Herpesviridae 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


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Herpes Zoster Ophthalmicus

HPI Me reports that he has had similar episodes in the past that were treated with an antiviral drug. His records indicate that he suffered the first attack at the age of 7, at which time his condition was diagnosed and treated as a severe follicular keratoconjunctivitis his records also indicate a history of recurrent episodes of herpes labialis. Treatment Trifluridine eye drops acyclovir has been shown to decrease recurrences.

Introduction to herpesviruses

The herpesviruses derive their name from the Greek word herpein, meaning to creep. More than 100 herpesviruses have been isolated from a range of hosts that includes mammals, birds, fish, reptiles, amphibians and molluscs. Eight of these viruses are human viruses (Section 11.2). A notable characteristic of herpesviruses is that, once they have infected a host, they often remain as persistent infections for the lifetime of the host. These infections are often latent infections, which can be reactivated from time to time, especially if the host becomes immunocompromised. Both primary and reactivated herpesvirus infections can either be asymptomatic or can result in disease of varying severity. The outcome depends on the interplay between the particular virus and its host, and especially on the immune status of the host.

Herpes simplex viruses 1 and

Herpes simplex viruses 1 and 2 (HSV-1 and HSV-2) initially infect epithelial cells of the oral or genital mucosa, the skin or the cornea. The virus may enter neurones and may be transported to their nuclei, where they may establish latent infections. HSV-2 is the usual causative agent of genital herpes, which is a sexually transmitted disease. In newborn

Human cytomegalovirus

In the vast majority of infections with human cytomegalovirus symptoms are either absent or they are mild. In a pregnant woman, however, the virus can infect the placenta and then the foetus, for whom the consequences may be serious. In the US about one per cent of babies are born infected with the virus (about 40 000 per year). In about seven per cent of these there is evidence of virus-induced damage at birth, including small brain size and enlargement of the liver and spleen. In other individuals damage develops at a later stage the damage may be manifest in a number of ways, such as hearing loss and mental retardation. Human cytomegalovirus can also cause severe disease (e.g. pneumonitis, hepatitis) in immunocompromised patients such as those with AIDS, those who have received treatment for cancer and those who are immunosuppressed because they have received an organ transplant.

The herpesvirus virion

Herpesviruses have relatively complex virions composed of a large number of protein species organized into three distinct structures capsid, tegument and envelope (Figure 11.2). The virus genome is a linear dsDNA molecule, which varies in size within the herpesvirus family from 125 to 240 kbp. The DNA is housed in the capsid, which is icosahedral, and the capsid is surrounded by the tegument. The HSV-1 tegument contains at least 15 protein species and some virus mRNA molecules. The envelope contains a large number of spikes (600-750 in HSV-1) composed of ten or more glycoprotein species. There are several different sizes of spike. A number of schemes have evolved for the nomenclature of herpesvirus proteins, with the result that an individual protein may be referred to in the literature by two or more different names. Most of the structural proteins are commonly named VP (virus protein). In HSV-1 the most abundant proteins in the capsid and the tegument are VP5 and VP16, respectively....

Cytomegalovirus CMV Antibody Test

Cytomegalovirus is a human viral pathogen that belongs to the herpes virus family. This virus causes serious illness in people with AIDS, in newborns, and in individuals being treated with immunosuppression therapy. CMV is the most common cause of posttransplant infection. The most severe form of CMV infection is seen in congenital infections. Infected newborns can exhibit permanent damage such as microcephaly, hydrocephaly, and chronic liver disease. Newborn diagnosis of CMV infection can be ac

Herpes Simplex Keratitis

Herpes simplex keratitis is a common corneal ulceration caused by the herpes simplex virus (HSV). c. Treatment. Treatment of herpes simplex includes topical application of idoxuridine 1 percent (Stoxil ) drops or ointment as prescribed by a doctor. It is necessary to be cautious when administering this drug to pregnant women or women of childbearing potential. If no signs of healing are apparent within three to five days, debridement is done with a cotton-tipped applicator. If healing is not apparent within a week, refer the patient to ophthalmology.

Cytomegalovirus Retinitis

Cytomegalovirus Retinitis

CMV is one of the most puzzling members of the Herpesviridae family. Ocular involvement has been reported during congenital infection and in patients with acquired immunodeficiency syndrome (AIDS) 34 . Primary infection satellite infiltrates. The optic disk is rarely infiltrated initially, but papillitis may be observed when retinitis progresses toward the posterior pole. Mild vitritis is associated with minor anterior segment inflammation. Despite slow progression of retinitis, destruction of the entire retina occurs within 3-6 months in the absence of anti-CMV therapy. Cicatricial lesions are at-rophic retina with vessel rarefaction. Fluores-cein angiography may be helpful in complex cases, when other differential diagnoses such as retinochoroidal toxoplasmosis, candida en-dophthalmitis, syphilitic retinitis, herpes simplex and herpes zoster retinitis are suspected.

Recurrent Herpes Simplex Secondary Herpetic Lesions

Recurrent Herpes Simplex Impetigo

The herpes simplex virus may be reactivated (recurrent) in an extraoral form on the lips or, inside the mouth, in an intraoral form. a. Extraoral Herpes. Cold sore blisters, also called herpes labialis (figure 1-8), are often associated with colds, trauma, fatigue, fevers, and prolonged exposure to the sun and the wind. The common site of occurrence is on the lips at the border with the skin of the face (called the vermilion border). The lesions usually consist of clusters of small vesicles that, in the early stage, contain a clear, transparent fluid. After a few hours, the vesicles rupture and form a crust or scab. The disease is self-limiting and usually disappears in 10 to 14 days. The individual is infective until complete healing has occurred. NOTE Cold sore blisters on the upper lip of this patient are caused by the herpes simplex virus. This recurring infection may be activated by prolonged exposure to sunlight and or wind. Figure 1-8. Extraoral herpes. b. Intraoral Herpes....

Primary Herpetic Gingivostomatitis

Initial exposure to the herpes simplex virus results in a generalized oral inflammation followed by vesicle formation and subsequent ulceration. Systemic symptoms of generalized illness accompany this initial attack. Most individuals have their primary exposure to this virus as infants however, this disease may also occur in young adults and elderly patients. This condition is contagious. Healing occurs spontaneously with the virus remaining in the nerve tissue, lying dormant in a latent form. Future recurrence of the condition may be either intraoral or extraoral.


Acyclovir is the most important of the available antiviral drugs. It has replaced vidarabine (ara-A), the first available antiviral agent for systemic use in serious infections. It is a synthetic purine nucleoside analogue, structurally related to guanosine. Its unique mechanism of action inhibits DNA synthesis and thus viral replication. It therefore does not affect the latent virus. There is a low incidence of development of resistance, but unwarranted use is unwise. The antiviral effects of acyclovir are particularly relevant for herpesviruses, as follows. It is especially effective against herpes simplex virus (HSV) types 1 and 2 ineffective against cytomegalovirus (CMV) (the related agent, ganciclovir, is however effective against CMV q.v.). The greatest value of acyclovir is in HSV encephalitis, in which trial results have shown a survival rate of about 80 and complete neurological recovery in about 50 . It is also of value in oral-labial, genital, rectal and neonatal HSV...

Herpes Simplex

Herpes simplex is a viral infection characterized by localized primary lesions, latency, and recurrence in the localized areas. There are two types of herpes simplex virus herpes simplex type 1 (HSV-1) and herpes simplex virus type 2 (HSV-2). HSV-1 is the causative agent for fever blisters and cold sores, as well as more serious diseases such as meningoencephalitis. HSV-2 is the causative agent for herpes genitalis, a sexually transmitted disease of the urogenital tract. Primary and recurrent infections may occur with or without symptoms. Painful, vesicular eruptions can occur on the skin and mucous membranes of the genitalia, anus, rectum, and mouth depending on sexual practices. Serologic identification of the specific HSV relies on tests that identify the type-specific antibody. Enzyme immunoassay and IFA are two tests that identify the presence of HSV antibodies in the blood. In addition to providing diagnostic information concerning HSV infections, HSV antibody testing is used...


Cytomegalovirus (CMV) is a ubiquitous DNA virus and one of the 7 human herpesviruses. It is present in many bodily fluids and is transmitted from person to person across the placenta, in breast milk, in child care centres, from communal living, from close personal contact, in blood transfusion and in transplanted organs.

Family Herpesviridae

The herpesviruses, of which more than 100 are known, infect vertebrates. A partial listing of these viruses is given in Table 6.6, together with their hosts and the diseases they cause. Most herpesviruses infect mammals or birds, but reptilian, amphibian, and fish herpesviruses exist as well. The viral genome is large, 120-230 kb, and the viruses encode many dozens of proteins, which allows them to finely regulate their life cycle. Virions are enveloped, 100-300 nm in size, with an icosahedral nucleocapsid (Figs. 2.1 and 2.16). Herpesviruses are ancient viruses that have coevolved with their vertebrate hosts. Phylogenetic trees of a number of viruses belonging the subfamily Alphaherpesvirinae are shown in Fig. 6.10. Figure 6.10A shows a tree of 14 viruses representing four genera. Genera Simplexvirus and Varicellovirus, both of which contain important human viruses as well as viruses of other animals, form well-defined taxa. Figure 6.10B compares the tree for four sim-plexviruses with...


