggering agent, it must be observed that other medicaments could have caused the crystalluria, and only resulted in nephrolithiasis on combination with indinavir (e.g. ampicillin, acyclovir, aspirine, ciprofloxacin, methotrexate, vitamin C, sulfonamide and also other drugs that lead to an increase in uric acid).

Dermatological examination and therapy in HIVinfected patients

HIV-infected patients with advanced disease often suffer from common skin diseases (Table 1), but they also present with rare dermatoses, unique to HIV infection. Careful dermatologic evaluation may lead to the diagnosis of serious systemic infections in this population such as cryptococcosis, bacillary angiomatosis, oral hairy leukoplakia, and Penicillium marneffei infections of the skin. Common dermatoses often present with atypical findings and may pose diagnostic dilemmas. For example, herpes simplex labialis may present as large superficial erosions or deeply ulcerating lesions rather than the classical small vesicles on an erythematous base. Eruptions of secondary syphilis may ulcerate and form rupial lesions accompanied by high fever and constitutional symptoms (malignant syphilis). It is therefore important to pursue diagnosis of all cutaneous eruptions through appropriate tests such as tissue cultures, biopsy, and swabs of lesions prior to the initiation of therapy. Because...