Cytomegalovirus Ebooks Catalog

Stop Herpes Now

You'll discover: What foods are bad for you, encouraging outbreaks. What foods are good for discouraging outbreaks. The connection between genital herpes and stress. What herbs actually suppress the herpes virus. How to heal your body naturally and safely. How to manage stress in your life.

Stop Herpes Now Overview


4.6 stars out of 11 votes

Contents: EBook
Author: Dr. David Hogg
Price: $49.95

Download Now

Herpesvirus saimir in T cells of nonhuman primates

The use of herpesvirus saimir has recently been focused on human T cells, but its potential use in various monkey systems should not be overlooked, as, on the one hand, herpesvirus saimir is a tumour virus of New World monkeys, and, on the other, Old World monkeys like macaques are widely used as a model for human diseases.

Herpes Simplex Viruses

Herpes simplex viruses (HSV) are enveloped double-stranded DNA viruses in the herpesvirus family. HSV I and II have the capacity to invade and replicate in the central nervous system, establish latent infection, and recur in the presence of humoral and cell-mediated immunity. Latent stages of HSV I and II occur as a result of viral entry into sensory nerve endings following primary infection. The virus is then transported to the nuclei of sensory ganglia where, in the majority of patients, it remains for the life of the individual. Reactivation often follows local or systemic stimuli, that is, physical or emotional stress, fever, exposure to ultraviolet light, tissue damage, or immunosuppres-sion. The spectrum of HSV disease includes primary and recurrent infections of mucous membranes (i.e., gingivostomatitis, herpes labialis, and genital HSV), kerato-conjunctivitis, neonatal herpes, visceral HSV infections in immunocompromised hosts, and HSV encephalitis (17,18). More than one third...

Herpes simplex Virus HSV

Pathogen, pathogenesis, and clinical picture. The viral genome codes for about 90 proteins, categorized as immediate early (regulatory functions), early (DNA synthesis), and late (structural) proteins. Herpes simplex viruses are classified in types 1 and 2, which differ both serologically and biologically (host-cell spectrum, replication temperature). Initial infection with herpes simplex type 1 usually occurs in early childhood. The portal of entry is normally the oral mucosa (oral type) and the infection usually manifests as a gingivostomatitis. The viruses then wander along axons into the CNS, where they persist in a latent state in the trigeminal (Gasseri) gang- 420 8 Viruses as Human Pathogen Herpesviruses - lion. As with all herpesviruses, the pathogen remains in the macroorganism permanently after the primary infection. Following reactivation (endogenous recidivation), the viruses follow the same route back to the periphery, where they cause the familiar vesicular exanthem...

Cytomegalovirus Infections

Cytomegalovirus (CMV) infections and end-organ disease following bone marrow or solid organ transplant usually represent reactivation of latent infection more rarely, they are new infections in a seronegative host. Such infections are associated with a high degree of morbidity and mortality. Although effective antiviral therapies such as ganciclovir and foscarnet are available, they are associated with significant toxicities, and at least in the case of HIV-associated CMV infections, resistance to these agents has been demonstrated. Because of this potential synergistic effect with antiviral therapy, and the antibody's long half-life after intravenous administration (approximately 14 days), several trials were conducted of the administration of MSL 109 with standard therapy (either gan-ciclovir or foscarnet ) for the treatment of CMV retinitis in patients with the acquired immunodeficiency syndrome. The first was a phase I II study in which patients received either 0.25, 0.5, 1.0,...

Host NK Cells Play a Central Role in Host Defense Against Cytomegalovirus

A complex network of cells, soluble factors, cellular receptors, and intracellular signaling pathways organize the innate response against MCMV infection 15, 62, 76, 81, 95 . NK cells have a unique and nonredundant role in combating viral disease, particularly during the very early stages of infection 11 . In certain mouse strains relatively resistant to MCMV infection, depletion of NK cells results in an increase of viral titers by approximately one thousandfold in certain tissues 92,105 . Moreover, the identification of spontaneous mutations, as well as the characterization of models of targeted mutagenesis, helped to define NK cells as a major participant in host defense against herpesviruses. For example, a link between resistance to MCMV infection and NK cell function was established by studies showing that beige mice (whose NK cells have defective cytolytic granule formation) have increased susceptibility to MCMV 94 . Similarly, mice carrying targeted mutations within genes...

Herpes Simplex Virus Infection

Herpes simplex virus type 1 and 2 (HSV-1 and HSV-2) are common human pathogens infecting respectively more than 90 and 20 individuals in Russia, respectively (Barinskii et al. 2005). HSV-1 and HSV-2, producing primary and reactivation infections, are the causative agents of human diseases, including pharyngitis, herpes labialis, encephalitis, and eye and genital infection (Cunningham et al. 2006). HSV interacts with epithelial cells and replicates. Then HSV is transported within the axons of sensory nerve endings at the infection site to the peripheral ganglion, where the virus establishes latent infection (Garner 2003). Rarely, HSV leads to the development of encephalitis. After replicating in epithelial cells, HSV remains latent in sensory neurons. However, while HSV-1 usually affects oral mucosa, HSV-2 injures genital mucosa. Herpes virus infection in an expectant mother can result in prenatal transmission to a newborn (Hollier and Grissom 2005 Abrahams and Mor 2005). viral...

Herpes Simplex Virus Type Ii Hsv2

Genital herpes simplex virus (HSV) infection is not a reportable disease but is considered to be extremely common in the U.S. with approximately 45 million adults (approx 22 of the population aged 15-74 yr) estimated to be infected in 1990, based on the serologic results of a random sampling of civilian adults examined as part of the National Health and Nutrition Examination Survey (NHANES III) (12). This represents a 32 increase compared to 1978, when the seroprevalence of HSV-2 was 16 among the adult population during NHANES II (13). The prevalence of HSV-2 infection increased with increasing age, and the odds of having HSV-2 were higher in women (odds ratio OR 1.6), blacks (OR 5.7), previously married individuals (OR 2.0 - 2.8), and those with lower family income (OR 1.2) (13). The highest seroprevalences in NHANES III were seen in black men and women aged 60-74 (61 and 81 , respectively) (12). Therefore, HSV-2 infection is prevalent in older adults and should be considered in the...

Human Herpesvirus HHV

Pathogen, pathogenesis, clinical picture. HHV-6 was isolated in 1986 in patients suffering from lymphoproliferative diseases and AIDS. The virus shows T-cell tropism and is biologically related to the cytomegalovirus. HHV-6 exists in two variants, HHV-6A and HHV-6B. The pathogenic implications of their reactivation have not yet been described. HHV-6B is the causal pathogen in exanthema subitum (roseola infantum), a disease that is nearly always harmless, characterized by sudden onset with high fever and manifests as a typical exanthem in small children. Reports of HHV-6-caused illness in adults are rare and the clinical pictures described resemble mononucleosis (EBV-negative mononucleosis). Apparently, how- 8 ever, this virus can also cause severe infections in bone marrow transplant patients (pulmonary and encephalitic infections). HHV-6A has not yet been convincingly implicated in any clinical disease. Diagnosis and epidemiology. HHV-6 can be cultured in stimulated umbilical...

Transformation of macaque B cells with herpesvirus papio

B cells from macaques like Rhesus monkeys (Macaca mulata) and cynomol-gus monkeys (Macaca fascicularis) can be transformed by herpesvirus papio, an EBV-like virus of baboons (Papio hamadryas) (71-73). The herpesvirus papio-producer cells S594 (71) are seeded at 2 X 105 ml in complete RPMI and cultivated for 10 d at 37 C. The supernatant is then filter-sterilized and stored in aliquots at -80 C. Transformation of fresh macaque mononuclear cells is performed in the same way as for the human EBV protocol. The success rate seems to be lower than seen with human B cells and EBV (73). In a similar way, the Rhesus lymphoma cell-line LCL 8664 (ATCC CRL-1805) can be used to produce Rhesus-EBV (74). The cells are seeded at 2 X 105 ml in complete RPMI medium and cultivated for 10 d at 37 C and thereafter for 10 d at 33 C, before the virus-containing supernatant is harvested. The use of human AB serum instead of FCS when employing Rhesus-EBV for B-cell

Introduction To Herpesviruses

What is a Herpesvirus Identification of a virus in the family Herpesviridae is based on the morphology of the virus particle. Viewed through an electron microscope, the virions of different members of the Herpesviridae family are indistinguishable and consist of four distinct components the core, capsid, tegument, and envelope (Fig. 1) (1). The core contains a double-stranded DNA genome arranged in an unusual torus shape that is located inside an icosadeltahedral capsid that is approx 100 nm in size and contains 162 capsomeres (2). Located between the capsid and the viral envelope is an amorphous structure termed the tegument that contains numerous proteins. The tegument structure is generally asymmetrical, although some virus members (such as human herpesvirus 6 HHV-6 and human herpesvirus 7 HHV-7 ) have been shown to have well-defined tegument structures (3,4). Presumably, the tegument is responsible for connecting the capsid to the envelope and acting as a reservoir for viral...