Herpes simplex virus is a double-stranded, DNA-containing enveloped virus that causes a number of problems involving the skin, eye, oral mucosa, CNS, and genital tract. There are two types of herpes simplex virus, HSV-1 and HSV-2. HSV-1 may cause genital disease but more commonly causes nongenital infections of the mouth, lips, eyes, and CNS. HSV-2 is responsible for genital infections and neonatal infections and may cause oral lesions. Risk Factors Etiology. Genital herpes is usually caused by HSV-2 and is more commonly seen in teenagers and adults. It is transmitted by sexual activity. Presentation. Fever, regional adenopathy, and dysuria may be present in patients with primary genital herpes infection. Diagnostic Tests. The Tzanck stain may be performed on scrapings from the herpetic lesion. If herpes is present, then multinuclear giant cells and intranuclear inclusions will be detected. ELISA and immunofluorescent techniques may be useful. The diagnosis may also be...

Herpes Simplex Virus

Mucous Membrane With Herpes

HSV infection is a member of the herpesviridae family. Two serotypes of HSV have been identified HSV-1 and HSV-2. HSV-1 most often affects the mouth and is usually transmitted in childhood by contact with infected saliva. HSV-2 is generally herpes simplex hand, foot, and mouth disease rickettsialpox impetigo zoster immuno-globulin within 96 hr of exposure for naive patient otherwise, acyclovir, valacyclovir, famciclovir within 48-72 hr of rash Herpes zoster herpes simplex, associated with anogenital infection, and it usually is transmitted from anogenital or oral-genital sexual contact or transmission from a mother to her newborn. However, 14 to 47 of genital herpes results from HSV-1 (7). Thirty to fifty percent of pregnant women with a primary HSV outbreak transmit the disease to their newborn (8). Transmission generally occurs from skin-to-skin contact and introduction of the virus into the basal cell layers of susceptible mucosal surfaces. Following the primary infection, the...

Bacteriophage Lambda Terminase and the Mechanism of Viral DNA Packaging

The developmental pathways of many double-stranded DNA (dsDNA) viruses, both prokaryotic and eukaryotic, are remarkably similar. In viruses as diverse as bacteriophage X and the herpesviruses, DNA replication proceeds through a rolling circle mechanism where the circular genome serves as a template for the synthesis of linear concatemers multiple genomes in length. Concurrendy, viral gene expression produces structural proteins, which self-assemble into procapsids and, in the case of the bacteriophage, tails necessary to assemble an infectious virion. Virus assembly requires that monomeric virion DNA molecules be produced from concatemers during packaging of the DNA into a procapsid. Thus, packaging represents the convergence of the DNA replication and capsid shell assembly pathways. Genome packaging in bacteriophage X has been extensively studied and this system has been used as a paradigm for virus assembly. Here we summarize current knowledge, present a working model, and indicate...

DNA Packaging in Bacteriophage T4

The above represents an overall pathway for DNA packaging in T4, which, in many respects, is a common DNA packaging pathway among a number of well-characterized dsDNA phages. Common features among the dsDNA packaging phages include the dodecameric ring structure of the portal, a terminase complex formed by multiple copies of one small and one large subunit, the enzymatic functions associated with the terminase proteins, and the headful nature of the packaging process.2 Recent evidence suggests that the ATPase motifs in terminase are particularly well conserved among the phage packaging proteins,5 indeed, phage genomics reveals that these are among the signature proteins defining a phage quasi-species.6 The conservation appears to extend to the putative terminase from herpes viruses, which shows a particularly close resemblance to bacteriophage T4.5'7 Thus, it is likely that the dsDNA bacteriophages and herpes viruses package DNA by a common mechanism. Phage T4, with its large genome...

Building a Protective Shell for Viral DNA

Like other large dsDNA viruses, P22 assembles a protein procapsid and then inserts the DNA chromosome into this preformed container (Fig. 1). This strategy appears to be common to all dsDNA bacteriophages as well as the Herpesviridae. The genes required to build the procapsid and fill it with DNA map in a contiguous cluster on the P22 chromosome (Fig. 2). The four critical protein players in this process in P22 are analogous to those in other dsDNA viruses coat, scaffold, portal and terminase (Table 1). The coat protein shells of P22 procapsids and virions have T 7 icosahedral symmetry (each procapsid contains 420 molecules of coat, less any that are replaced by portal), and three-dimensional reconstructions of both kinds of particles have been made from cryo-electron micrographs.1115 Procapsids contain about 250 molecules of scaffolding protein in the interior, all of which leave at or before the time of DNA packaging.8,16 Scaffolding protein has essential roles in procapsid assembly...

The Portal Vertex UL6

It has long been recognized that absence of a functional HSV-1 Ul6 gene precludes cleavage of concatemeric viral DNA.44'56'65'68,69 A high degree of homology exists between Ul6 homologs encoded by herpesvirus family members indicating that the encoded proteins likely play similar roles in the life cycles of all herpesviruses. pU ,6 is a component of procapsids, types A, B and C capsids, and virions.53'56 Thus, the capsid association of pUi,6 is unaffected by scaffold loss, capsid angularization or DNA packaging, and strongly suggests that pUi,6 is an integral component of the capsid shell.

The Putative Terminase UL15 UL28 Ul33

It is logical to presume that herpesviruses encode a multisubunit functional homolog of bacteriophage terminases that specifically recognizes genomic ends within the DNA, links the DNA to the capsid, and mediates the packaging of DNA through the hydrolysis of ATP. Although the absence of an in vitro packaging system in HSV precludes definitive proof, a complex of the UlI 5 and Ul28 gene products is the most likely to fulfill the role of terminase at the present time. (The Ul28 protein was originally referred to as ICP18.582). If the Ul15 and Ul28 proteins were subunits of the HSV terminase it would be expected that they would interact with one another, transiendy associate with capsids, hydrolyze ATP, and specifically bind and cleave Pac DNA sequences. Although evidence is indirect in some cases, most of these activities have been associated with the products of UlI 5 and Ul28 and their homologs in other herpesviruses. Indirect evidence that the Ul28 and Ul15 proteins interact has...

Intranuclear Transport Proteins Ul17 Ul32

During infection with Herpes simplex virus 1, gene expression and DNA replication occur within globular intranuclear compartments termed replication compartments.99 At least four cleavage and packaging proteins, Ul6, Ul15, Ul32 and Ul33, accumulate in replication compartments at relatively early times after infection (6-8 hours).93'100102 Moreover, capsids have also been observed to colocalize completely within replication compartments at these times.101 These results have led to the suggestion that DNA packaging occurs in replication compartments however, the mechanism by which capsids are directed to these compartments is not understood. Capsid transport is apparendy a regulated function inasmuch as aggregates of procapsids accumulate in cells infected with viruses containing temperature sensitive mutations within the viral protease.44 Upon shift to the permissive temperature, the procapsids mature and the resulting type A, B and C capsids redistribute away from regions containing...

Model of DNA Cleavage and Packaging

A model for the maturation of capsids in herpesvirus-infected cells that is consistent with the current literature is depicted in Figures 2 and 4. The procapsid containing unprocessed scaffold proteins is depicted as the precursor to the angular type A, B, and C capsids found within cells infected with wild type viruses (Fig. 4). As described above, procapsids contain the unprocessed versions of the pUi26 and pUi26.5 gene products. It is believed that immature capsids are delivered via pUi,17 and pUL32-mediated transport to intranuclear replication compartments (not shown). 1. van Zijl M, Fairhurst J, Jones TR et al. Novel class of thiourea compounds that inhibit herpes simplex virus type 1 DNA cleavage and encapsidation Resistance maps to the UL6 Gene. J Virol 2000 74 9054-9061. 2. Krosky PM, Underwood MR, Turk SR et al. Resistance of human cytomegalovirus to benzimida-zole ribonucleosides maps to two open reading frames UL89 and UL56. J Virol 1998 72 4721-4728. 3. Underwood MR,...

Viral Genome Packaging Machines

Doughnut Packaging Packaging Structure

Virus assembly is a complex process that requires the temporal and coordinated activities of numerous proteins of both viral and host origin. Assembly pathways vary among the virus types, but common features are observed within certain groups. For instance, double-stranded DNA (dsDNA) viruses include the poxviruses, adenovirus, the herpesvirus groups, and many of the bacteriophages. Despite their obvious differences, common development pathways exist among these viruses, as follows. Infection of the host cell ultimately leads to the synthesis of capsid proteins that are assembled into procapsid structures. Concurrendy, viral DNA is replicated producing numerous copies of the viral genome. The assembly of an infectious virus requires that a single genome be packaged into the restricted confines of an empty procapsid. This extraordinary process represents the intersection of the capsid and DNA synthetic pathways, and is an essential step in virus assembly. Not unexpectedly, the details...

