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Detection of herpes virus DNA in post-operative thyroid tissue specimens of patients with autoimmune thyroid disease.
Thomas D, Liakos V, Michou V, Kapranos N, Kaltsas G, Tsilivakos V, Tsatsoulis A.

Department of Endocrinology, Diabetes and Metabolism, Metaxa Memorial Anticancer Research Hospital, Piraeus, Greece. [email protected]

Abstract
AIM: To demonstrate any differences in the detection of herpes simplex virus type 1 and 2, cytomegalovirus, human herpes virus type 6 and 7 DNA from thyroid tissue blocks of patients with autoimmune thyroid disease and multi-nodular goiter and to propose few mechanisms, which could explain the possible role of herpesvirus infection in the development of thyroid autoimmune responses. MATERIAL-METHODS: Thyroid tissue specimens were obtained postoperatively from 4 patients with multinodular goiter and 18 patients with autoimmune thyroid disease (Graves' disease and Hashimoto thyroiditis). Herpes virus DNA was detected using polymerase chain reaction based assays. RESULTS: No statistically significant differences were observed between autoimmune thyroid disease and multinodular goiter tissue specimens concerning herpes simplex virus type 1, 2 DNA isolation (44.4% vs 0%, P=0.094), human herpes virus type 6 DNA isolation (11.1% vs 0%, P=0.48), human herpes virus type 7 DNA isolation (33.3% vs 25%, P=0.75). No CMV DNA was isolated from any tissue specimen. At least one kind of herpes virus DNA was detected in 13 out of 18 (72.22%) AITD tissue specimens and in 1 out of 4 (25%) MNG tissue specimens (P=0.01). CONCLUSIONS: Although no data are available relating the direct effect of herpes infection on thyroid epithelial cells, a better understanding of how an aberrant immune response against the thyroid gland is initiated and propagated through herpes virus infection is required. Elucidation of the underlying mechanisms may allow the development of new etiologically based therapeutic modalities.

PMID: 18240111 [PubMed - indexed for MEDLINE]

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Dimitrios Thomas1, 2 , Feneli Karachaliou2, Konstantina Kallergi3, Elpis Vlachopapadopoulou2, Georgia Antonaki3, Fotini Chatzimarkou1, 2, Aspasia Fotinou3, Philippos Kaldrymides1 and Stefanos Michalacos2

(1) Department of Endocrinology, Metabolism and Diabetes, ``Metaxa'' Memorial Anticancer Research Hospital, Botasi 51 Str, Piraeus, Greece
(2) Department of Growth and Development, ``P. &. A. Kyriakou'' Children's Hospital, Athens, Greece
(3) Department of Microbiology, ``P. & A. Kyriakou'' Children's Hospital, Athens, Greece

Received: 4 March 2008 Revised: 21 April 2008 Accepted: 30 April 2008 Published online: 13 May 2008

Abstract Background Elevated titers of antibodies against different herpes virus antigens have been reported in some immunodeficient and systemic autoimmune disorders. Objective To examine if Herpes Simplex Virus (HSV), Epstein-Barr virus (EBV), and cytomegalovirus (CMV) IgG and IgM antibodies are detected more frequently in children with autoimmune thyroid disease (AITD) compared to controls. Subjects and methods Thirty-four children with AITD, aged 9.62 � 2.35 years, and 31 matched controls, aged 9.24 � 2.98 years, were studied. Results The percentage of EBV IgG+ children with AITD was statistically higher than the percentage of EBV IgG+ controls (82.35% versus 51.61%, P = 0.008). The percentage of EBV IgG+ children with AITD and hypothyroidism was statistically higher than the percentage of EBV IgG+ children with AITD, without hypothyroidism (100% versus 70%, P = 0.024). No other statistically significant differences were observed in HSV−1+2, and CMV IgG or IgM antibodies between the subgroups of children studied. Conclusions EBV seroprevalence is higher in children with AITD compared to controls and the underlying pathology remains to be elucidated.