Herpes Simplex Virus Treatment with Antimicrobial Peptides

The herpes virus infection represents a significant challenge for public health. The innate immunity plays an important role in herpes simplex virus (HSV) elimination. The innate antiviral immunity has not been comprehensively studied. The recent investigations demonstrate that Toll-like receptors are actively involved in the virus recognition. The complement and natural antibodies, as well as cytokines and antimicrobial peptides, are the first molecules to bind to virions. In this chapter, some mechanisms of the innate antiviral immunity are discussed and treatment regimens are proposed. The complex of native cytokines and antimicrobial peptides (CCAP or Superlymph) proved to inhibit the virus reproduction in vitro. Protegrines, as a CCAP component, were active against the virus. Considering all the data, we conclude that the complex of native cytokines and antimicrobial peptides produces both immunomodulating and antiviral effects.

Herpes Virus Infections 51 Varicella Zoster

Varicella-zoster virus (VZV) is a DNA virus and a member of the herpes virus family. It causes two distinct clinical syndromes primary disseminated infection, which is manifested as chickenpox, and reactivation of latent virus in the dorsal root ganglia, leading to herpes zoster or shingles. Herpes zoster is a painful, vesicular exanthem which erupts in one to two dermatomes after a prodrome of days to weeks and may take up to a month to heal (86). Most patients report a deep aching or burning sensation, altered sensation to touch with paresthesias, dysesthesia, or hyperesthesia. Herpes zoster is a common condition with a cumulative lifetime incidence of 10-20 with most of the risk concentrated in older age (87). The overall incidence is 215 per 100,000 person-years, but rates rise sharply with increasing age to 1425 100,000 for persons older than 75 yr. Therapy for Acute Herpes Zoster Within 72 Hours of Rash Acyclovir 800 mg, five times a day 7-10 d Because PHN is often refractory to...

Treatment of HSV Infections

Nowadays, a wide range of drugs against herpes infection is manufactured, including acyclovir, which blocks viral DNA synthesis. However, since herpes virus is associated with lowering activity of NK and production of IFNs, it is conceivable to use cytokines, such as IFNs, for antiviral therapy. There are three TLR agonists (poly I C, imiquimod, and CpG ODNs), which have proven efficacy against experimental HSV-2 infections (Pyles et al. 2002). Synthetic versions of these agonists have been tested in human clinical trials for other purposes and, generally, were well tolerated. Synthetic stabilized version of dsRNA triggers TLR3 pathways to elicit production of IFN and other antiherpetic cytokines. TLR3 signaling is mediated by IFN regulatory factor 3, a potent transcriptional regulator of the antiviral immune response, or by the MyD88 pathway. Poly I C also significantly enhanced disease resolution in animals (Thompson et al. 1996). Synergistic effect of CCAP and acyclovir was noticed...


Three human herpesviruses belong to the alphaherpesvirus subfamily HSV-1, HSV-2, and VZV. HSV-1 and HSV-2 belong to the genus simplexvirus, are very closely related at genetic and nucleic acid levels, and produce similar diseases (reviewed by Whitley and Gnann (13)). Clinically, both HSV-1 and HSV-2 cause a variety of syndromes ranging from inapparent infections and self-limiting cutaneous lesions to fatal encephalitis. In addition, both viruses establish and maintain a latent state in nerve cells from which recurrent HSV infections arise. In a primary infection, HSV enters the body through a mucosal membrane or abraded skin and establishes infection locally in epithelial cells. Viral replication in the epithelial cells results in the amplification of virus, the formation of a virus-filled blister, and the elicitation of both cellular and humoral immune responses. The virus then spreads from the site of primary infection by retrograde transport to the nuclei of sensory neurons that...


There are three human herpesviruses belonging to the subfamily betaherpesvirinae CMV, HHV-6, and HHV-7. CMV was originally given the name salivary gland virus when it was cultivated in 1956 from several salivary gland tissues (51-53). The more descriptive name of cytomegalovirus was given by Weller in 1960 (54). CMV infects epithelial cells, polymorphonuclear leucocytes, and T cells in the infected host (55). CMV is the prototype of the betaherpesvirinae, and until 1986 it was the sole human member of this subfamily. In 1986, a novel virus was isolated from the lymphocytes of individuals with lymphoproliferative disorders (58). This subsequently was found to be a newly discovered herpesvirus and is now termed human herpesvirus 6 (HHV-6). Four years later, in 1990, another novel herpesvirus was isolated from cultured lymphocytes of a healthy adult (59). This virus was found to be highly related, yet distinct from HHV-6 and was given the name human herpesvirus 7 (HHV-7). HHV-6 and HHV-7...


There are currently two human herpesviruses belonging to the gammaherpesvirinae subfamily EBV and HHV-8. EBV is the prototype for the Lymphocryptovirus genus while HHV-8 belongs to the genus Rhadinovirus. Members of both genera are characterized by a tropism for lymphoid cells and the ability to induce cell proliferation in vivo resulting in lymphoproliferative disorders. In 1994, using representational difference analysis Chang and colleagues (79), described the detection of DNA sequences in AIDS-associated Kaposi's sarcoma (KS) lesions belonging to a new human herpesvirus termed Kaposi's sarcoma-associated herpesvirus (KSHV) or HHV-8. The predicted amino acids encoded by these DNA sequences were found to share homology to proteins encoded by herpesvirus saimiri (HVS) and EBV. Latency of the gammaherpesvirinae is quite unique distinct from that of the alpha-herpesvirinae and betaherpesvirinae. EBV infection of B cells triggers the expression of several latent-specific proteins whose...

Herpesvirus saimir

Herpesvirus saimir (16) is the prototype of the genus -herpesviruses or rhadinoviruses (17, 18). The closest relative of HVS in humans is human herpesvirus type 8 (HHV-8), which is associated with Kaposi's sarcoma and rare types of B-cell lymphoma (19). Herpesvirus saimir is not pathogenic in its natural host, the squirrel monkey (Saimir sciureus), and can easily be isolated from the peripheral blood of most animals (20, 21). In other South American monkeys such as common marmosets (Callithrix jacchus), cotton-top tamarins (Saguinus oedipus), and owl monkeys (A o tus trivirgatus), as well as in some breeds of rabbit HVS infection causes fulminant polyclonal T-cell lymphomas and acute lymphatic leukaemias (22-27). The various strains of herpesvirus saimir are assigned into subgroups A, B, and C on the basis of DNA sequence divergence in the transformation associated region (28, 29). Strains of subgroup A and C are highly oncogenic in various species of New World monkeys (genus...


This drug is used cautiously in patients with pre-existing neurologic, renal, hepatic, respiratory, or fluid and electrolyte abnormalities. The nurse gives the drug with caution to patients with a history of seizures. Acyclovir is a Pregnancy Category C drug and is used cautiously during pregnancy and lactation. Incidences of extreme drowsiness have occurred when acyclovir is given with zidovudine. There is an increased risk of nephrotoxicity when acyclovir is administered with other nephrotoxic drugs. When administered with amphotericin B, the risk of nephrotoxicity is increased. Administration with probenecid causes a decrease in the renal excretion of acyclovir, prolonging the effects of acyclovir and increasing the risk of drug toxicity.


Properties of Herpesviridae 318 Herpes Simplex Viruses 323 Cytomegalovirus 334 Human Herpesvirus 6 341 Herpes B Virus 346 All herpesviruses have the capacity to persist in their hosts indefinitely in the form of an episome in the nucleus of the cells that harbor them. Virtually every vertebrate species that has been carefully searched is found to support at least one host-specific herpesvirus which has evolved with that host species for millennia. Sometimes, as in humans, host-specific herpesviruses of different subfamilies occupy distinct ecologic niches, noncompetitively, in particular types of cells within a given individual (Table 20-1). Varicella (chick-enpox) and herpes simplex viruses establish latent infections in neurons. On reactivation, the varicella virus precipitates an attack of herpes zoster (shingles), whereas herpes simplex type 1 typically causes recurrent attacks of labial herpes herpes simplex type 2 is mainly responsible for genital herpes. Cytomegalovirus,...

Immune Suppression Infections And Tumors

Biologically relevant immunosuppression is always accompanied by repeated infections with opportunistic bacteria or unusual tumors. The fact that opportunistic infections and tumors are unique makes them easily recognizable by physicians. Different opportunistic infections are associated with T, B, and neutrophil cell defects (Table 1).A Neutrophil defects are associated with recurrent streptococcus, E. coli, and pseudomonas infections. Defects in T cells are associated with increased infection with intracellular microbial agents such as herpes, Pneumocystis, toxoplasma, and Coccidioides. Cytomegalovirus Herpes simplex Herpes zoster Listeria Legionella Mycobacteria Pneumocystis Toxoplasma Candida albicans Cryptococcus Coccidioides

Design and Construction of the Lentiviral Transfer Vector

(For a general reference on retroviral design, see (Lois et al. 2001). The basic design of the transfer vector consists of a cassette in which a promoter (P) drives the expression of a gene of interest (G) and this P+G cassette is inserted into a lentiviral vector flanked by LTR sequences (Lois et al. 2002). In most cases the engineering of a lentiviral transgene construct is a straightforward procedure. In some situations, however, some P+G combinations might be problematic and require some modifications. Several considerations have to be taken into account before engineering a lentiviral transfer vector. First, the capsid of the retrovirus has a maximum capacity of approximately 12 kB. Because the transfer vector contains LTRs and some sequences necessary for reverse transcription and packaging, the theoretical maximum size of the P+G cassette is 10 kB. Second, lentiviruses have an RNA genome and, therefore, the production of recombinant viruses might be affected by RNA processing...