ATP Binding Site I

The consensus sequence of the Walker-A nucleotide binding motif, (G A)XXXXGK(T S), is present in a large number of enzymes capable of nucleotide binding and or hydrolysis. Two Walker-A motifs have been identified in gpl7,9,18 the N -terminus proximal SRQLGKT16M67 (Walker-Ai) and a centrally locatedTAAVEGKS299-306 (Walker-An). As shown recendy, Walker-Ai is highly conserved among all the four T4-family (T4D, RB49, KVP40, KVP20) terminase sequences (Fig. 3) as well as in numerous other phage terminases and herpes virus terminases.5'19 Extensive combinatorial mutagenesis analyses of this site revealed a striking conservation of its features. No substitutions were tolerated in the highly conserved GKT signature sequence of theT4 gpl 7 Walker-A, including the conservative substitutions G165A, K166R, andT167A19 (Fig. 4, also, see below).


With its similarity to the putative herpes viral terminases and the presence of a single critical ATPase center (other terminases reportedly have two or more ATPase sites18'71'72), the proposed ATPase motor in the large terminase subunit gpl7 offers an excellent model to elucidate the DNA packaging mechanism. The collection of unique mutants generated by the powerful molecular genetic and biochemical approaches, including the very rare conditionally lethal mutants, offer a unique resource to dissect the molecular details of ATP energy transduction into mechanical movement of DNA. The data may also have broad implications to the general understanding of energy and signal transduction mechanisms. The ATP (GTP) consensus motif is apparendy one of the most common motifs found in genomes (up to 5-10 of all expressed proteins), and may represent one of the fundamental (and ancient) motifs in biological systems.73 Numerous ATPase (GTPase) systems and molecular motors use this motif to trap...


P22 virion assembly is one of the prototypic virus nucleic acid packaging systems. Its terminase, portal, scaffold, coat and head completion proteins have little sequence similarity to the analogous proteins of other well-studied dsDNA virus types, yet a perfect parallel exists between these P22 general functions and those of their analogs in other systems. This relationship suggests that either the large dsDNA viruses (perhaps including herpesviruses, and even iridoviruses and adenoviruses 4 45) have an extremely distant common ancestor from which all their DNA packaging machines are derived or that the procapsid DNA packaging strategy represents an optimal solution arrived at more than once during the evolution of bacterial and eukaryotic viruses.

Concluding Remarks

The phenomenology of bacteriophage SPP1 DNA packaging is well known and some of the molecular mechanisms involved are among the best understood in tailed phages systems. These include the terminase recognition and cleavage of its target sequence pac, the structure and function of the portal protein, the mechanism of headful sensor, and connector assembly. Other aspects of the DNA packaging process were not yet studied in detail like the terminase-procapsid interaction, the properties and assembly of the DNA translocating complex, or the mechanism of DNA translocation. A complete picture of the DNA packaging process requires knowledge of all these molecular mechanisms and their integration in the dynamics of the infected cell. An interdisciplinary approach combining genetics, biochemistry, structural biology and bacterial cell biology, on one side, and comparative analysis of the strategies used in different virus systems, on the other side, will undoubtedly be necessary to...

Capsid Maturation

Herpesvirus Assembly

During the herpesvirus cleavage packaging reaction, DNA is inserted into preformed capsids. Cleaved viral genomes are not detected in cells infected with viruses that fail to assemble capsids, suggesting that capsids contain essential parts of the cleavage packaging machinery.32 There are four morphologic types of capsids that can be distinguished by electron microscopic examination of thin sections of herpesvirus-infected cells, and they are designated procapsids and capsid types A, B, and C.33'34 The capsid shell of procapsids is morphologically distinct from all other capsid types and appears porous and roughly spherical by electron microscopy.33'35 Procapsids contain internal scaffold proteins. Capsid types A, B and C are more angularized icosahedrons of approximately 120 nm in diameter. Type A capsids consist of only the icosahedral shell, type B capsids contain the angular shell and a roughly spherical internal scaffold, and type C capsids contain DNA and lack the...

Spread from the Portal of Entry

Lymphatic spread occurs in most cases once the organisms gain access to subepithelial tissues or serosal surfaces. Lymphatic vessels are distributed in most tissues of the body, with few exceptions such as the brain. Lymph is carried by lymphatic vessels to regional lymph nodes, where it circulates through the node and eventually returns to the systemic circulation through the thoracic duct and the great lymphatic vein. One to three liters of lymph is returned to the systemic circulation every day. Most pathogens are filtered in lymph nodes before reaching the systemic circulation, but some actually reproduce either in the endothelium of lymphatic vessels (e.g., Mycobacterium leprae)2,53 or in tissue macrophages present in the lymph nodes (e.g., Y. pestis and Brucella spp.) or lymphocytes (HIV and herpesviruses, including Epstein-Barr virus).54 Some organisms reach the systemic circulation after overwhelming the defenses in the lymph nodes (e.g., Bacillus anthracis and Y pestis)....

The Nature of Viruses

It is obvious that viruses that have larger genomes and encode larger numbers of proteins, such as the herpesviruses (family Herpesviridae), have more complex life cycles and assemble more complex virions than viruses with small genomes, such as poliovirus (family Picornaviridae). The smallest known nondefective viruses have genomes of about 3 kb (1 kb 1000 nucleotides in the case of single-stranded genomes or 1000 base pairs in the

The Many Kinds of Viruses

Three broad classes of viruses can be recognized, which may have independent evolutionary origins. One class, which includes the poxviruses and herpesviruses among many others, contains DNA as the genome, whether single stranded or double stranded, and the DNA genome is replicated by direct DNA DNA copying. During infection, the viral DNA is transcribed by cellular and or viral RNA polymerases, depending on the virus, to produce mRNAs for translation into viral proteins. The DNA genome is replicated by DNA polymerases that can be of viral or cellular origin. Replication of the genomes of most eukaryotic DNA viruses and assembly of progeny viruses occur in the nucleus, but the poxviruses replicate in the cytoplasm.

Immune Interactions Immune Evasion

There are multiple mechanisms by which microbes can persist in the body and evade the immune system. Tolerance is defined as specific reduction in the response of the immune system to a given antigen.101,102 In the case of transplacental infection, the fetus develops a certain degree of tolerance to antigens to which it is exposed. The immune system of fetuses is rather incompletely developed in utero, and microorganisms survive easily. Cytomegalovirus infects the fetus transpla-centally and produces extensive damage to multiple tissues. After delivery, infants continue shedding virions for weeks to months because they are unable to destroy the virus. Other mechanisms include the production of superantigens that stimulate a large population of T cells, which then become deleted if the encounter occurs during early development. Exposure to massive amounts of antigen in the circulation can also lead to tolerance.2,98 Immunosuppression is a well-demonstrated phenomenon that occurs during...

Chronic Allergic Eye Diseases

Chronic allergic ocular disease encompasses several disorders, such as seasonal atopic conjunctivitis, perennial atopic conjunctivitis, atopic keratoconjunctivitis (AKC) and vernal keratoconjunctivitis (VKC) 7 . Seasonal atopic conjunctivitis (SAC) is a time-limited disease and in most cases conjunctivitis is only one manifestation of additional allergic reactions (rhinitis, hay fever or a hay fever like symptomatology, and in severe cases conjunctivitis is associated with different forms of pulmonary affection). Atopic keratoconjunctivitis is a severe, bilateral, ocular allergic disease affecting adults. A familial history for atopy and an association with systemic atopic dermatitis are common. Symptoms commonly include itching, burning, and tearing. Signs include involvement of mainly upper conjunctiva in the form of a papillary conjunctivitis. The corneal epithelium reveals mild to moderate inflammatory changes that can result in scarring and neovasculariza-tion leading to...

Principles of Transmission

Other important concepts are those of horizontal and vertical transmission. Horizontal transmission refers to spread of infection from individual to individual in a given population. In contrast, vertical transmission refers to spread of infectious agents from parent to offspring. The latter is important for the maintenance of some arboviruses and rickettsial organisms in their arthropod hosts. They are transmitted transovarially from the female arthropod vector to its offspring. Human pathogens, such as T. pallidum, cytomegalovirus, hepatitis B virus, and HIV-1, are also transmitted vertically.

Is not effective in the chronic fatigue syndrome

Acyclovir is not protein-bound but is distributed evenly throughout the total body water, except in the CSF in which the level is 25 50 of that in plasma. The urinary concentration is about 10 times the plasma concentration. It has a half-life of about 3 h, which rises six-fold in severe renal failure, since it is primarily excreted in the urine. It is 60 removed by dialysis. It is probably not mutagenic nor carcinogenic. Although fetal risk has not been shown, it crosses the placenta and should be used in pregnancy only if there is a strong maternal indication. It is excreted into breast milk. Although the solution is widely compatible, it undergoes irreversible crystallization if refrigerated. Intravenous acyclovir is normally well tolerated, but it is potentially phlebitic because of its alkaline nature unless given diluted and slowly, and it can sometimes give rise to nausea or a rash. Rarely, reversible Ganciclovir is structurally similar to acyclovir and is given in the same...