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count of the CD-57 subset of the natural killer cells). As a result, not only is the infection with Bb perpetuated
and allowed to advance, but the entire issue of co-infections arises. Ticks may contain and transmit to the host
a multitude of potential pathogens. The clinical presentation of Lyme therefore reflects which pathogens are
present and in what proportion. Apparently, in early infections, before extensive damage to the immune system
has occurred, if the germ load of the co-infectors is low, and the Lyme is treated, many of the other ticktransmitted
microbes can be contained and eliminated by the immune system. However, in the chronic patient,
because of the inhibited defenses, the individual components of the co-infection are now active enough so that
they too add to features of the illness and must be treated. In addition, many latent infections which may have
pre-dated the tick bite, for example herpes viruses, can reactivate, thus adding to the illness.

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Introduction
Herpes viruses are a leading cause of human viral disease, second only to influenza and cold viruses. They are capable of causing overt disease or remaining silent for many years only to be reactivated, for example as shingles. The name herpes comes from the Latin herpes which, in turn, comes from the Greek word herpein which means to creep. This reflects the creeping or spreading nature of the skin lesions caused by many herpes virus types.

There are at least 25 viruses in the family Herpesviridae (currently divided into three sub-families). Eight or more herpes virus types are known to infect man frequently (table 1 and 2, figure 1).



FIGURE 2 (below)
Herpes virus structure
Herpes Virus structure. Between the nucleocapsid and the membrane is the ill-defined tegument

Herpes Simplex Virus-1 A-capsid from 400kV Spot-scan Electron Cryomicroscopy � 1994 Zhou et al. Baylor College of Medicine

Herpes simplex virus. Negative stain. Copyright Dr Linda M Stannard, University of Cape Town, South Africa, 1995 (used with permsssion)

TABLE 1 HERPES VIRUS TYPES THAT INFECT HUMANS

Herpes simplex virus Type 1 (HSV-1)
Herpes simplex virus Type 2 (HSV-2)
Epstein Barr virus (EBV)
Cytomegalovirus (CMV)
Varicella Zoster Virus (VZV)
Human herpes virus 6 (exanthum subitum or roseola infantum)
Human herpes virus 8 (Kaposi's sarcoma-associate herpes virus)

Once a patient has become infected by herpes virus, the infection remains for life. The initial infection may be followed by latency with subsequent reactivation. Herpes viruses infect most of the human population and persons living past middle age usually have antibodies to most of the above herpes viruses with the exception of HHV-8.

Herpes viruses are classified by their location in the latent state (table 2).



Liquid-Crystalline, Phage-like Packing of Encapsidated DNA in Herpes Simplex Virus (F.P.Booy, W.W.Newcomb, B.L.Trus, J.C.Brown, T.S.Baker, and A.C.Steven, in CELL, Vol 64 pp 1007-1015, March 8, 1991)
3-D computer reconstruction from cryo-electron micrographs of herpes simplex virus capsids. Rotating image. National Institutes of Health

Herpesvirus (entire particle) solved by cryo-electron microscopy and image reconstruction MPEG version

Herpesviruses have an envelope surrounding an icosahedral capsid, approximately 100nm in diameter, which contains the dsDNA genome. When the envelope breaks and collapses away from the capsid, negatively stained virions have a typical "fried-egg" appearance. Copyright Dr Linda M Stannard, University of Cape Town, South Africa, 1995 (used with permission)

TABLE 2 - Properties of Herpes viruses

Human herpes type Name Sub Family Target cell type Latency Transmission
1 Herpes simplex-1 (HSV-1) Alphaherpesvirinae Mucoepithelia Neuron Close contact
2 Herpes simplex-2 (HSV-2) Alphaherpesvirinae Mucoepithelia Neuron Close contact usually sexual
3 Varicella Zoster virus (VSV) Alphaherpesvirinae Mucoepithelia Neuron Contact or respiratory route
4 Epstein-Barr Virus (EBV) Gammaherpesvirinae B lymphocyte, epithelia B lymphocytes Saliva
5 Cytomegalovirus (CMV) Betaherpesvirinae Epithelia, monocytes, lymphocytes Monocytes, lymphocytes and possibly others Contact, blood transfusions, transplantation, congenital
6 Herpes lymphotropic virus Betaherpesvirinae T lymphocytes and others T lymphocytes and others Contact, respiratory route
7 Human herpes virus-7 (HHV-7) Betaherpesvirinae T lymphocytes and others T lymphocytes and others Unknown
8 Human herpes virus-8 (HHV-8)
Kaposi's sarcoma- associated herpes virus (KSHV)
Gammaherpesvirinae Endothelial cells Unknown Exchange of body fluids?