Geneenvironment Interactions

Infectious diseases result from interactions between the host and pathogen, and understanding these diseases requires understanding not only alterations in gene and protein expressions within the infected cells but also alterations in the surrounding cells and tissues. Although genome and transcriptome analyses can provide a wealth of information on global alterations in gene expression that occur during infections, proteomic approaches allow the monitoring of changes in protein levels and modifications that play important roles in pathogen-host interactions. During acute stages of infection, pathogen-coded proteins play a significant role, whereas in the chronic infection, host proteins play the dominating role. Viruses, such as hepatitis B (HBV), hepatitis C (HCV), and human papillomavirus (HPV), are suitable for proteomic analysis because they express only eight to ten major genes.45 Analyzing a smaller number of genes is easier than analyzing the proteome of an organism with...

Detection of antimicrobial resistance

PCR-based methods for the detection of antimicrobial resistance have been applied to bacteria including methicillin-resistant S aureus, vancomy-cin-resistant enterococci, and multidrug-resistant N tuberculosis. Detection of resistance to antiviral agents by molecular methods has also been described for acyclovir-resistant herpes viruses and HIV resistant to reverse transcriptase inhibitors and to protease inhibitors. Currently, none of these assays are available commercially but they have been used in a number of reference and research laboratories. The identification of methicillin resistance in S aureus represents an ideal application of NAA methods because the reliable detection of methicillin-resistant S aureus using culture and susceptibility tests may be problematic because expression of resistance (mec A gene) is usually heterogeneous and is influenced by culture conditions, especially in strains with low-level resistance 99,100 . Multiplex PCR and RT-PCR allow the...

Ebv And The Immune System

EBV, a large (172,000 basepairs) herpesvirus, preferentially infects B lymphocytes in humans and causes lifelong infection. In developing countries, well over 90 of individuals are infected before the age of 2 yr (2,3). In industrialized countries, such as the United States, only 25-40 of children have been infected by the age of 2, but approx 75-90 of individuals will have acquired the infection by the age of 25 (4). Primary infection by EBV results in two main responses, depending on the age of the individual and the maturity of the immune system. If the primary infection occurs in early childhood, the immune response and clinical symptoms are almost always clinically silent, that is, quiescent seroconversion in contrast, about two-thirds of infected older children and adults will develop overt IM (2).

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.

Human genome amplification

PCR is not the tool of choice for performing exhaustive mutational analyses of large human genes that comprise many exons, such as the cystic fi-brosis or breast cancer genes 24 . Interpretation of NAA test results is not always clear-cut. For example, assays may detect the residual DNA of a pathogenic microorganism even after successful treatment, and it is not clear whether this represents the presence of a small number of viable organisms or amplified DNA from nonviable organisms. PCR tests should not be used to monitor the effectiveness of a course of therapy and physicians must be aware of the laboratory testing procedures. In addition, the meaning of a positive PCR test result has not been validated for all infections. For example, it is uncertain whether a positive PCR test result for cytomegalovirus or Chlamydia from a patient's peripheral blood mononuclear cells or synovial fluid or tissue represents active disease, latent infection, or is reactive. Similarly, detection of...

Replication of Viral DNA

Herpesviruses encode many or all of the replication proteins required for DNA replication, including a DNA polymerase, a helicase, a prirnase, a single-stranded DNA-binding protein, and a protein recognizing the origin of replication. Poxviruses, which replicate entirely within the cytoplasm, are self-sufficient in DNA replication. Hepadnaviruses, like the retroviruses, utilize plus sense ssRNA transcripts as intermediates for the production of DNA bv reverse transcription. The ssDNA parvoviruses use 3' palindromic sequences that form a double-stranded hairpin structure as a primer for cellular DNA polymerase.

Affinity Centrifugal Ultrafiltration MicroconcentratorESIMS

An ultrafiltration microconcentrator is a useful tool for separating high-molecular-weightbiopolymers from small molecules. These devices consist of a centrifuge tube, which has mounted on its base an ultrafiltration membrane, which is designed to retain molecules above a selected molecular-weight cutoff. On centrifugation, the higher-molecular-weight components are retained and concentrated in a small volume of retained solvent. These microconcentra-tor devices have been evaluated and used to rapidly and efficiently screen drug candidate libraries by centrifuging incubated drug candidates and protein targets whereby the proteins and noncovalently bound protein-drug complexes are retained and the free drug candidates pass through the ultrafiltration membrane to waste. The protein-drug complexes are then denatured. The formerly bound low-molecular-weight drug candidates are finally separated from the protein and identified by ESI-MS. Henion and co-workers 48 developed an affinity...

Emergence and persistence in macro and micro environments

Unlike the human herpesviruses, the mosquito-borne viruses that are normally maintained in (for example) birds have been under no selective pressure to accommodate to human immune response mechanisms. The same may be true for many of the emerging pathogens that impact on humans and domestic animals suddenly, or sporadically, as a consequence of changes in culture, behaviour and or environment. The need to deal effectively with this enormous spectrum of novel infectious agents is likely to have been one factor driving the extreme diversity of both the B cell (immunoglobulin) and T cell receptor (TCR) families 1,7, 42 . Another may be the rapid variation associated with the error-prone copying mechanisms of some RNA viruses. Furthermore, as the T cells focus on complexes (epitopes) formed by the binding of processed viral peptides to major histocompatibility complex (MHC) molecules 131 , the extreme polymorphism of the MHC 34,92 can also be considered to reflect the evolutionary need to...

Helper and effector CD4 T cells

Activated CD4+ T cells play a very important role as direct mediators of immune control in the host response to intracellular bacteria 67 and herpesviruses 81 . In general, a primary requirement for these CD4+ T cell effectors 28 is the production of IFN-y. Mice that are CD4+ T cell deficient as a consequence of disruption of the H2I-Ab gene can only partially limit the lytic phase of murine Y herpesvirus 68 (y HV68) infection, and succumb after about 100 days with a late-onset, wasting disease 25 . Experiments with the influenza A viruses suggest that CD4+ T cells promote recovery by providing help for the antibody response 121 , though there is other evidence that they can function directly in the site of pathology 136 . Selective priming of CD4+ T cell memory can lead to a more rapid antibody response to Sendai virus, to greater localization of CD4+ T cells to

Oligonucleotide Mapping

Several hundred bacterial endonucleases, called refuel ion endomu lenses, have been identified and purified from various bacteria Each recognizes a unique short, palindromic sequence of nucleotides (a sequence that reads fhe same backward as forward), usually four to six nucleotide pairs long A given restriction endonuclease cleaves the DMA into a precise number of fragments of precise sizes, determined by the location and fiequency of the particular palindromic sequence it recognizes. These DNA fragments may be separated by gel electrophoresis. Different viruses, even very closely related strains of the same virus, yield characteristically diflerent restriction endonuclease fragment patterns, sometimes called fingerprints or restriction fragment length polymorphisms (RFLPs). These have been invaluable for distinguishing between different species or strains of viruses with large genomes, such as poxviruses or herpesviruses. The order of the fragments can be determined to provide a...

Properties of human growthtransformed T cells

Well-characterized CD4+ T-helper cell clones specific for myelin-basic protein (12, 60), tetanus toxoid (2), bovine 70-kDa heat-shock protein (Hsp70), Lolium perenne group I antigen, Toxocara canis excretory antigen, purified protein-derivative from Mycobacterium tuberculosis (58), have all been successfully transformed, with preservation of their antigen-specificity. Growth transformation of CD8+ EBV-reactive T cells by herpesvirus saimiri has also been reported (45).

The Epsteinbarr Virus

The DNA-enveloped virus uncovered by Epstein, Achong, and Barr in 1964 (6) is a member of the Herpesviridae, with 162 capsomers arranged as dodecahedron enclosing a linear, double-stranded DNA of about 172 kb. The complete genomic sequence of EBV was reported in 1982 by Kieff et al. (33). The genomic structure of EBV is that of a herpesvirus group C, with both terminal and internal repeats, dividing the genome into both short and long unique sequences that contain tandem repeat elements. Such nucleotide repeats are reflected in proteins by amino acid repeat domains that can be used to characterize EBV strain isolates (34). Furthermore, the characteristic number of terminal repeats enabled the description of the monoclonality of EBV-associated tumors (35). In infected B cells, the viral genome is episomal, intranuclear, and circular, essentially as an extra chromosome that is anchored at the nuclear membrane. In latent EBV infection, replication of episomal EBV occurs during the S...

Effects of Viruses on Plasma Membrane

A conspicuous feature of infection of cell monolayers by lentiviruses, paramyxoviruses, some herpesviruses and some other viruses is the production of syncytia (see Fig. 5-2C and 5-3C), which result from the fusion of the infected cell with neighboring infected or uninfected cells. Such multinucleate syncytia may also be seen in the tissues of persons inlected with these viruses and may represent an important mechanism of spread which avoids exposure of virions to neutralizing antibodies and also allows infection to be transmitted by subviral entities such as nucleocapsids or even viral nucleic acid.