Loss of Function Experiments

Nique are exciting, a number of problems may limit its application in studies of the brain. Embryo lethality resulting from toxin expression in cells essential for embryo survival is clearly a potential hazard even where tissue-specific promoters are used, minimal ectopic expression may be sufficient to result in death caused by the potent nature of these toxins. The recent development of an attenuated DT-A gene (26), which requires a higher level of expression to produce a lethal effect, may prove to be a more versatile tool in genetic ablation experiments. Another problem with these studies regards the possibility that early ablation of one cell type may lead to abnormal development of other cells through the absence of cell interactions. Specificity of ablation may not be obtained and hence any loss of function would be uninterpretable. The use of an inducible toxic gene, such as tk from herpes simplex virus in transgene constructs (27), may circumvent the developmental side...

Dysfunction of the Afferent System

Several ocular and systemic diseases cause trigeminal dysfunction and decreased tear production. Herpes zoster ophthalmicus can reduce corneal sensation in the distribution of the first division of the trigeminal nerve, and herpes simplex keratitis can result in sectoral or diffuse reduction of corneal sensation both conditions can decrease tear production 12 . Diabetes mellitus can cause a polyneuropathy that reduces corneal sensation and causes secondary tear deficit and LKC. Reduced corneal sensation and aqueous tear deficiency are considered risk factors for diabetic keratoepithe-liopathy.

Transmission of vertebrate viruses

Some viruses may be released from lesions, for example foot and mouth disease virus from lesions on the feet and in the mouth, papillomaviruses from warts, and herpes simplex virus from lesions on the lips. These viruses could be transmitted directly by contact between an infected host and a non-infected host, or they could be transmitted indirectly through contamination of the environment. Transmission of rabies virus, for example from dog to human, requires

Inclusion Conjunctivitis

Discussion Infectious mononucleosis is a systemic viral infection that is caused by Epstein-Barr virus (EBV), a herpesvirus, and is transmitted through respiratory droplets and saliva. In developed countries, it most commonly affects teenagers and young adults (kissing disease) in underdeveloped countries, it is seen as a subclinical infection of early childhood. EBV infection is associated with an increased risk of Burkitt's lymphoma, Hodgkin's disease, and nasopharyngeal carcinoma.

Transformation of Cells

The normal outcome of the infection of a cell by a virus is the death of the cell and the release of progeny virus. The major exceptions are the persistent infection of cells by retroviruses and the latent infection of cells by viruses such as herpesviruses, in which the cell survives with its properties little altered except for the new ability to produce virus. However, another possible outcome is the transformation of the cell, which involves not only the survival of the cell but an alteration in its growth properties caused by deregulation of the cell cycle. Transformed cells may be able to induce the formation of a tumor if they are produced within an animal or are injected into an animal after formation ex vivo. Transformation of a cell needs to be distinguished from tumorigenicity, the ability of the transformed cell to cause a tumor. Transformed cells may fail to cause a tumor because they are rejected by the host's immune system or because the transformed cells lack some...

Virus Receptors and Entry

Cocchi, F., Menotti, L., Mirandola, P. et al. (1998). The ectodomain of a novel member of the immunoglobulin subfamily related to the poliovirus receptor has the attributes of a bona fide receptor for herpes simplex virus types 1 and 2 in human cells. J. Virol. 72 9992-10002.

Comparison of Icosahedral Viruses

A gallery of structures of viruses determined by cryoelec-tron microscopy is shown in Fig, 2,5, All of the images are to scale so that the relative sizes of the virions are apparent, The largest particle is the nucleocapsid of herpes simplex virus, which is 1250 A in diameter and has T 16 symmetry (the virion is enveloped but only the nucleocapsid is regular), The rotavirus and reovirus virions are smaller and have T 13, Human papillomavirus and mouse polyoma virus are pseudo-T 7, Ross River virus (family Togaviridae) is enveloped but has regular symmetry, with T 4, Several examples of viruses with T 3 or pseudo-T 3 are shown (dengue 2, flock house, rhino-, polio-, and cowpea mosaic viruses, of which dengue 2 is enveloped but regular and the rest are not enveloped), B19 parvovirus has T 1, The general correlation is that larger particles are constructed using higher triangulation numbers, which allows the use of larger numbers of protein subunits, Larger particles accommodate larger...

Glioblastoma Multiforme

A common cause of polyneuropathy in adults that is usually preceded by GI or respiratory infection or by specific illnesses such as Epstein-Barr, Campylobacter enteritis, and cytomegalovirus infection. Respiratory paralysis may occur, necessitating mechanical ventilation. p.235

Structure of Other Enveloped Viruses with Icosahedral Nucleocapsids

The herpesviruses are large DNA viruses that have a T 16 icosahedral nucleocapsid (Fig. 2.5). A schematic diagram of an intact herpesvirion is shown in Fig. 2.16A. Underneath the envelope is a protein layer called the tegu FIGURE 2.16 Two views of herpes simplex virus. (A) Cutaway schematic representation showing the outer envelope with projecting spikes, the irregular inner margin of the envelope due to the tegument, and the icosahedral core containing 162 capsomeres in a T 16 arrangement. (B) Negatively stained electron micrograph of an intracellular particle without the outer envelope. One of the triangular faces of the icosahedron is outlined in red in each case. Adapted from Murphy et al. (1995, p. 114) and Dalton and Haguenau (1973, p. 92), respectively. FIGURE 2.16 Two views of herpes simplex virus. (A) Cutaway schematic representation showing the outer envelope with projecting spikes, the irregular inner margin of the envelope due to the tegument, and the icosahedral core...

Maturation Cleavages in Viral Structural Proteins

FIGURE 2.21 Gallery of budding figures of viruses representing several different families. (A) Thin section of a herpes simplex virion (Herpesviridae) in an infected Hep-2 cell. The particle is apparently coated with an inner envelope and is in the process of acquiring its outer envelope from the nuclear membrane. From Roizman (1969). (B) Row of SV5 virions (Paramyxoviridae) budding from the surface of a monkey kidney cell. Cross sections of the nucelocapsid can be seen within several of the particles. From Compans et al. (1966). (C) Influenza virions (Orthomyxoviridae) budding at the surface of a chicken embryo fibroblast. There are distinct projections on the surface of the budding virions, but not on the adjacent membrane. From Compans and Dimmock (1969). (D) Machupo virus (Arenaviridae) budding from a Raji cell. From Murphy et al. (1969). (E) Sindbis virus (Togaviridae) budding from the plasma membrane of an infected chicken cell. From Strauss et al. (1995). (F) Rubella virions...

Neutralization of Charge on the Virion Genome

DNA or RNA has a high net negative charge, and there is a need for counterions to neutralize this charge in order to form a virion. In many viruses, positively charged polymers are incorporated that neutralize half or so of the nucleic acid charge. The DNA in the virions of the polyomaviruses is complexed with cellular histones. The viral genomes in these viruses have been referred to as minichromosomes. In contrast, the adenoviruses encode their own basic proteins that complex with the genome in the core of the virion. Another strategy is used by the herpesviruses, which incorporate polyamines into the virion. Herpes simplex virus has been estimated to incorporate 70,000 molecules of spermi-dine and 40,000 molecules of spermine, which would be sufficient to neutralize about 40 of the DNA charge. Among RNA viruses, the nucleocapsid proteins are often quite basic and neutralize part of the charge on the RNA. As one example, the N-terminal 110 amino acids of the capsid protein of...

Nucleocapsid assembly 821 Helical viruses

The genome enters the procapsid through a channel located at a site that will become one of the vertices of the icosahedron. Any enzymes involved in packaging the genome are located at this site. The procapsids of some viruses, including herpesviruses, are modified at this site by the insertion of a 'portal' composed of one or more protein species.

Principles and Components

The Tc-controlled transcription activator tTA, a fusion protein comprising the N-terminally located wild-type TetR fused to the transcription activation domain of protein 16 of the herpes simplex virus, VP16 (Fig. 1A). 2. A minimal (i.e., enhancerless) cytomegalovirus immediate early (IE) promoter fused to heptamerized tetO sequences, the cognate binding sites of TetR (Fig. 1B). This promoter construct is henceforth called Ptet-1 (3) (the variants of tTA-responsive promoters are collectively referred to as Ptet). Fig. 1. (see facing page) Tetracycline-controlled fusion proteins and their target promoters. (A) Fusions between TetR rTetR with domains capable of either activating or silencing transcription, respectively. tTA is a fusion protein between the Tet repressor of the Tn10 Tc resistance operon of E. coli consisting of 207 amino acids and the 128-amino acids long carboxyterminal portion of the transactivator protein VP16 from herpes simplex virus. In tTA2, the VP16 moiety of tTA...