Glycoprotein "spikes" on the HSV surface. Glycoprotein B (gB) is clearly visualised in clusters of spikes about 10 nm in length. Between the capsid and the envelope is an ill-defined layer of proteins, collectively known as the tegument. Copyright Dr Linda M Stannard, University of Cape Town, South Africa, 1995 (used with permission)

Herpes Virus Structure - General

Envelope
Herpes viruses are enveloped viruses. They bud from the inner nuclear membrane which has been modified by the insertion of herpes glycoproteins (in the mature virus, these glycoproteins determine the cell to be infected because of the availability of the appropriate receptors). The viral membrane is quite fragile and a virus with a damaged envelope is not infectious (This means that the virus readily falls apart and so the virus can only be obtained by direct contact with mucosal surfaces or secretions of an infected person - it cannot be caught from toilet seats). Besides drying, the virus is also sensitive to acids, detergents and organic solvents as might be expected for an virus with a lipid envelope.

Tegument
The space between the envelope and the capsid is the tegument. This contains virally-encoded proteins and enzymes involved in the initiation of replication

Capsid
These viruses have a doughnut shaped capsomere of about 100-200 nm in diameter with an icosahedral nucleocapsid. The latter contains 162 capsomeres

Genome
These viruses have double stranded DNA. The size of the genomes differs with cytomegalovirus having the largest genome



FIGURE 3 (below)
Genomes of herpes viruses
Genomes of herpes viruses. HSV, VZV and CMV have inverted repeat sequences. This results in the formation of more than one isomer by recombination. Because VZV has only two inverted repeats, it can only form two isomeric forms. Direct repeats do not allow recombination and so EBV and HHV6 have only one isoform.


Herpes virus replication
i) Binding to the cell surface: As with many other viruses, cell tropism is determined by the availability of the correct receptor on the surface of the cell to be infected. The virus fuses with the cell membrane at ambient pH and so there is the possibility of syncytia formation between infected cells and therefore cell to cell transmission even in the presence of neutralizing humoral antibodies. This means that cell-mediated immunity is important in suppressing herpes virus infections.

ii) Nucleocapsid enters cytoplasm: The tegument-surrounded nucleocapsid is carried to the nuclear membrane where the nucleocapsid binds. The DNA genome then enters the nucleus.

iii) Transcription: This is a very complex process, as might be expected from the large size of genome. There are three classes of proteins that need to be made for the production of a mature virus.

Alpha proteins: These are the immediate-early proteins. They are involved in transcriptional regulation and are not found in the mature virion. They are also involved in the control of beta protein synthesis (figure 4).

MOVIE
Replication of herpes
(requires Flash)

FIGURE 4
Herpes virus gene expression
Expression of immediate early, early and late genes of herpesviruses

FIGURE 5
Maturation of herpes viruses

Stages in the exocytosis of herpes virus from the nucleus, in which the virus core is assembled, to the plasma membrane


Beta proteins. These are the early proteins and are involved also in DNA replication (they include the DNA polymerase and transcription factors). Only a few copies of DNA polymerase need to be made for replication to occur (figure 4).
Gamma proteins. These are the late proteins and are structural components of the virus. The synthesis of gamma proteins is initiated after the start of DNA synthesis (figure 4).
iv) RNA transcription: The herpes DNA is transcribed to RNA by a cellular enzyme (DNA-dependent RNA polymerase I). However, the transcription of the various genes is dependent on both nuclear factors of the cell AND proteins encoded by the virus. This control of viral mRNA, and therefore, viral protein, synthesis determines whether infection will result in the production of new virus particles and cell death (a lytic infection), persistent shedding of virus (persistent infection) or latency. Whether latency occurs is the property of the host cell, that is some cells do not allow the replication of viral DNA. If the cell permits progression beyond the immediate early genes, a lytic infection will ensue.