Other Morphological Changes in Virus Infected Cells

As seen at the higher resolution provided by the electron microscope, the specific and nonspecific changes in virus-infected cells are dramatic and varied. Early changes in cell structure often involve proliferation of various cell membranes for example, herpesviruses cause increased synthesis of the nuclear membrane, flaviviruses cause proliferation of endoplasmic reticulum, picornaviruses and caliciviruses cause a distinctive proliferation of microvesi-cles in the cytoplasm, and many retroviruses cause peculiar fusions of cytoplasmic membranes, infection by many viruses also leads to a disruption ol cyloskeletal fiber systems by depolymerization of microfilaments and or microtubules, despite the fact that the cytoplasmic cytoskeleton and the nuclear matrix, which provide the physical site for many metabolic activities of the cell, are also used for the subcellular compartmentalization of viral replicative processes. Later m the course of infection, many lytic viruses cause nuclear,...

Antilymphangiogenic Therapies in the Cornea

Angiogenesis and lymphangiogenesis tend to follow strong inflammatory processes in the cornea 27, 28 . There is evidence that corneal neovasculariza-tion, at least in some instances, is not only a result, but can also be a cause of corneal inflammation. The pathogenesis of herpetic keratitis seems to depend on corneal angiogenesis 29 . Anti-angiogenic therapies can prevent herpetic keratitis 29 and, indeed, could become part of future therapeutic regimens against corneal herpes infections.

Shutdown of Cellular Protein Synthesis

Most cytocidal viruses code for proteins that shut down the synthesis of cellular proteins. The shutdown is particularly rapid and profound in infections of cultured cells by picornaviruses and some poxviruses and herpesviruses. With some other viruses (e.g., adenoviruses), the shutdown occurs later and is more gradual, whereas with noncytocidai viruses such as arenaviruses and retroviruses there is no shutdown and no cell death. The mechanisms are varied, and not all are clearly understood. In cases where the inhibition of cellular protein synthesis develops gradually and late in the replication cycle, it may possibly be due to competition for ribosome subunits by the large excess of viral mRNA. Even when viral mRNA is not in excess, the shutdown may provide a selective advantage by allowing the viral message to bind to ribosomes and initiate translation, as has been described with reovirus. An adenovirus early protein inhibits the transport of processed cellular mRNAs from nucleus...

Shutdown of Cellular Nucleic Acid Synthesis

Some viruses reduce transcription of cellular mRNA, but the mechanisms are not well understood. Inhibition of cellular DNA synthesis is common, except with those DNA viruses that replicate in the nucleus. This is an inevitable consequence of inhibition ol protein synthesis, but more specific mechanisms have been described for certain viruses, these include degradation of cellular DNA by a poxvirus DNase and displacement of cellular DNA from its normal site of replication, seen with herpesviruses.

Innate Response to Pathogens

The use of genetically modified mice deficient for the type I IFNAR or components of the IFN signaling pathway, such as STAT1, clearly establish the importance of type I IFN in the resistance to viral infection in vivo. Both IFN-a p and STAT1 knockout mice are highly susceptible to viral infection and unable to establish an antiviral state. Similarly, the availability of genetically manipulated mice lacking either individual TLR receptors or cytoplasmic receptors has advanced the understanding of the cellular recognition of invading pathogens. However, it is still not completely clear what determines the specificity of the recognition and whether the receptor recognizes both the viral genome and replication intermediate. As shown with HSV-1, which is an effective IFN inducer, recognition may be complex. The unmethylated HSV-1 DNA genome is a very effective inducer of IFNa in human pDC, and this induction is dependent on TLR9 (Lund et al. 2003), while in human PBMCs, HSV-1 glycoprotein...

Cold Autoimmune Hemolytic Anemia

IgM antibodies are found less often in association with hemolysis in the pediatric age group. Most IgM autoantibodies that cause immune hemolytic anemia in humans are cold agglutinins, and cold hemagglutinin disease is almost always caused by an IgM antibody. The destruction of red blood cells is usually triggered by cold exposure. Cold hemagglutinin disease usually occurs during Mycoplasma pneumoniae infection. It may also occur with other infections, such as infectious mononucleosis, cytomegalovirus, and mumps. Cold hemagglutinin disease or IgM-induced hemolysis is usually due to reaction with antigens of the I i system. Anti-I is characteristic of M. pneumoniae-associated hemolysis and anti-i cold agglutinins are usually found in infectious mononucleosis. M. pneumoniae adherence to the red cell membrane appears to be mediated by sialic acid-containing receptors, associated with terminal galactose residues of the I antigen. The association of the infecting organism with the red...

Infection by Other Routes

The genital tract is the route of entry of several important pathogens. Herpes simplex viruses and papillomaviruses produce lesions on the genitalia and perineum. Many others, for example HIV, HTLV, and hepatitis B and C viruses, do not produce local lesions but are sexually transmitted.

How to Design a Meaningful Experimental Human Cell or Gene Therapeutic Neurosurgical Study

8 Before implantation cells can be equipped with the herpes simplex virus thymidine kinase gene (HSV-tk), rendering them susceptible to the cytotoxic effects of ganciclovir which subsequently will kill the cells that were implanted. An inflammatory response to remove the debris is the consequence.

Invasion of the Central Nervous System

The other important route of infection of the central nervous system is via the peripheral nerves, as seen, for example, in rabies, varicella, and herpes simplex. Viruses may pass either (1) centripetally from the body surface to the sensory ganglia or (2) centrifugally from the ganglia to the skin, as in the reactivation of herpes simplex or varicella (as zoster). 1 he rate of travel is quite slow, at up to 10 mm per hour Herpesvirus capsids travel to the central nervous system in axon cytoplasm, and while doing so also sequentially infect the Schwann cells of the nerve sheath. Rabies virus travels to the central nervous system in axon cytoplasm without infecting cells of the nerve sheath. Following an animal bite, the virus enters the axon cytoplasm from motor axon terminals at neuromuscular junctions less commonly, after exposure to rabies virus aerosols (as among speleologists in some parts of the world), it passes up the olfactory nerve. Lytic infections of neurons, whether due...

Herbal Alert Lemon Balm

Lemon balm is a perennial herb with heart-shaped leaves that has been used for hundreds of years. Its scientific name is Melissa officinalis. Traditionally the herb has been used for Graves' disease (see Chap. 51), as a sedative, antispasmodic, and an antiviral agent. When used topically, lemon balm has antiviral activity against herpes simplex virus (HSV). No adverse reactions have been reported when lemon balm is used topically.

Display 141 Description of Viral Infections

CYTOMEGALOVIRUS (CMV) CMV, a virus of the herpes family, is a common viral infection. Healthy individuals may become infected yet have no symptoms. However, immunocompromised patients (such as those with HIV or cancer) may have the infection. Symptoms include malaise, fever, pneumonia, and superinfection. Infants may acquire the virus from the mother while in the uterus, resulting in learning disabilities and mental retardation. CMV can infect the eye, causing retinitis. Symptoms of CMV retinitis are blurred vision and decreased visual acuity. Visual impairment is irreversible and can lead to blindness if untreated. HERPES SIMPLEX VIRUS (HSV) HSV is divided into HSV-1, which causes oral, ocular, or facial infections, and HSV-2, which causes genital infection. However, either type can cause disease at either body site. HSV-1 causes painful vesicular lesions in the oral mucosa, face, or around the eyes. HSV-2 or genital herpes HERPES ZOSTER Herpes zoster (shingles) is caused by the...

Infection of the Fetus

Most viral infections of the mother have no harmful effect on the fetus, but some blood-borne viruses cross the placenta to reach the fetal circulation, sometimes after establishing foci of infection in the placenta. Severe cytolytic infections of the fetus cause fetal death and abortion, a result that was common in smallpox, for example More important, paradoxically, are the teratogenic effects of less lethal viruses like rubella virus and cytomegalovirus (Table 6-4)

Respiratory and Oropharyngeal Secretions

Many different viruses that cause localized disease of the respiratory tract are shed in mucus or saliva expelled from the respiratory tract during coughing, sneezing, and talking. Viruses are also shed from the respiratory tract in several systemic infections, such as measles, chickenpox, and rubella. A few viruses, for example, the herpesviruses, cytomegalovirus, and EB virus, are shed into the oral cavity, often from infected salivary glands, or from the lung or nasal mucosa, and are transmitted by salivary exchange in kissing and other social activities.

Promoting an Optimal Response to Therapy

Treatment with acyclovir is begun as soon as symptoms of herpes simplex appear. The drug may be given topically, orally, or intravenously. When the drug is given orally, the nurse may give the drug without regard to food. However, if GI upset occurs, acyclovir is administered with food. Patients with a history of congestive heart failure may not be able to tolerate an increase in fluids, so it is important to monitor them closely to prevent fluid overload. Neurologic symptoms such as seizures may occur with the administration of acyclovir. When the drug is administered topically, the nurse should use a finger cot or glove to prevent spread of infection.

Other Routes of Shedding

Cytomegaloviruses, replicate in tubular epithelial cells in the kidney and are shed in the urine, this is not a major mode of transmission from human to human. Several species of viruses, for example, cytomegalovirus, are excreted in milk, which may serve as a route of transmission to the newborn infant. Many viruses can be found in semen or vaginal secretions. Viruses shed from the genital tract depend on mucosal contact for successful transmission. They include HIV, herpes simplex type 2 virus, and some papillomaviruses. Several other viruses, such as other herpesviruses, hepatitis B and C viruses, and HTLV, are now known to be readily transmissible sexually.