Generating tTArtTA Mouse Lines for Tissue or Cell Type Specific Tet Regulation

In general, this is a disadvantage, and as long as we do not know more about promoters in the context of various chromatin settings, we will not be able to circumvent this problem predictably. However, there are positive aspects of this phenomenon. Since the insertion site affects not only the specificity of a promoter but also its activity, there will automatically be a selection for animals in which tTA rtTA is not overexpressed. Thus even strong promoters like the cytomegalovirus IE promoter have been used successfully to drive tTA and rtTA in transgenic mice (16). The second advantage is that, depending on the insertion site, promoters can gain artificial specificities, which sometimes restrict Tet regulation to just a subgroup of cells for which the promoter is specific. An example is the highly hepatocyte-specific tTA mouse line, TAlap-2, (16) generated with the liver-enriched activator protein (LAP) promoter (36). Thus, it can be foreseen that a number...

Other Forms of Immunopathology

A serious condition known variously as hematophagocytic syndrome (HPS), hematophagocytic lymphohistiocytosis, and reactive macrophage activation syndrome is associated with macrophages in the bone marrow and spleen ingesting ery-throcytes and sometimes nucleated blood cells.59 The Th1 cytokines INF-y and TNF-a are largely responsible for the abnormally activated macrophages. A subgroup of those with a familial form of HPS have mutations in their perforin gene. More commonly, the condition is nonfamilial and associated with certain infections, including Epstein-Barr virus, herpes 6, malaria, and Salmonella infections and HPS may also be associated with autoimmune conditions and leukemia.

Studies With Transgenic Mice Revealing Regulatory Regions Of Genes Specifically Expressed in Megakaryocyte

In transgenic mice in which expression of the herpes simplex virus thymidine kinase gene was directed by the 5'-untranslated region of the human aIIb gene, reporter gene expression was restricted to megakaryocytes and multipotential erythroid-megakaryocytic progenitors, reflecting the expression pattern of human aIIb gene. Treatment of transgenic animals with gancyc-lovir (GCV) resulted in anemia and reversible thrombocytopenia associated with a decreased number of megakaryocytes (Tronik-Le Roux et al., 1995). Prolonged GCV treatment induced erythropenia in the transgenic mice. Assays of hematopoietic progenitor cells in vitro demon

Vaccine Formulations and Delivery

Requires that the coding DNA for the candidate vaccine antigen be placed into a plasmid, usually containing a strong eukaryotic promoter such as cytomegalovirus. Purified plas-mid in saline is then injected intradermally or intramuscularly and transfection of cells occurs. The transfected cells produce the candidate antigen, which, being intracellular, is processed and then expressed on the cell surface via class I MHC. If the cell is lysed, additional candidate antigen is released, which can then be processed via the extracellular class II pathway, or the cross-presentation pathway (see Fig. 11-4). Thus, via this methodology it is possible to generate MHC class I- and MHC class II-dependent responses to the candidate antigen.

Viral Glycoproteins that Modify Membrane Permeability

In addition to small hydrophobic viral proteins, there are other virus products that promote membrane permeabilization. This occurs with a number of virus glycoproteins (GP) that are known to increase cell membrane permeability, such as the human immunodeficiency virus gp41 (Chernomordik et al., 1994 Arroyo et al, 1995), the Ebola virus GP (Yang et al., 2000), the cytomegalovirus US9 protein (Maidji et al., 1996), the Vaccinia virus A38L protein (Sanderson et al., 1996), rotavirus VP7 and NS4 proteins (Charpilienne et al., 1997 Newton et al., 1997), the hepatitis C virus E1 protein (Ciccaglione et al., 1998), and the alphavirus E1 protein (Nyfeler et al., 2001 Wengler et al., 2003).

Human Immunodeficiency Virus HIV1 HIV2 Acquired Immunodeficiency Syndrome AIDS Test

Infection with HIV-1 is most common in the United States and HIV-2 is predominantly reported in West Africa. An individual is diagnosed as having AIDS if he or she has contracted the human immunodeficiency virus and exhibits one or more of the specific signs or symptoms associated with AIDS. Some of these signs include various types of pneumonia, cancer, and fungal and parasitic infections. Specific diseases associated with AIDS are Kaposi's sarcoma, chronic cryptosporidiosis, wasting syndrome, extrapulmonary tuberculosis, and pulmonary cytomegalovirus infection.

HLA Associations with Ocular Infections

While infections are clearly due to exogenous agents and therefore an environmental factor par excellence for ocular inflammatory disease, it is similarly clear that the host response is critical in determining disease outcome. An elegant animal model of herpes simplex virus (HSV) stromal keratitis that illustrates this, as well as the complexities of HLA in disease, has been reviewed elsewhere 16 . An HSV coat protein, UL-6, shares a seven amino acid sequence with IgG2a. Mice were protected from stromal keratitis if they had a certain IgG2a al-lele, IgG2a b. When mice were infected with HSV, it was thought that a corneal peptide that cross reacted with the specific IgG2a b allele and viral UL-6 was unmasked if mice had the IgG2a b allele they would have developed central tolerance and an immune response was not elicited. Acute retinal necrosis (ARN) is due to infection with either herpes zoster or simplex viruses. As for other manifestations of disease secondary to herpes viruses, it...

Parvovirus replication

The small genome of a parvovirus can encode only a few proteins, so the virus depends on its host cell (or another virus) to provide important proteins. Some of these cell proteins (a DNA polymerase and other proteins involved in DNA replication) are available only during the S phase of the cell cycle (Figure 4.5), when DNA synthesis takes place. This restricts the opportunity for parvovirus replication to the S phase. Contrast this situation with that of the large DNA viruses, such as the herpesviruses (Chapter 11), which encode their own DNA-replicating enzymes, allowing them to replicate in any phase of the cell cycle.

Attachment and entry

A virion attaches to receptors on the surface of a potential host cell (Figure 12.6). In the case of B19 virus the host cell is a red blood cell precursor and the receptor is the blood group P antigen. The virion enters the cell by endocytosis and is released from the endosome into the cytoplasm, where it associates with microtubules and is transported to a nuclear pore. With a diameter of 18-26 nm, the parvovirus virion is small enough to pass through a nuclear pore, unlike the herpesvirus nucleocapsid (Section 11.5.1), though there is evidence that the virion must undergo some structural changes before it can be transported into the nucleus. Nuclear localization signals have been found in the capsid proteins of some parvoviruses.


The two major serotypes of VSV are Indiana and New Jersey. They generally cause nonfatal but economically important disease in cattle, pigs, and horses. The name of the virus comes from the vesicles that it induces on the tongue and lips. Human infection is common in rural areas where VSV is endemic in domestic animals 25-90 of farmers in such areas may have anti-VSV antibodies, showing past infection by the virus. Human infection is largely asymptomatic or associated with a mild febrile illness, sometimes accompanied by herpes-like lesions in the mouth or on the lips or nose. The virus can also replicate in mosquitoes and other arthropods, and has been isolated from mosquitoes during VSV epidemics. The epidemiologic importance of mosquitoes or other hematophagous arthropods in transmission of the virus is not clear.

B Dengue Fever Dandy Fever Breakbone Fever

Although arboviruses from mosquitoes, birds, or small rodents are the principal vectors, there are many other viruses that may produce encephalitis. The masslike lesions in the temporal lobes are caused by herpes simplex. The mumps virus, other enteroviruses, or poliovirus can be the cause of encephalitis. It is also produced by the rabies virus.

Viral Delivery Systems

Viral vectors are used in the vast majority of gene therapy trials owing to their relatively high gene transfer efficiency. They may be either RNA or DNA virus based. The DNA viruses include adenovirus, vaccinia, and herpes simplex viruses. The RNA viruses include retroviruses and lentiviruses. To improve their safety, viral vectors may be designed to be replication-deficient, with no further virus particles generated following infection of the target cells. Alternatively, they may be replication-competent or replication-attenuated, in which case viral replication can occur in permissive cells. Vaccinia and Herpes Viruses The main advantages of herpes viruses are their large insert size of 35kb and their ability to infect dividing and nondividing cells. However, they are limited by their potential pathogenicity, poor transduction efficiency, and transient gene expression.

Atypical Toxoplasma chorioretinitis

Unusual manifestations of ocular toxoplasmosis exist. Bilateral, multifocal, and extensive ocular toxoplasmosis can rarely occur, and these cases have usually been in immunocompromised individuals. Toxoplasmosis can mimic acute retinal necrosis (ARN), an explosively blinding chorioretinitis usually caused by herpes viruses. Rarely, toxoplasmosis can mimic viral acute retinal necrosis (Moshfeghi et al., 2004). Since diagnosis is usually made by clinical appearance alone, therapy is usually directed first against the herpes virus, and subsequently a broader differential is entertained if instituted therapy fails to stop progression of disease. An anti-Toxoplasma regimen may be instituted in severe posterior uveitis as empiric therapy.