v) DNA synthesis: Herpes viruses encode their own DNA-dependent DNA polymerase. In addition, some herpes viruses encode enzymes (such as thymidine kinase) that allow the virus to grow in non-dividing cells that do not therefore contain the precursors of DNA synthesis. Without this enzyme, neurotropic herpes viruses could not replicate because of the low amounts of certain DNA precursors in nerve cells.

vi) Assembly: Nucleocapsids are assembled in the nucleus and are filled with DNA They then bud through the double nuclear membrane and leave the cell via the exocytosis pathway or they may bud through another cell membrane such as the plasma membrane (figure 5).



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Schematic representation of herpes simplex virus infection - animated
Requires Flash

Schematic representation of genes/proteins involved in herpes simplex virus infection - animated
Requires Flash


Herpes simplex Virus (HSV) (figure 6)
These are very large viruses and their genome encodes at least 80 proteins. Many of these proteins (about half) are not directly involved in the virus structure or controlling its replication but function in the interaction with the host cell or the immune response of the host.

There are two types, HSV-1 and HSV-2 with very similar characteristics

The genome of HSV also encodes a number of enzymes:

DNA-dependent DNA polymerase
Thymidine kinase (phosphorylates thymidine and other nucleosides)
Ribonucleotide reductase (converts ribonucleotides to deoxyribonucleotide
Serine-protease (convert a scaffolding protein to its final form) (figure 7)
The genome encodes 11 surface glycoproteins. These are involved in:

Attachment (gB, gC, gD and gH)

Fusion of the viral membrane with that of the host cell (gB)

Immune escape and other functions (gC, gE and gI). An example of the immune escape function is gC which binds complement C3 protein and thus depletes it from the host's serum and inhibits complement-mediated reactions. The virus gE and gI proteins can also bind IgG via the Fc portion of the immunoglobulin. This coats the virus with immunoglobulin and hides it from the immune system.


FIGURE 6
Herpes simplex virus - Electron micrographs
Herpes Simplex Virus (TEM x169,920) Copyright Dr Dennis Kunkel (used with permission)

Transmission electron micrograph of herpes simplex virus. Some nucleocapsids are empty, as shown by penetration of electron-dense stain. CDC/Dr. Erskine Palmer

Figure 7

The serine protease of herpes viruses. Click on the image at left to link to an interactive structure of the cytomegalovirus protease. This protease is essential for the production of mature infectious virions, as it performs proteolytic processing of a viral assembly protein precursor. (Requires a Chime plug-in. Get Chime here)

HSV replication

Almost any human cell type can be infected by HSV. In many cells, such as endothelial cells and fibroblasts, infection is lytic but neurones normally support a latent infection.

Binding
The initial step of the interaction of virus with the cell is binding to the proteoglycan, heparan sulfate. This molecule is found on the surfaces of many cells.

Fusion
After binding, the virus fuses directly with the plasma membrane (no entry into low pH endosomes/lysosomes is necessary). After fusion occurs, the virus releases some proteins into the cytoplasm. These include some toxins, a protein kinase and a gene transcription initiator.

Protein synthesis
Immediate early genes are first transcribed which promote transcription of early genes. If the infection is to be latent, the only mRNAs that are made are the latency-associated transcripts. The early gene products include the DNA polymerase plus enzymes that degrade cellular mRNA and proteins. If early and late proteins are made, the cell is set on a route to lysis.

As noted above, only a few DNA polymerase proteins need to be made for replication of viral DNA. At first, circular concatomers are made but then synthesis switches to linear chains of individual molecules that are cleaved into monomers. This occurs by a rolling circle mechanism (see lecture). Late genes are now transcribed in large amounts, probably triggered by the synthesis of DNA. They are translated in the cytoplasm and transported back into the nucleus where they are assembled into the procapsid. The latter is filled with viral DNA.