Abbreviations Ab antibody Ag antigen MHC major histocompatibility complex MHC-I major histocompatibility complex class I MHC-II major histocompatibility complex class II pMHC peptide-major histocompatibility complex Th T helper cells Thl type I T helper cells Th2 type II T helper cells Treg regulatory T cells TCR T cell receptor Hsp60 heat shock protein 60 ABPA allergic bronchopulmonary aspergillosis HVEM herpes virus Entry Mediator ICOS inducible co-stimulator SLAM signaling lymphocyte activation molecule CTLA-4 cytotoxic T lymphocyte antigen-4 PD-1 programmed death-1 BTLA B and T lymphocyte attenuator APC antigen presenting cells DC dendritic cells IL interleukin PBMC peripheral blood mononuclear cells IFN interferon TNF tumor necrosis factor Trl type I regulatory T cells Th3 type III T helper cells GITR glucocorticoid inducible tumor necrosis factor receptor PCP P. carinii pneumonia BCR B cell receptor CD40 L CD 40 ligand

Genetic Determinants of Viral Virulence

Ol necessity, most experimental work has been carried out with laboratory animals. The most detailed studies have been those conducted with retroviruses and oncogenic DNA viruses to determine the genetic basis of cellular transformation and oncogenicity (see Chapter 11). Experiments with herpesviruses are beginning to reveal the genetic basis of latency with these viruses (see Chapter 10). With viruses causing acute infections, those with segmented genomes have provided a more easily manipulated experimental model, since each segment of the genome of influenza viruses and reoviruses, lor example, is in most cases equivalent to one gene, and reassortants can be readily obtained. Study of a number of r assortants involving difterent genome segments enables the functions that relate to virulence to be assigned to particular genes. Using a different approach, a detailed understanding of the basis of virulence at the molecular level has been obtained with polioviruses, where it has been...

Safety Aspects of Gene Transfer

Gene transfer inserts a copy of the particular gene into the nuclear DNA. It could potentially revolutionise medicine, as a working copy of a defective gene could be inserted to treat genetic metabolic disorders, such as lysoso-mal storage diseases that account for mental retardation and affects the CNS in young children. Nowadays inserting genes into brain cells may also offer ways to slow down, or even reverse the damage from neurological disorders and stimulate brain reconstruction upon cellular therapy. Gene transfer to post-mitotic neurons (and other neural cells) has been achieved by several classes of viral vectors (Hermens and Verhaagen 1998). Herpes simplex viral and adenoviral vectors for gene transfer into brain cells must be banned for clinical trials (except perhaps for the killing of a brain tumor), because of the toxicity for several neuronal cell types. However, the use of AAV and LV vectors may be feasible in patients as absence of toxicity and destructive...

Physiologic Factors Affecting Resistance

In laboratory animals the first few weeks of life are a period of very rapid physiologic change. For example, during this time mice pass from a stage of immunologic nonreactivily (to many antigens) to immunologic maturity. This change profoundly affects their reaction to viruses like lymphocytic choriomeningitis virus, which induces a persistent tolerated infection when inoculated into newborn mice, but an immune response in mice infected when over 1 week old. In humans, the umbrella of transplacental acquired maternal antibody protects the infant against many viruses for the first few months of life The importance of this cover is shown by the fact that viruses such as herpes simplex or varicella virus can cause lethal disease in infants who are born without maternal antibodies. Rotaviruses and respiratory syncytial viruses are the most striking examples of viruses that cause severe disease only in infants in the first year or so of life. There are few striking differences in the...

Pathologic Types Of Aidslymphomas

Certain pathologic features of AIDS-lymphomas are shared, while others are quite distinct. Essentially all AIDS-lymphomas are tumors of B lymphocytes, derived either from the germinal (follicular) center of lymph nodes, or from postfollicular B cells, in the process of terminal differentiation. Four distinct pathologic types of lymphoma comprise the vast majority of all AIDS-lymphomas (8,10). Small noncleaved lymphomas, also termed Burkitt's or Burkitt-like lymphoma, tend to occur relatively early in the course of HIV infection, when CD4 cells are relatively high (1). These comprise approx 30 of systemic AIDS-related lymphomas (10). Diffuse large cell lymphoma and immunoblastic lymphomas are seen in another 30 of cases, respectively, and are often associated with lower CD4 cells in the blood, and more advanced HIV disease (9,10). These lymphomas, comprised of germinal center and preterminally differentiated B lymphocytes, are the most common lymphomas confined to the brain, but are...

Clinical Presentation Of Aidsrelated Lymphoma

Between 80 and 90 of patients with AIDS-lymphoma complain of systemic B symptoms at initial diagnosis (8,38,39), consisting of fevers, drenching night sweats, and or > 10 loss of normal body weight. Of importance, many opportunistic infections may present in similar fashion, including Mycobacterium avium complex (MAC), cytomegalovirus infection (CMV), Cryptococcus, and others. It is important for the clinician to consider lymphoma in the differential diagnosis of an HIV-infected patient with fever, weight loss, and or night sweats.

Dendritic Cells In Hiv Infection

The induction of antigen-specific immune responses is certainly the most pertinent function of DCs, and this function has been amply demonstrated. DCs exposed to infectious influenza virus or influenza nucleoprotein peptide, sendai, herpes simplex, Moloney leukemia virus, or HIV induce both proliferative and antiviral CTL responses, in vitro, in mouse and human systems (20-23). In our earliest studies of human DCs, we demonstrated that these cells, but not monocytes or B-cells, can sensitize naive T-cells to soluble protein antigens, enabling the generation of antigen-specific CD4+ helper and CD8+ cytotoxic T-lymphocyte (CTL) lines, in vitro (24,25). Nonetheless,

Dendritic Cells In Other Nonhiv Infections

Several viruses have evolved mechanisms that compromise the ability of DCs to mount an immune defense. DCs infected by measles virus are reported to lose their immunostimulatory functions and become immunosuppressive (54) Human cytomegalovirus (CMV), a ubiquitous pathogen that is normally benign in healthy individuals, is a serious cause of morbidity and mortality in immunocompromised hosts. This virus and its closely related immune murine counterpart employ many diverse strategies to avoid detection by the host immune system. Among these are their ability to interfere with MHC class I and II expression on APCs (55). Both human and murine CMV infect APCs, including macrophages and DCs, downregulate IFN-7, and induce IL-10 production, leading to decreased expression of MHC class I and II, which in turn causes immunosuppression. Chlamydia trachomatis is a common cause of sexually transmitted diseases and a leading cause of preventable blindness worldwide (57). Host defense against...

Recovery from Viral Infection

The approach least subject to laboratory artifact is simple clinical observation of viral infections in experimental animals or children suffering from primary immunodeficiencies such studies indicate a key role for T lymphocytes in recovery from generalized viral infections. Animals or humans with severe T-cell deficiencies due to thymic aplasia, lymphoreticular neoplasms, or chemical immunosuppression show increased susceptibility to herpesviruses and to many other viral infections that cannot be controlled by antibody. Perhaps the most informative example is that of measles in infants with thymic aplasia. In these T-cell-deficient infants there is no sign of the usual measles rash but rather an uncontrolled and progressive growth of virus in the respiratory tract, leading to fatal pneumonia. This reveals two aspects of the role of T cells evidently, in the normal child, the T-cell-mediated immune response controls infection in Ihe lung and plays a vital role in the development of...

Viral Infections in Immunocompromised Patients

Patterns of disease in persons with immune dysfunction depend on the nature of the disorder and the arm ol the immune system that is primarily involved in containing (or sometimes exacerbating) the particular viral infection. Thus, many viral infections in immunocompromised subjects follow the disease pattern seen in normal persons Rarely, if symptoms are largely due to the immune response, the disease may actually be milder in immunocompromised patients. Usually, however, the immunocompromised patient suffers more severe disease, and sometimes relatively innocuous viruses can prove lethal. For example, measles in patients with impaired cell-mediated immunity may produce giant cell pneumonia, sometimes several months after the acute infection, and often with fatal consequences, immunocompromised individuals are not only threatened by exogenous infections but suffer reactivation of latent viruses, notably the human herpesviruses, as well as adenoviruses and polyomaviruses. These...

Primary Effusion Lymphoma

Primary effusion lymphoma (PEL), originally termed primary effusion lymphoma or body cavity lymphoma, is uncommon, representing only a small fraction of all AIDS-lymphomas (12). PEL is associated with a newly discovered human herpesvirus, termed Kaposi's sarcoma associated herpesvirus, or HHV-8 (see also Chapter 11) (69,70). The disease has been reported in both HIV positive and HIV negative patients, although it appears more common in the former. Of interest, PEL has also been described in a cardiac transplant recipient, whose explanted heart was found, retrospectively, to be infected by HHV-8 (71). Morphologically, the malignant cell is large, and appears anaplastic with immunoblastic features. The PEL cell usually lacks B-cell markers, but is B lymphoid in origin, based upon presence of immunoglobulin gene rearrangement on Southern blot analysis. HHV-8 is present, while the malignant cell often harbors EBV as well. Clinically, patients present with effusions, such as ascites, or...