Eent Diseases And Disorders Section I Ocular Diseases And Disorders 31 Introduction

Disorders which affect our ability to see, hear, smell, or speak cause considerable anxiety because such conditions affect those functional areas which influence the way we interact with our environment. Most of the EENT problems seen in the field setting can be treated adequately without extensive medical intervention. Learning to differentiate, however, between those EENT disorders which must be evacuated and those which will soon be resolved will be critical in the management of casualties. Common ocular diseases and disorders include the following exudation (conjunctival discharge) gonococcal conjunctivitis inclusion conjunctivitis (swimming pool disease) herpes simplex keratitis (dendritic) uveitis cataracts corneal ulcer eye strain floaters (spots before the eyes) blepharospasm (tics) hordeolum (stye) lid disorders and other related diseases and disorders.

Recurrent Aphthous Ulcers

Recurrent aphthous ulcer (RAU) (figure 1-10) is a chronic inflammatory disease with repeated episodes of ulcerations. Recent investigations seem to indicate that the aphthous lesion is associated with an altered local immune response. This disease is characterized by small, whitish ulcers with red borders. The disease normally occurs as a single lesion or, infrequently, as multiple lesions on the wet mucous membranes of the lip, tongue, cheek, or floor of the mouth. Lesions appear as depressions on the mucous membrane and are covered by a grayish-white or light-yellow membrane. There is no vesicle formation before the ulcer appears, distinguishing this disease from viral diseases of the oral mucosa. Associated with the development of a recurrent aphthous ulcer is generally trauma, endocrine change, psychic factors, or allergy. The lesions are painful however, the condition is self-limiting with the lesions usually healing in 10 to 14 days without leaving scars. Recurrent aphthous...

Differential diagnosis

Congenital toxoplasmosis must be differentiated from other possible causes of the classic clinical acronym 'TORCH' for a series of etiologies that share similar signs and symptoms. The acronym includes Toxoplasma, rubella, cytomegalovirus, syphilis, and herpes simplex virus. However, emerging pathogens such as West Nile Virus must be considered as part of any differential in known congenital infection (Alpert et al., 2003). Recurrent toxoplasmosis with its unilateral active lesion associated with multiple adjacent chori-oretinal scars with the appropriate clinical history is virtually pathognomonic. However, clinical syndromes such as serpiginous chorioretinitis, and other infectious etiologies such as cytomegalovirus, may occasionally be considered. For the many other possible and unusual manifestations of ocular toxoplasmosis, such as pars plani-tis, the differential diagnosis is even broader, and includes autoimmune disorders such as multiple sclerosis and infections such as Lyme...

Genitalia and Anal Cultures

Ted diseases, pelvic inflammatory disease, or abnormal discharge and itching. Toxic shock syndrome and infections associated with the herpes simplex virus can also indicate a need for genital and anal cultures. Variations from Normal. Pathogenic organisms identified by genitalia and anal culture are Chlamydia, Candida, Mycoplasma, Gardnerella vaginalis, Neisseria gonorrhoeae, Treponema pallidum, and Trichomonas vaginalis. These cultures are also used to distinguish toxin-producing strains of Staphylococcus aureus and infectious processes associated with herpes simplex virus.

Varicella Zoster Virus VZV

Uveitis is much more common after herpes zoster ophthalmicus. Nearly two-thirds of patients with herpes zoster involving the ophthalmic division of the trigeminal nerve may present ocular involvement, especially without acyclovir prophylaxis. Uveitis is less frequent after an episode of varicella. Ocular inflammation is often delayed relative to the onset of cutaneous lesions. An interval of 2-4 weeks may separate both diseases. Uveitis seems to be more severe when it is delayed and associated viral retinitis should be eliminated, especially in im-munocompromised or elderly patients. Grey or brown keratic precipitates are localized in the inferior part of the cornea, but may be more diffuse with a leopard pattern (Fig. 10.4). Ischaemia of the anterior segment is classically associated with VZV uveitis. The presence of sector and patchy atrophy may be related to virus-induced ischaemia. Anterior uveitis is often acute, unilateral, granulomatous, and associated with posterior synechiae...

Human tcell leukemia virus type 1 htlv

A systemic viral infection caused by Epstein-Barr virus (EBV). a herpesvirus, it is transmitted through respiratory droplets and saliva. In developed countries, it most commonly affects teenagers and young adults (kissing disease) in underdeveloped countries, it is seen as a subclinical infection of early childhood. EBV infection is associated with an increased risk of Burkitt's lymphoma and nasopharyngeal carcinoma. QQQ p.201

Necrotizing Herpetic Retinopathies NHR

Acute retinal necrosis (ARN), progressive outer retinal necrosis (PORN) and cytomegalovirus retinitis are well-defined entities. Diagnosis is quite unequivocal when the clinical presentation is typical, but fundus examination can be difficult in the presence of cloudy media. Cun- ningham et al. reported the first two cases of AIDS-associated herpetic retinitis, confirmed by PCR and restriction analysis of the vitreous biopsy 14 . The amount of herpes virus DNA, detectable by PCR techniques in ocular fluids of patients without ocular inflammation in a control study published by Pendergast et al., appears to be quite low 53 . Therefore, the authors suggest that a positive result obtained in a patient presenting with vitreoretinal inflammation should be regarded as significant. In 1991, Fox et al. confirmed by PCR the presence of CMV genome in the AH, vitreous and subretinal fluid of patients with a clinical diagnosis of CMV retinitis 20 . Ganatra et al. used PCR to confirm the diagnosis...

Acute Retinal Necrosis

Antivirals represent the major tools in the treatment of viral retinopathies. Any delay in the initiation of antiviral therapy may be dangerous for the visual outcome of the patient. Despite a few reports on the efficacy of oral valacyclovir, intravenous administration of acyclovir remains the classical approach. It is effective against HSV and VZV. Close monitoring of the retina is necessary in order to confirm antiviral efficacy. Lesions must be stabilized after a mean period of 48 h. In resistant cases, more aggressive antiviral therapy should be initiated based on intravenous foscarnet or ganciclovir. Associations are recommended and intravitreal injections of ganciclovir seem to be efficient, especially in immunocompromised patients. Intravenous antiviral therapy must be proposed for a period of 14-21 days, after which 4g daily acyclovir or 3 g daily valacyclovir is necessary for an additional period of 1-3 months before regular tapering. The total duration of antiviral therapy...

HIV Associated Immunosuppression

CMV was among the most common opportunistic infections in patients with AIDS. Prior to HAART, CMV retinitis accounted for 75-85 of cytomegalovirus disease in patients with AIDS, with an estimated lifetime risk of CMV retinitis of 30 1 . Since the introduction of HAART, the incidence of CMV retinitis has dropped by 80 , and has stabilized at about 15 of the population at risk, mainly as an AIDS defining infection.

Treatment And Prognosis

The introduction of syndromic STI management has significant implications for the management of donovanosis. Traditional syndromic algorithms for genital ulcers have advised treating for syphilis and chancroid although, more recently, herpes management has also been included. Optimal treatment for donovanosis differs from chancroid and areas with significant prevalences of donovanosis should therefore have their own local algorithms that will ensure adequate treatment for possible cases. A good example of this local approach is in Australia where azithromycin is the drug of choice when donovanosis is suspected amongst aboriginals.16 In the past, azithromycin has often been excluded from treatment protocols because of cost but its price has decreased considerably and it should now be the universal first choice treatment for donovanosis.

Local Delivery Photodynamic Therapy Psoriasis Local Anesthesia and Anti Inflammatory Effect

One of the first suggested applications of iontophoresis was the treatment of herpes labialis and keratitis in surface tissues (82,83) in fact, iontophoresis of idox-uridine has been shown to be effective against herpes simplex viral lesions on the lip. More recently, iontophoresis has also effectively increased acyclovir skin permeation in vitro (67,84). The distribution of this antiviral agent after iontophoresis in human skin in vitro is more homogeneous than that obtained after passive application.

Gases Respiratory Care

The answer is d. (Goodnough, Am J Surg 159 602-609, 1990.) Cytomegalovirus (CMV) is harbored in blood leukocytes. CMV infection is endemic in the United States, and its prevalence increases steadily with age. While acute CMV infection may cause transient fever, jaundice, and hepatosplenomegaly in cases of large blood donor exposures, posttransfusion CMV infection (seroconversion) is not a significant clinical problem in immunocompetent recipients, and therefore blood is not routinely tested for the presence of CMV Posttransfusion non-A, non-B hepatitis, however, not only represents the most frequent infectious complication of transfusion, but is associated with an incidence of chronic active hepatitis up to 16 and an 8-10 incidence of cirrhosis or hepatoma or both. The etio-logic agent in over 90 of cases of posttransfusion hepatitis has been identified as hepatitis C.