Glycoprotein synthesis
All glycoproteins are made in the rough endoplasmic reticulum where they receive high mannose sugar chains. The glycoproteins are moved to the nuclear membrane, probably by a process of diffusion since the membrane of the endoplasmic reticulum is continuous with the outer nuclear membrane. How the proteins get around the nuclear pore is unknown. The nucleocapsids now bud through the nuclear membrane via areas in which the viral proteins are concentrated. In some way, the virus enters the exocytotic pathway since it is modified in the Golgi body where is receives sugar chains that are characteristic of Golgi-processed proteins (that is, they contain galactose and sialic acid).

Release of virus
Several pathways seem to occur. The virus can proceed along the exocytotic pathway or it can enter the cytoplasm and be released by cell lysis. It also appears to be able to pass through intercellular junctions and thereby spread from cell to cell.



Pathogenesis

The hallmark of herpes infection is the ability to infect epithelial mucosal cells or lymphocytes. The virus then travels up peripheral nerves to a nucleated neurone where it may stay for years followed by reactivation. A reddened area gives rise to a macula which crusts to form a papula. The fluid in this blister is full of virus. As long as the virus is kept moist it can remain infectious

Herpes simplex 1 and 2 can infect both humans and other animals but only humans show symptoms of disease. As noted above, HSV-1 and HSV-2 first infect cells of the mucoepithelia or enter through wounds. They then frequently set up latent infections in neuronal cells. The site of the initial infection depends on the way in which the patient acquires the virus. It is often noted that HSV-1 causes infections above the waist and HSV-2 below the waist but this reflects the mode of transmission rather than any intrinsic property of the virus. Both types of HSV can also persistently infect macrophages and lymphocytes. The presence of the virus is often indicated by the formation of syncytia and Cowdry type A inclusion bodies in the nucleus. Once epithelial cells are infected, there is replication of the virus around the lesion and entry into the innervating neurone. The virus travels along the neurone (by a process called retrograde transport) to the ganglion. In the case of herpes infections of the oral mucosa, the virus goes to the trigeminal ganglia whereas infections of the genital mucosa lead the virus entering the sacral ganglia. The virus can also travel in the opposite direction to arrive at the mucosa that was initially infected. Vesicles containing infectious virus are formed on the muscosa and the virus spreads. The vesicle heals and there is usually no scar as a result.

The immune response to HSV 1 and 2
As might be expected, both the cellular and humoral arms of the immune response are involved. Interferon is important in limiting the initial infection and natural killer cells are also involved at this stage. Cytotoxic T cells and macrophages form the cellular arm of the response and kill infected cells. The humoral arm of the response (usually antibodies against surface glycoproteins) leads to neutralization. As noted above, the virus can escape the immune system by coating itself with IgG via Fc receptors and complement receptors. The virus can also spread from one cell to another without entering the extracellular space and coming in contact with humoral antibodies. This means that cell-mediated responses are vital in controlling herpes infections. The cell mediated and inflammatory response lead to some of the disease symptoms.
Immune response to herpes





Latency
The virus particles can infect neurones and since only immediate early proteins are made, there is no cytopathic effect (although the presence of the virus can be detected by techniques such as immunofluorescence microscopy using antibodies against the immediate early proteins). Breakage of latency can occur in these cells and the virus travels back down the nerve axon. Lesions now occur at the dermatome, that is the area of skin innervated by a single posterior spinal nerve. This means that recurrence of infection (and therefore symptoms) occurs at the same site as the initial infection. There are several agents that seem to trigger recurrence, most of which are stress-related. It also appears that exposure to strong sunlight and perhaps fever can lead to recurrence. These factors may cause some degree of immune suppression that leads to renewal of virus proliferation in the nerve cell. Recurrent infections are usually less pronounced than the primary infection and resolve more rapidly.
Neurolatency hypotheses