Pathogenesis of Persistent Infections

Obviously a virus cannot persist in a cell it destroys. Therefore, long-term persistence of a potentially cytocidal virus can occur only if the viral genome remains fully or partially silent. Accordingly, latency is maintained only as long as no viral gene with the capacity to kill the cell is expressed. As a rule the few early genes that are transcribed are actually instrumental in the maintenance of latency. Latency is eventually overridden, perhaps following immunosuppression and or by the action of a cytokine or hormone that de-represses transcription of the whole viral genome, leading to reactivation of viral synthesis. This paradigm is best illustrated by the herpesviruses.

CD2 Family Receptors and Infection

Cytomegalovirus has evolved numerous mechanisms to evade NK cells (Lodoen and Lanier 2005). It has been reported that downregulation of CD58 on fibroblasts results from CMV infection and that this decreases NK cell lysis of the infected targets (Fletcher et al. 1998). As EBV modulates CD48 expression (Thorley-Lawson et al. 1982), it is possible that influencing CD2 family immune receptors is common among herpes viruses. Because there is a strong association between CD2-like receptors and infection, responding to pathogens may be a principal role for these receptors.


The most common causes of pharyngitis are respiratory viruses. Adenovirus and the rhinoviruses account for approx 80 of cases of sore throat in children seen by physician (66,67). Coxsackievirus, herpesvirus, and Epstein-Barr virus can cause tonsillitis, but are less common than adenovirus (68). Adenovirus, coxackievirus, and Epstein-Barr can cause exudative pharyngitis that can mimic the appearance of strep-tococcal infection. Although exudative tonsillitis is thought to be a hallmark of group A streptococcal infection, this sign is actually present more often from adenovirus than from streptococcus.

When the Wall Comes Tumbling Down

AIDS was first reported in 1981 by a group of young physicians at UCLA, who noted five cases over a short time period of Pneumocystis carinii pneumonia in five previously healthy men. P. carinii is a fungus and is what is known as an opportunistic pathogen. These are disease-causing microbes that infect someone and provoke a good immune response. But the immune response does not drive the pathogen completely out of the host. Rather, the pathogen lives in some sort of balance with the host's immune system, kept at subclinical levels most of the time but occasionally rearing its head, only to be slapped down again. The herpes virus that causes cold sores is a common example. But these pathogens can grow out to dangerous proportions in persons whose immune systems have somehow been compromised. They are a common complication of the immunosuppression given to transplant patients, for example (chapter 13).

Helicobacter Pylori Structure

Lectin Ligand Interaction

Several animal viruses, including the influenza virus, attach to their host cells through interactions with oligosaccharides displayed on the host cell surface. The lectin of the influenza virus, the HA protein, is essential for viral entry and infection (see Fig. 11-25). After initial binding of the virus to a sialic acid-containing oligosac-charide on the host surface, a viral sialidase removes the terminal sialic acid residue, triggering the entry of the virus into the cell. Inhibitors of this enzyme are used clinically in the treatment of influenza. Lectins on the surface of the herpes simplex viruses HS-1 and HS-2 (the causative agents of oral and genital herpes, respectively) bind specifically to heparan sulfate on the cell surface as a first step in their infection cycle infection requires precisely the right pattern of sulfation on this polymer.

Post Transplant Squamous Cell Skin Cancer

Malignancies arise in 20 to 40 of transplant recipients within 20 years of receipt of graft.141 Skin carcinomas account for up to 50 of these cancers. Viruses, including HPVs, Epstein Barr virus and human herpes virus-8 are involved in the pathogenesis of post-transplant tumors, especially skin carcinomas, B-cell lymphomas and Kaposi's sarcoma. Impaired host

Epstein Barr Virus Associated Lymphoproliferative Disorders in Immunocompromised Individuals

EBV is a gamma herpes virus, a subfamily distinguished by its limited tissue tro-pism and latency. EBV enters via the oropharyngeal route and infects resting B lymphocytes through the interaction between the EBV viral envelope glycoprotein (gp350 220) and the C3d complement receptor (CD21). Infected B cells induce the immunologic response of both virus-specific and virus-nonspecific T cells during primary infection, which leads to regression of a majority of infected B cells. However, the virus persists in its latent state lifelong, by its continued presence in a small number of B cells, which express latent membrane protein 2A (LMP 2A) and small EBV encoded RNA 1 and 2 (EBERs 1 and 2). See the following listing of the functions of EBV latent antigens.

T Cells Recognize Nonpeptide Ligands

Not all T cells are self-MHC restricted and recognize only peptide antigens displayed in the cleft of the self-MHC molecule. Indeed, Chapters 2 and 8 describe ap TCR-bearing T cells (NK1-T cells and CD1-restricted T cells) that are not restricted by conventional MHC molecules. In one study, a 78 T-cell clone was found to bind directly to a herpes-virus protein without requiring antigen processing and presentation together with MHC. Human 78 T cells have been reported that display MHC-independent binding of a phospholipid derived from M. tuberculosis, the organism responsible for tuberculosis (see Chapter 9). This finding suggests that in many cases the TCR receptors of 78 T cells bind to epitopes in much the same way that the immunoglobulin receptors of B cells do. The fact that most human 78 T cells all have the same specificity suggests that like other components of the innate immune system, they recognize and respond to

Death Receptors and the

Studies have also shown that introduction of herpes simplex virus into the eyes of wild-type mice produced a transient inflammation wherein the infiltrating cells underwent apoptosis 2 . In gld mice, the lack of FasL-induced apopto-sis in these inflammatory cells resulted in massive inflammatory damage. Experiments with bone marrow chimeras demonstrated that FasL expression in parenchymal (not bone marrow-derived) tissues was required for this protection. In subsequent studies, this effect was not restricted to viral infection as introduction of Toxoplasma similarly resulted in a transient inflammatory response. In animals lacking functional FasL, this erupted into immunological damage 16 . Most importantly, ocular tissue displays functional TRAIL as determined by in vitro killing of TRAIL-sensitive tumor cell lines. When TRAIL-sensitive tumors (that were not FasL sensitive) were injected into the AC of the eye, the growth of these cells was significantly inhibited compared to...

Differential diagnosis

The more common of the life-threatening entities should be recorded. The esoteric diagnosis need not be recorded initially. A carefully thought out history and physical will guide the physician. If the more common entities are ruled out, then additional diagnostic possibilities should be considered. In the case of chest wall pain, historical facts may make it necessary to first rule out myocardial ischemia, pleurisy, and pulmonary emboli. As new information is gathered, it may become necessary to rule out dissecting thoracic aortic aneurysm, metastatic cancer, herpes zoster, and so on. In today's world of cost containment and cost-effective medicine, a logical sequential approach to differential diagnosis should be employed and documented. However, time is of the essence.

Pathologic Manifestations

In the absence of potent antiretroviral therapy, any condition that causes an inflammatory immune response is likely to induce increased HIV replication in the infected host. This has been observed with a relatively mild stimulus, such as vaccination, as well as with the more potent stimulus of intercurrent illness, such as influenza. As the disease progresses to AIDS, the opportunistic infections that follow may do the added damage of driving HIV expression by the inflammatory response they provoke, in addition to the harm the infection itself causes. Globally, infection with both HIV and tuberculosis continues to be the most difficult public health problem complicating the HIV epidemic (28). HIV disease progresses much more rapidly in persons infected with tuberculosis, who are also at greater risk of harboring multidrug-resistant tuberculosis. Chronic parasitic infections also frequently accompany HIV infection, particularly in Africa. Successful treatment of the parasite disease...

Chemotherapy of Viral Diseases

Why has our hunt for antiviral agents yielded such a meagre harvest so far The explanation is not hard to find. Being obligate intracellular parasites, viruses are absolutely dependent on the metabolic pathways of the host cell for their replication. Hence, most agents that block the replication of viruses are lethal to the ceil. In recent years, however, we have come to know much more about the biochemistry of viral replication. This has led to a more rational approach to the search for antiviral chemotherapeutic agents. Two developments, the discovery of acyclovir and the production of interferon by recombinant DNA technology, provided the pharmaceutical industry with a

Strategy for Development of Antiviral Agents

A logical approach to the discovery of new antiviral chemotherapeutic agents is to isolate or synthesize substances that might be predicted to serve as a substrate or as an inhibitor of a known virus-coded enzyme, such as a transcriptase, replicase, or protease. A further refinement of this approach is well illustrated by the nucleoside analog acycloguanosine (acyclovir), an inhibitor of the herpesvirus DNA polymerase required for replication of viral DNA. Acyclovir is in fact an inactive prodrug which requires another

Inhibitors of Viral DNA Polymerase

Many of the successful antiviral agents described to date are nucleoside analogs, most of which are restricted in their antiviral activity to the herpesviruses. The early prototypes, such as adenine arabinoside, were relatively undis-criminating inhibitors of both cellular and viral DNA synthesis which produced toxic side effects, directed especially at dividing cells in the bone marrow and gastrointestinal tract. Acycloguanosine (Acyclovir) and Homologs A major breakthrough in antiviral chemotherapy occurred in 1977 when Elion and colleagues developed a prodrug that depends on a viral enzyme to convert it to form. Acycloguanosine, now commonly known as acyclovir, is a guanine derivative with an acyclic side chain, the full chemical name being 9-(2-hydroxyethoxymethyl)guanine Fig. 16-1). Its unique advantage over earlier nucleoside derivatives is that the herpesvirus-encoded enzyme, thymidine kinase (TK), which has broader specificity than cellular TK, is required to...