Suicide Gene Therapy

The commonest type of cytotoxic gene therapy used in bladder cancer is based on the herpes simplex virus thymidine kinase (HSV-tk) gene. This enzyme converts a prodrug ganciclovir into the active metabolite ganciclovir monophosphate, which is then further phosphorylated by cellular kinases and inhibits DNA polymerase leading to cell death (Fig. 15.2). As the prodrug is nontoxic, the aim is to target cell killing to the tumor. Both viral and nonviral methods have been used to deliver the HSV-tk gene to ortho-topic bladder tumors in animal models. Intratu-moral injection of an adenovirus containing the HSV-tk gene together with intraperitoneal ganciclovir administration led to a threefold reduction in tumor growth over 21 days of treatment in one study, which was associated with improved survival 37 . Another group had similar results, with twofold reduction in tumor 1) The adenoviral vector (AdV) delivers the Herpes simplex thymidine kinase (TK) gene to its target tumour cell. 1) The...

Selective Tumor Cell Killing

Other viruses have been studied in bladder cancer that are not bladder specific but cancer cell specific. PV701 is an attenuated strain of Newcastle disease virus that has been shown in a phase I trial to have tolerable toxicity levels 52 . It has several favorable characteristics, such as lack of antigenic drift, absence of human-to-human transmission, and minimal toxicity. The virus infects cancer cells at doses 1000 times lower than normal cells. Currently investigators at University of Chicago Cancer Research Center are undertaking a phase I trial of intravesical administration of PV701 prior to cystectomy (W.M. Stadler, lead investigator). The herpes simplex virus G207 also shows potential and has been demonstrated to be effective in an ortho-topic bladder cancer model 53 . Histological studies showed no viral infection of normal urothelium or distant organs.

Other biological effects

Two papers have drawn attention to possible antiviral activity attributable to resveratrol. The first described inhibition of the replication of Herpes simplex virus (HSV) types 1 and 2 in a dose-dependent and reversible manner by targeting an early event in the virus replication cycle it was most effective when resveratrol was added within 1 h of infection, less effective if added 6 h later, and ineffective at 9 h post-infection. Cell-cycle delay at the S G2M interphase was noted as the likely site of action (Docherty et al. 1999). It also synergistically enhanced the anti-HIV activity of a number of nucleoside analogues in combating infection in peripheral white blood cells (Heredia et al. 2000). A third noted the ability of resveratrol selectively to inhibit two bacteria responsible for gonorrhoea and meningitis (Docherty et al. 2001).

Generation of Adenoviral Vectors by Homologous Recombination in Bacteria The AdEasy System

The general outline of the Ad-easy system is as follows The gene of interest is first cloned into a shuttle vector. Four types of shuttle vectors are available, with and without a cytomegalovirus (CMV) promoter polyadenylation site, and with and without separate CMV-driven green fluorescent protein (GFP) genes. The resultant (kanamycin-resistant) plasmid is linearized by digesting with the restriction endonuclease Pmel. Subsequently, this linearized vector and an (ampicillin-resistant) adenoviral backbone plasmid are cotransformed into E. coli BJ5183 cells. Two backbone plasmids are available differing in

Adjuvant Reactogenicity

Limiting reactogenicity of adjuvanted vaccines to a tolerable level for widespread administration to humans has been a critical problem in transition from animal models to the clinic. The first priority in formulation of MF59 was to ensure safety, thus a very conservative formulation based upon low-risk components has been utilized. Clinical testing with both influenza and herpes simplex virus (HSV) vaccines in more than 18,000 subjects have demonstrated minimal reactogenicity of these formulations and the adjuvant has been approved for both commercial use and for further testing in both infants and pregnant women.

Pituitary Gonadotropin Gene Expression

In support of the fully functional role of the human FSHp transgene, Matzuk and colleagues showed that the presence of this transgene on an FSHp-deficient background fully restored fertility in males and females (22). Restoration by the genomic FSHp transgene was more efficient than that observed following ectopic expression of the a- and FSHp-subunits, predominantly in the liver (22). This is probably a result of maintenance of appropriate regulation of the genomic sequence in gonadotropes vs the high-level FSH expression achieved ectopically from the metallothionein promoter. From these studies, it is clear that the 10-kb genomic human FSHp clone contains the necessary cis-acting elements to convey appropriate cell-specific expression to the gonadotrope, as well as appropriate hormonal regulation. Identification of specific sequences has not been accomplished however, there is evidence that at least some of the required elements are located within the proximal promoter. This stems...

Central Nervous System

Axons utilize anterograde and retrograde axonal transport to move subcellular elements toward or away from the axon terminal. Anterograde transport utilizes microtubules, is mediated by kinesin, and moves vesicles and protein to the axon terminal. Retrograde axonal transport also uses microtubules, is mediated by dynein, and transports lysosomes and recycled membrane. Exogenous substances such as herpesvirus, polio virus, and tetanus toxin affect neuron cell bodies as a result of retrograde axonal transport.

Pathogenesis of Aneurysmal Disease

Chronic inflammation plays an important role in aneurysmal disease. Much of the vessel wall destruction is undoubtedly mediated by the inflammatory infiltrate composed of T cells, macrophages, B lymphocytes, and plasma cells, but the antecedent trigger for this cellular migration remains unclear. It has been suggested that aneurysmal disease is in fact an antigen-driven immune disease from work analyzing AAA disease. Proposed antigenic activators to subsequent inflammation include elastin, interstitial collagen, oxidized low-density lipoprotein, cytomegalovirus, and artery-specific antigenic proteins such as AAAP-40. Following T-cell antigen recognition, the inflammatory cascade begins, ultimately resulting in vessel wall degradation and progression to aneurysmal disease.

Tissue Specific Expression and Developmental Regulation

Truncations of the rat POMC promoter to nucleotide -323 or -234 had either a small or no discernible effect on pituitary expression, assessed by the ratio of expressionpositive to total transgenic pedigrees and qualitative levels of reporter expression in the positively expressing lines. However, continued deletion of the 5' flanking sequences to -160 clearly abolished expression. TATA box sequences from the herpes simplex virus-thymidine kinase (HSV-TK) promoter were equivalent to native POMC promoter sequences in the context of upstream flanking sequences, suggesting the absence of critical pituitary-specific DNA binding sites in the region between nucleotides -34 and +64. Building on these initial transgenic results and information from DNase I protection assays and gel-shift assays, which utilized POMC oligonucleotide probes and fractionated nuclear proteins from AtT20 cells, we designed a series of more discrete mutations in the rat POMC promoter. These final transgenic studies...

Introduction to emerging viruses

And reassortment result in new viable combinations of genes (Section 20.3.3) new strains of influenza A virus come into this category. Some 'new' viruses that are reported are actually old viruses of which mankind has recently become aware, such as Kaposi's sarcoma-associated herpesvirus (Chapters 11 and 22).

Geographic Distribution

It affects all races, both sexes and all ages. Although it rarely appears before the age of four months. The mean age for the first episode of genital herpes is 20-25 years. Oral-labial involvement is the most frequent manifestation. The incidence of genital herpes has increased and approximately 20 of women are carriers. In the United States from 1978-1990 the incidence increased to 32 , and it is estimated there are 20 million affected individuals with 300,000-500,000 new cases per year. Fifity-five million are estimated to be seropositive for HSV-2.

Clinical Features

They occur 3-8 times the first year, 53 each month, 33 every 2-4 months and 14 more sporadically. The primary episode is the most serious, with erythema, edema and even necrosis. It lasts about 2-6 weeks, and it is accompanied by local and systemic symptoms like headache, malaise and fever. Labial herpes is generally localized at the margin between the skin and mucosa. It predominates on the lips or close to the mouth, but herpetic gingivostomatitis and geometric herpetic glossitis have been described. Genital herpes affects the glans or vulva (Fig. 53.2). Perianal and rectal herpes is seen in homosexuals. It is accompanied by tenesmus and anal discharge and is rarely complicated by urinary retention. Herpetic whitlow in children affects fingers by autoinoculation, almost always arising from an oral infection. In adults, it may be caused by HSV-2, and it follows digital-genital contact. There may be involvement of any part of the body such as cheeks, thighs, and buttocks. Neonatal...

Inflammatory Abdominal Aortic Aneurysms

An early hypothesis suggesting the periaortic fibrosis was secondary to retroperitoneal blood leakage from tiny perforations in a previously noninflammatory aneurysm has been rejected. Similarly, other theories of an initial prodromal atherosclerotic AAA developing into an aneurysm of inflammatory type remain unproven. The suggested mechanism for this transformation is by either lymphatic vessel compression by the expanding aneurysm resulting in stasis, edema and subsequent fibrosis, or as a direct consequence of an inflammatory reaction between blood in the aneurysmal sac and the aortic wall. Viral infection with herpes simplex or cytomegalovirus has also been proposed as a causal factor, with evidence of their presence in the aortic wall proven by DNA polymerase reactions.