Figure 8
Site at which HSV-1 and HSV-2 cause disease in humans



Figure 9

Herpes simplex virus can set up a primary infection in the lips, move to the trigeminal ganglion where it can remain latent. Virus can subsequently reactivate, move to the original site of infection and result in cold sores
Epidemiology

HSV 1 and 2 infections are life-long and although latency is soon set up, the infected patient can infect others as a result of recurrence. The virus is found in the lesions on the skin but can also be present in a variety of body fluids including saliva and vaginal secretions. Despite the apparent above the waist/below the waist rule, both types of HSV can infect oral or genital mucosa depending on the regions of contact (figure 8). However, HSV-1 is usually spread mouth to mouth (kissing or the use of utensils contaminated with saliva) or by transfer of infectious virus to the hands after which the virus may enter the body via any wound or through the eyes. A large proportion of the population has evidence of HSV-1 infection as judged by antibodies. As a result of poor hygiene in underdeveloped countries, HSV-1 antibodies are found in more than 90% of children.

HSV-2 is normally spread sexually and is found in the anus, rectum and upper alimentary tract as well as the genital area. In addition, as noted above, an infant can be infected at birth by a genitally-infected mother. The infant can also be infected in utero if the mother's infection spreads. Because of the infant's underdeveloped immune system, the resulting infection can be very severe and sometimes lead to death.

Anyone who comes in contact with fluid containing infectious virus is at risk. There is a disease that affects health care workers called herpetic whitlow that results in lesions on the fingers (it can be caused by either type of HSV). As might be expected, HSV-2 infections are more prevalent later in life as the number of sexual contacts increases. Thus, the lowest rates of infection are found in children and the highest rates in prostitutes among whom as many as 80% are infected with HSV-2.

Herpes simplex lesion of lower lip, second day after onset. CDC/Dr. Herrmann
Herpes simplex 1: Cold sores � Bristol Biomedical Image Archive. Used with permission

Herpetic gingivitis � Bristol Biomedical Image Archive. Used with permission

Gingivostomatitis looks different from a cold sore, occurs only once and is usually so mild as to go unnoticed. � Australian Herpes Management Forum
Diseases caused by Herpes Simplex Viruses

Herpes simplex 1 and 2 are frequently benign but can also cause severe disease. In each case, the initial lesion looks the same. A clear vesicle containing infectious virus with a base of red (erythomatous) lesion at the base of the vesicle. This if often referred to as a 'dewdrop on a rose petal'. From this pus-containing (pustular), encrusted lesions and ulcers may develop.

Oral herpes - Cold sores
As already stated, this can be the result of an HSV-1 or an HSV-2 infection. Because of the association of HSV-2 with sexual transmission, infections in children are usually the result of HSV-1. In primary herpetic gingivostomatitis , the typical clear lesions first develop followed by ulcers that have a white appearance. The infection, often initially on the lips spreads to all parts of the mouth and pharynx. Reactivation from the trigeminal ganglia can result in what are known as cold sores. Herpes pharyngitis is often associated with other viral infections of the upper respiratory tract. The disease is more severe in immunosuppressed people such as AIDS patients (figure 9)

Herpes keratitis
This is an infection of the eye and is primarily caused by HSV-1. It can be recurrent and may lead to blindness. It is a leading cause of corneal blindness in the United States.



Figure 10
Herpetic whitlow on the wrist � Bristol Biomedical Image Archive. Used with permission


Herpes whitlow
This disease of persons who come in manual contact with herpes-infected body secretions can be caused by either type of HSV and enters the body via small wounds on the hands or wrists. It can also be caused by transfer of HSV-2 from genitals to the hands (figure 10).
Herpes gladiatorum
This is contracted by wrestlers. It apparently spreads by direct contact from skin lesions on one wrestler to his/her opponent, and usually appears in the head and neck region (which are frequently sites of contact in wrestling holds). Oddly, the lesions are more often on the right side of the body (perhaps because most wrestlers are right handed). It is also seen in other contact sports such as rugby where it is known as scrum pox (Herpes Rugbeiorum).