DCommon adverse effects

Increased susceptibility to infection, primarily viral, such as herpes zoster, but also bacterial, and gastrointestinal intolerance, such as nausea and vomiting. aZa can lead to liver enzyme abnormalities and even clinically significant hepatitis. At times, hepatitis may be part of a hypersensitivity reaction with associated fever and hypotension. If this occurs, AZA should be stopped permanently. Pancreatitis may occur and clears when the drug is stopped.

Nonorganspecific autoantibodies

Tubuloreticular structures have been identified in labial salivary gland tissue and renal endothelium from SS patients. No successful viral isolation from salivary gland tissues has been accomplished. In one study, elevated titers of antibody to cytomegalovirus were found in SS.

Generation of antiviral CTL

Stimulator-cell population is used these cells have been previously infected with virus and are used at a time when there is maximal expression of viral proteins, but before massive shutdown of host protein synthesis or cell death has occurred. Similar principles have been applied for the generation of CTLs specific for respiratory syncytial virus (RSV), where RSV-infected B-LCLs are used as stimulator cells (11) human cytomegalovirus (H-CMV), where infected fibroblasts constitute the stimulator population (12) and measles virus (infected B-LCLs) (13). The disadvantage of using infected B-LCLs as stimulators is that because these cells express a range of EBV antigens, they also have the potential to elicit an EBV-specific response. An alternative to using whole virus is to stimulate CTLs with purified viral proteins. Although there is a theoretical advantage to using whole virus, in that it will more readily enter the class I processing pathway, purified surface antigen from the...

Immune Control Of Hiv1 Infection

Complexed with HLA class II molecules. T-helper epitopes are typically larger than HLA class 1-restricted epitopes, in the 12-17-amino acid range. They are presented via the exogenous antigen pathway and complexed with HLA class II molecules at the cell surface, where they are recognized by CD4+ T-cells. It is not known exactly what constitutes help, but it is probably composed of released lymphokines and a series of direct cell-cell interactions. The critical role of T-helper cells in response to chronic viral infection has been firmly demonstrated in animal models. For example, after LCMV infection of mice, an LCMV-specific CTL response develops that controls viremia. However, in the absence of CD4+ T-cells, either because of genetic knockout or antibody-mediated depletion, the CTL response cannot be maintained and results in persistent viremia (40-42). In contrast to other infections such as cytomegalovirus (CMV), helper responses in HIV-1 infection are typically low or absent in...

Therapeutic Strategy and Timing of Medical and Surgical Management

Initial investigations include abdominal examination focused on peritoneal signs (sometimes masked by previous corticosteroid therapy), complete blood count, serum profile, blood cultures, stool testing for Clostridium difficile, cytomegalovirus (CMV), Escherichia coli, salmonella, shield, amoeba, coagulation studies and plain abdominal and chest X-rays. A limited proctosigmoidoscopy with minimal insufflation can be helpful in previously undiagnosed patients to exclude pseudomembranous colitis or ischaemic colitis. However, barium enema and colonoscopy are usually contraindicated in the presence of acute fulminating colitis or toxic megacolon because overdistension may lead to colonic perforation. Endoscopic findings of deep ulcers can provide useful prognostic information, facilitating the decision to proceed with medical or urgent surgical treatment. Intravenous fluids are given to correct metabolic derangement, and blood products are administered for anaemia or coagulopathy. A...

The Role of IL10 in Human Infectious Diseases

Induce host IL-10 production, which may play a significant role in selectively reducing the expression of MHC class II and costimulatory molecules on the surface of antigen presenting cells, leading to reduced antigen presentation and consequently impaired immune responses (Fig. 1).89 We have demonstrated that peripheral blood mononuclear cells (PBMC) from a subset of patients infected with HSV and exhibiting recurrent genital lesions produce high levels of IL-10. The elevated levels of IL-10 persisted for prolonged periods after a recurrence, while levels of IFN-y diminished during this period. This suggested that IL-10 exerts a critical influence on recurrence of infection and HSV immunopathogenesis.90'91 Some viruses such as Epstein-Barr Virus (EBV) and Cytomegalovirus (CMV) may also encode IL-10 homologs to evade host cell defenses.92'93 The significant role of IL-10 in host immune responses against infectious agents has received tremendous scrutiny and has led to phase I clinical...

Severe combined immunodeficiency disease SCID

Due to the T cell abnormality, shortly after birth affected babies may develop disseminated yeast infections (usually caused by Monilia spp.), severe pneumonia (caused by Pneumocystis carinii) and recurrent infections caused by other opportunistic pathogens (organisms which, in healthy individuals, are normally prevented from causing disease by the immune system). Since these infections usually affect the skin and the pulmonary and gastrointestinal tracts, their prevalence in patients with SCID suggests that the defect also affects the immune mechanisms normally involved in surface and mucosal immunity. Since both the cell-mediated and humoral systems are affected, patients may die as a result of infection with common viruses such as varicella, herpes and cytomegalovirus. In addition, affected children often have chronic diarrhoea and malabsorption of nutrients from the gut, resulting in a failure to thrive.

Postoperative Considerations

The use of ice packs may reduce postoperative pain and minimize swelling. Analgesics are usually not required unless extensive areas are treated. Prophylactic courses of antiviral agents should be considered in patients with a history of herpes simplex infections in the to-be-treated area. Topical antibiotic ointment applied twice daily is indicated if posttreatment epidermal injury occurred. Mild topical steroid creams may be prescribed to reduce swelling and erythema. Any trauma, such as picking or scratching of the area, should be avoided. During the first week of healing, sun exposure should be avoided or sunblocks used. Make-up may be applied on the next day unless blistering or crusts have developed. The damaged hair is often shed during or after the first week of the treatment. Patients should be reassured that this not a sign of hair regrowth.

Immune Control Of Viral Replication

Although complete viral eradication remains a worthy goal of HIV treatment, these preliminary observations and studies suggest that long-term immunologic control over HIV replication may be more eminently achievable and just as beneficial in the long run. Analogous to other common human viral pathogens (cytomegalovirus, Epstein-Barr virus, varicella-zoster virus, and so on) that maintain some form of clinical latency following a temporary or subclinical illness, it is conceivable that immune-based therapies can induce a life-long truce with HIV that falls short of a complete cure. Avoidance of damaging high levels of viral replication without the need for costly and complex ongoing therapies would result in a dramatic change in the natural history of HIV infection for each infected individual and could potentially alter our perspective on the overall AIDS epidemic.

Epidemiology and Classification of Uveitis

Infectious causes of uveitis include viruses, bacteria, protozoa, parasites and rickettsiae. Typical organisms involve Toxoplasma gondii, Histoplasma capsulatum, Toxocara canis, cytomegalovirus, Borrelia burgdorferi, and Mycobacterium tuberculosis, for example. Most recently, a presumed viral etiology (i.e. rubella) for a form of AU, namely Fuchs heterochromic cyclitis, has been reported 13 . There is a lingering suspicion that many cases of AU are the result of infection with a pathogen that has not been recognized or is difficult to identify.

Pathology caused by the cellmediated immune response

Mononuclear cells also cause pathological changes during a cell-mediated response by lysing host cells. When the latter are infected by a virus, antigens are expressed on their surfaces providing a target for cell-mediated responses. In this way, cell-mediated immunity may contribute to the pathology of hepatitis B infection and many herpes and poxvirus infections. In addition, the autoimmune damage associated with Chagas' disease may be due to the adsorption of antigens from Trypanosoma cruzi on uninfected host cells, allowing recognition by Tcyt or destruction by antibody-dependent cellular cytotoxicity.

Infection Prophylaxis

Decontamination of bacterial and fungal organisms of the intestinal allograft is attempted before procurement by administering enteric antibiotics to the donor. Mechanical cleansing has turned out to be impractical in deceased donors. Since the graft is certainly not sterile, broad-spectrum antibiotics together with antifungal agents are given to the recipient during transplantation. Because of the powerful immunosuppression, patients are particularly at high risk for developing viral infections. The matching of allografts for cytomegalovirus is difficult to put into routine practice. Patients are given an antiviral agent (usually ganciclovir) prophylactically. Some centers add to this therapy CMV specific hyperimmunoglob-ulin in recipients of CMV positive grafts. Early diagnosis of CMV infection by a variety of means permits pre-emptive treatment of asymptomatic viremia 14 .

The paradigm and the problem

For example, Hepatitis B virus persists in approximately 20 of infected people, and 80 have only acute infections 2 . Sixty-80 of people infected with Hepatitis C virus develop persistent infections, with 20-40 having only acute infections 3 . Adenoviruses and measles virus persist in only a small percentage of infected people 4, 5 , while herpesviruses persist in most, if not all, infected people 6 . Most retroviruses establish persistent infections in their susceptible hosts, and HIV infections are both persistent and usually progressive, leading to the gradual loss of helper CD4+ T-lymphocytes and susceptibility to opportunistic infections. Although, induced immune responses appear to control Human Immunodeficiency Virus (HIV) burdens following acute infection, they apparently do not eliminate the virus. Nevertheless, a number of studies over many years have presented evidence that occasionally only the transient appearance of either HIV-specific immune...