Brain Abscess With Cyanotic Heart Disease

LP cells 400 uL with mononuclear pleocytosis mildly elevated protein normal glucose CSF PCR reveals herpes simplex virus type 1 (HSV-1) serum complement-fixing antibody titer > 1 1000. EEG spiked and slow waves localized to temporal lobes. Intravenous acyclovir. Herpes simplex virus is the most common cause of acute sporadic encephalitis in the United States. In the newborn, HSV-2 is usually the cause after the neonatal period, most cases result from HSV-1. Neonatal infection (usually HSV-2) occurs after exposure to maternal genital infection at the time of delivery. The precise pathogenesis of HSV-1 encephalitis in the older child or the adult is not clear, but viral spread into the temporal lobe by both olfactory and trigeminal routes has been postulated. p.201

Epstein Barr viruslinked cancers

Burkitt's lymphoma (BL) is a B cell tumour that occurs with a high frequency in children in central Africa. Shortly after it was first described (by Denis Burkitt) Anthony Epstein established cell lines from the tumour of a patient. The cells were found to be persistently infected with a herpesvirus, which was named Epstein-Barr virus (EBV). Please see Chapter 11 for general characteristics of herpesviruses. Cases of BL also occur in other parts of the world, but generally without an association with EBV. Another tumour that has an association with EBV is nasopharyngeal carcinoma (NPC). This tumour, like BL, is more prevalent in particular regions (Figure 22.4). In both tumours the EBV genome is present in the tumour cells as cccDNA molecules. You will recall that when a herpesvirus infects a cell the linear virus genome becomes circularized (Section 11.5.1).

Virusassociated cancers in animals

A number of cancers in animal species have been found to be associated with viruses. Outbreaks of some of these diseases can have serious economic consequences in agriculture. A few examples are given here of animal cancers associated with retroviruses and a herpesvirus. Marek's disease in chickens is a lymphoma, similar to that caused by retroviruses, but the causative agent is a herpesvirus and the transformed lymphocytes contain multiple copies of the viral genome. Papillomaviruses, already discussed as causative agents of human cancers (Section 22.2), cause cancers in cattle, horses and rabbits.

Specific Discussion

The answers are 139-d, 140-a. Unilateral elevation of the hemidiaphragm can be seen as a result of an enlargement or displacement of an abdominal organ, a subpulmonic process such as effusion, loss of volume of the lung with lobar atelectasis or surgical resection, or hemidia-phragmatic paralysis. Diaphragmatic paralysis results from interruption of the phrenic nerve supply to the diaphragm. The most common cause is malignancy, such as bronchogenic carcinoma, or postsurgical trauma. Twenty percent of patients who undergo open heart surgery sustain injury to the phrenic nerve. Other causes of diaphragmatic paralysis include polio, herpes, infections, lead poisoning, pulmonary infarctions, pneumonia, mediastinitis, and pericarditis. The diagnosis of unilateral paralysis of the diaphragm is suggested by the finding of an elevated hemidiaphragm on the chest x-ray. With diaphragmatic paralysis, the negative pleural pressure tends to pull the paralyzed diaphragm upward. Normally...

Lymphocytic Choriomeningitis

HPI A clinical diagnosis of HSV encephalitis had previously been made, for which the patient was treated with two courses of acyclovir without any amelioration of symptoms the disease continued to progress both radiologically and clinically. On serology she tested HTV positive. Stereotactic biopsy sections show abnormal brain with rarefaction, numerous reactive astrocytes, foamy histiocytes, and inflammatory infiltrate around some vessels JC virus in situ hybridization shows many positive nuclei no herpesvirus inclusions seen electron microscopy demonstrates cells with typical papovavirus structures in nuclcus.

Progressive Multifocal Leukoencephalopathy

Has no history either of a similar rash over his face or of any visual symptoms (to rule out herpes zoster ophthalmicus). Vesicular skin lesions with herpes viral inclusions, i.e., intranuclear, acidophil inclusions with a halo around them ( COWDRY TYPE A INCLUSIONS) syncytial cells also seen. Herpes zoster of the geniculate ganglion, or Ramsay Hunt syndrome, presents as a vesicular rash on the pinna followed by ipsilateral LMN facial nerve palsy.

Typhoid fever enteric fever

A highly contagious dermotropic viral disease caused by varicella-zostcr virus, a DNA herpesvirus, it is transmitted by direct contact. Complications include secondary bacterial infection of the skin and pneumonia high-risk individuals may be protected passively with immunoglobulin.

Interactions Of Viruses With Their Hosts

The virulence of a virus for its host depends in part on the epidemiology of the virus, how it gets from one host to another. The herpesviruses set up a lifelong infection in which they are effectively transferred once per generation. It is in the virus's interest not to incapacitate the host so that the host can pass it on perhaps 20 years later, and her-pesviruses cause minor illness or no illness in most humans. On the other hand, arboviruses must cause a viremia (virus circulating in the blood) high enough to infect an insect taking a blood meal. Because many of these viruses are RNA viruses that do not encode functions to ablate the immune response, rapid and vigorous replication is required to establish the viremia before immunity is established, and this is often harmful to the host because many cells are killed in the process. To take another example, respiratory viruses that are transmitted as

Semantic Knowledge Impairments

A number of different neurological conditions affect semantic knowledge. For example, patients with Alzheimer's disease invariably develop semantic memory impairment (see Milberg & McGlinchy-Berroth, 2003, for a review), although this is generally preceded and overshadowed by an episodic memory impairment. Herpes encephalitis, stroke, and head injury may also affect semantic knowledge in some cases (to be discussed later in this chapter). In rare cases, there is a progressive yet strikingly selective loss of semantic memory, with preservation of nonsemantic aspects of language (syntax, phonology), episodic learning and memory, visual-spatial cognition, and some measures of nonverbal reasoning. This syndrome has come to be called semantic dementia. Warrington and Shallice first observed a loss of knowledge ofliving things in two postencephalitic patients, and published their findings in 1984 to considerable skepticism. Although these patients were generally impaired at tasks such as...

Genome Instability in Transgenic Plants

Acquisition the insect gypsy-like elements (Song et al. 1994), the plant Athila-like elements (Wright and Voytas 1998, 2002), and the Osvaldo element from Drosophila buzzatii (Pantazidis et al. 1999). The nematode Cer elements acquired their env gene from phleboviruses and the Tas element may have acquired it from a Herpesvirus-like ancestor (Malik et al. 2000). LTR-retro-transposons have been found inserted into baculovirus genomes (Malik et al. 2000), e.g. the TED retrotransposon found in the genome of associated Autographa californica nucleopolyhedrosis virus (ACNV) (Friesen and Niessen 1990). Thus, LTR retrotransposons can insert into viral genome, from which it has been suggested they obtained their env gene (Malik et al. 2000).

Transgenesis by Pronuclear Injection in Cancer Research

Certain promoter elements have stood out in cancer studies as highly successful in giving reproducibly strong expression. For ubiquitous expression, the cytomegalovirus (CMV) immediate early promoter has been widely used (14,15). Good examples of widely used and successful lineage-specific promoters are the E -immunoglobulin heavy chain gene enhancer promoter for the B-cell lineage (8), the mouse mammary tumor virus long terminal repeat and whey acid protein gene promoter for the mammary gland (16), and the human keratin 14 promoter for skin (17). It is likely that an increasing number of studies will involve the use of in vivo regulatable promoters. One successful example of such a system is the Tet-off regulated promoter series. In the presence of tetracycline, or its analog doxycyclin, a mutant form of

Emerging Technologies

Human tumors are characterized by frequent unbalanced chromosomal rearrangements (98). In some cases entire chromosomes can be lost (resulting in monosomy) or gained (resulting in trisomy). Smaller gains and losses such as deletions, duplications, and nonreciprocal translocations are also common. Many of these events occur recurrently in human cancers and are thought to be the result of selective pressure that is, these changes give the tumor clone a growth or survival advantage. Unbalanced chromosomal rearrangements can now be modeled in the mouse germline using ES cell technology. In order for deletions to be generated in ES cells, two different approaches have been developed. One approach, pioneered by Dr. John Schimenti and colleagues, involves introducing a herpes simplex virus thymidine kinase (TK) gene into the ES cell genome, irradiating the ES, and selecting the irradiated cells against TK expression using gancyclovir (99). A significant percentage of the resultant...

Prevention And Control

Unfortunately, because of the high rate of clinically inapparent infections and healthy carrier states, hygienic measures are not very effective in prevention of HSV infections. However, patients with extensive mucocutaneous disease should be isolated as secretions and contact with lesions may result in transmission. Condom use has been shown to reduce, but not eliminate, the risk of genital HSV transmis-sion.79,80 A recent landmark study has shown that suppressive oral valaciclovir therapy (500 mg daily) can also significantly reduce, but not eliminate, the risk of transmission of genital HSV-2 infection among monogamous heterosexual couples.81 Evidence suggests that cesarean delivery will reduce but not eliminate the risk of maternal-fetal transmission for women with active genital herpes at term.82 This strategy is not without its consequences since it is estimated that four mothers die from cesarean-related complications for every seven babies prevented from developing fatal...