Immunotherapy for Virus Associated Malignancies

Estimates of the fraction of human malignancies that are associated with viral infections range from 10 to 20 (1). Among viruses and their associated cancers are Epstein-Barr virus (EBV), which is associated with many different malignant diseases including lymphoproliferative disease (LPD) in immunosuppressed patients, Hodgkin's disease, Burkitt's lymphoma and nasopharyngeal carcinoma human papillomaviruses (HPV) types 16 and 18 with cervical cancer hepatitis B (HBV) and hepatitis C viruses with hepatocellular carcinoma human T-cell leukemia virus-1 with adult T-cell lymphoma and human herpes virus-8 with Kaposi's sarcoma in patients with AIDS.

Transmembrane Interactions as Immunotherapeutic Targets Lessons from Viral Pathogenesis

Multichain immune recognition receptors (MIRRs) represent a family of structurally related but functionally different surface receptors expressed on different cells of the immune system. A distinctive and common structural characteristic of MIRR family members is that the extracellular recognition domains and intracellular signaling domains are located on separate subunits. How extracellular ligand binding triggers MIRRs and initiates intracellular signal transduction processes is not clear. A novel model of immune signaling, the Signaling Chain HOmoOLigomerization (SCHOOL) model, suggests possible molecular mechanisms and reveals the MIRR transmembrane interactions as universal therapeutic targets for a variety of MIRR-mediated immune disorders. Intriguingly, these interactions have been recently shown to play an important role in human immunodeficiency virus and cytomegalovirus pathogenesis. In this chapter, I demonstrate how the SCHOOL model, together with the lessons...

Postoperative Care and Complications

Infection from either a viral, bacterial, or yeast fungal source can also prolong erythema. Infections need to be treated promptly with a change in oral agents based on culture identification and sensitivity results or based on empiric observation. If herpes simplex viral infection (HSV) is suspected, the antiviral medication should be increased to a herpes zoster dose. Valcyclovir is the antiviral agent of choice, recommended for its ability to attain higher blood levels in comparison to other anti-HSV drugs (Data on file, GlaxoSmithKline). For suspected yeast infections, additional doses of fluconazole or spectazole are recommended.

Nk And Lak Cells In Disease

The NK and LAK cells play a role in the termination of viral infections. During the early stages of a viral infection, NK cells are the primary effector cells until a CD8 T-cell response occurs. Also, NK cells may supplant the T-cell response during infections with adeno- and herpesviruses that downregulate the MHC I marker expression.

Gene Transfer with Viral Vectors

Different virus families have been investigated for their potential as gene therapy vector (see Table 1). These include vectors mainly derived from Retroviruses, Adenoviruses, Adeno-associated viruses and Herpesviruses (Herpes-Simplex virus type 1 (HSV-1), Cytomegalo-virus (CMV), Epstein-Barr virus (EBV)). Below advantages and disadvantages of viral vectors derived from different families will be briefly described. A common feature of all recombinant viral vectors is the deletion of essential genes within the viral genome. This is an important prerequisite due to biosafety issues of viral vectors and necessary to generate enough space within the viral genome for the insertion of the therapeutic gene. These manipulations lead to the generation of replication-deficient viral particles which subsequently need for their in-vitro replication either a packaging line providing the deleted genes in trans or a helper virus.16,19 In addition to the virus families described above, the family of...

Virusassociated Malignancies

EBV, also designated human herpesvirus 4, is associated with malignancies of B-cells, epithelial cells, T-cells, natural killer cells, and muscle (56,57). The development of EBV-positive tumors is associated with the latent life cycle of the virus during which it expresses up to nine viral proteins that provide targets for CTLs.

Pathogenesis of Acute Retinal Necrosis

Although much is known about the clinical presentation of ARN, about diagnosing ARN, about which among the human herpesviruses cause ARN, and about the biology of those viruses, many of the questions about the pathogenesis of ARN remain to be answered e.g. by which route(s) does the virus gain access to the retina, how much virus is needed to cause disease, and, since ARN is usually observed in immunocompetent patients, what is the contribution of immune effector cells and or of immunomodulators to retinal destruction As with many human diseases, some aspects of the pathogenesis of ARN may be understood by judicious interpretation of results from animal studies. In 1924, von Szily 32 reported that injection of HSV into one eye of a rabbit resulted in retinal destruction in the uninoculated, contralateral eye. Over 50 years later, Whittum et al. 33 described acute retinal necrosis characterized by vasculitis, retinitis and retinal schisis, with loss of the retinal architecture, in the...

Immunodeficiencies Associated With Killer Cells

Primary NK cell immunodeficiencies are rare. Perhaps the most studied of the NK deficiencies is the Chediak-Higashi syndrome that affects the nervous system, melanocytes, and the immune system. In these patients, NK cells bind to target cells but fail to deliver the lethal hit because of abnormal cytoplasmic granules. These patients have less than 10 of the normal NK cell function (Roder et al., 1983). There is an association between NK defects and severe herpes or varicella infections. NK cell defects associated with other immunodeficiencies are shown in Table 3.

Puzzles and Questions

Although there is a considerable body of knowledge about ARN from studies in human patients and from the mouse model, there remain a number of puzzles and questions about ARN. Since a large percentage of the adult human population is seropositive (and latently infected) with one or more of the neurotropic herpesviruses that cause ARN, it is not known why the incidence of ARN is so low compared with the total number of individuals who are seropositive for these herpesviruses. More information is needed about non-trigeminal sites of herpesvirus latency and also about the role of the immune system in controlling virus replication and spread at synapses, in nerve cell bodies, and in neurons. Such information might be used to design immune-based therapies to limit herpesvirus spread during acute or reactivated infection or to prevent virus reactivation. Since ARN affects only a very small subset of individuals who are acutely or latently infected with her-pesvirus and since some or all of...

Type I Ifn Induction by Nucleic Acids in Immune Cells

In contrast to TLR3, both TLR7 and 9 depend on the signaling adapter MyD88. Accordingly, PDCs derived from TLR9- or MyD88-deficient mice are unable to produce type I IFN in response to DNA viruses such as herpes simplex viruses (HSV) and murine cytomegalovirus (MCMV) (Krug et al. 2004a, 2004b Lund et al. 2003 Tabeta et al. 2004). While TLR9 was responsible for detecting viral DNA, TLR7 was shown to recognize RNA TLR7 detects synthetic short (20-27 bases) single-stranded RNA (Diebold et al. 2004 Heil et al. 2004) and short interfering double-stranded RNA (siRNA) (Hornung et al. 2005 Judge et al. 2005 Sioud 2005 reviewed in Schlee et al. 2006). The amount of type I interferon induction was dependent on the RNA sequence. Ironically, Hornung and colleagues came across a very potent type I interferon inducing small RNA sequence core motif (5'-GUCCUUCAA-3') in the attempt to knock down the interferon inducer TLR9 in PDCs using the siRNA technology (Hornung et al. 2005). It was demonstrated...

Immunity to infection in pregnancy

A number of infectious agents are thought to behave differently in pregnant women as a result of the altered immune response. These include viruses (e.g. cytomegalovirus (CMV), Epstein-Barr virus (EBV), influenza A virus), bacteria (e.g. Neisseria gonorrhoeae, Streptococcus pneumoniae) and fungi. Increased susceptibility to these infections may result from changes in the humoral immune response. Serum IgG decreases with advancing gestation. A decrease in the levels of IgM and IgM-bearing lymphocytes has also been reported in the first trimester, but these levels do not continue to decrease with advancing gestation. Antibody production in response to infection during pregnancy is probably unaltered. Despite this range of changes in immune reactivity, the human foetus usually remains relatively unaffected by maternal infectious diseases. However, there are some infectious agents which may have serious effects if the foetus is exposed during the early stages of its development. These...

Infection Associated Hemophagocytic Lymphohistiocytosis

Table 22-14 lists the triggering organisms and clinical outcomes for IAHLH. Viruses include Epstein-Barr virus, human herpes virus 6 (HHV-6), cytomegalovirus (CMV) (most common of the viruses), adenovirus, parvovirus, varicella zoster, herpes simplex virus (HSV), Q-fever virus, and measles.

Viruses and MHC Regulation and Function

Viruses can alter the function of MHC molecules by producing proteins that interact with the MHC during synthesis, translocation, or reactions with molecular chaperons (Table 1). The ICP47 protein produced by the herpesvirus interferes with the binding of the TAP protein to class I MHC molecules. Thus, MHC cannot be effectively transported across the membrane of the endoplasmic reticulum. Adenoviruses interfere with MHC I expression at a later step in the process. The adenovirus E19 protein binds to class I MHC and prevents egress from the endoplasmic reticulum. EBV produces the protein BZLF2 that binds to the B chain of the MHC II molecule in the endoplasmic reticulum. OnBZLF2-MHC3I interaction, antigen presentation is inhibited (Ploegh, 1995). Cytomegalovirus Herpes