Figure 11
Mother with cold sore on lip holding baby with eczema herpeticum � Bristol Biomedical Image Archive. Used with permission


Eczema herpeticum
This is found in children with active eczema, preexisting atopic dermatitis, and can spread over the skin at the site of eczema lesions (figure 11). The virus can spread to other organs such as the liver and adrenals. A similar disease may also be caused by vaccinia (eczema vaccinatum).
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Genital Herpes
(CDC)

Genital herpes
Genital herpes is usually the result of HSV-2 with about 10% of cases being the result of HSV-1. Primary infection is often asymptomatic but many painful lesions can develop on the glans or shaft of the penis in men and on the vulva, vagina, cervix and perianal region of women (figure 12). In both sexes, the urethra can be involved. In women, the infection may be accompanied by vaginal discharge. Genital herpes infections, which involve a transient viremia, can be accompanied by a variety of symptoms including fever, myalgia, glandular inflammation of the groin area (inguinal adenitis). Secondary episodes of genital herpes, which occur as a result of reactivation of virus in the sacral ganglion, are frequently less severe (and last a shorter time) than the first episode. Recurrent episodes seem usually to result from a primary HSV-2 infection. Patients who are about to experience a recurrence usually first experience a prodrome in which there is a burning sensation in the area that is about to erupt. Some patients have only infrequent recurrences but others experience recurrences as often as every 14-21 days. Whether there is an apparent active disease or not, an infected patient remains infectious without overt symptoms. Clearly, these persons are very important in the spread of herpes infection.

HSV proctitis
This is an inflammation of the rectum and the anus (figure 13).

HSV Encephalitis
This is usually the result of an HSV-1 infection and is the most common sporadic viral encephalitis. HSV encephalitis is a febrile disease and may result in damage to one of the temporal lobes. As a result there is blood in the spinal fluid and the patient experiences neurological symptoms such as seizures. The disease can be fatal but in the US there are fewer than 1000 cases per year.

HSV Meningitis
This is the result of an HSV-2 infection. The symptoms seem to resolve spontaneously.



Figure 12
Genital herpes on the penis � Australian Herpes Management Forum

Genital herpes on the penis � Australian Herpes Management Forum

Classical primary genital herpes affecting the vulva. This clinical picture is seen in a minority of cases � Australian Herpes Management Forum

Figure 13

Misdiagnosed perianal herpes. This woman also has severe secondary
Staphylococcal infection � Australian Herpes Management Forum



Figure 14
Neonatal herpes simplex infection of the liver � Bristol Biomedical Image Archive. Used with permission


HSV infection of neonates

This results from HSV-2 and is often fatal, although such infections are rare. Infection is especially possible if the mother is shedding virus at the time of delivery. Thus prospective mothers should avoid contracting herpes during pregnancy. A first episode of HSV-2 infection during pregnancy creates a greater risk of transmission to the newborn. If a woman has active genital herpes at delivery, a cesarean-section delivery is usually performed. The virus can either be obtained in utero or during birth with the latter being more common. Because the neonate has an underdeveloped immune system, the virus can spread rapidly to many peripheral organs (e.g. lungs and liver) and can infect the central nervous system (figure 14).


Figure 15
Herpes simplex 1, Human Plaque Assay. Cells grown on African green monkey cells. Phase contrast image. � Bristol Biomedical Image Archive. Used with permission

Herpes simplex 1: Histological stain. Note the multinucleate cell with dark staining inclusions. � Bristol Biomedical Image Archive. Used with permission
Diagnosis of HSV Infections

Cells may be obtained from the base of the lesion (called a Tzank smear) and histochemistry performed. Since a characteristic of herpes virus is fusion at neutral pH, infected cells can fuse forming syncytia. These can be seen in the smears as multinucleated giant cells and contain Cowdry type A inclusion bodies (figure 15). The cells can also be stained with specific antibodies in an immunofluorescence test and it is also possible to detect viral DNA by in situ hybridization. Type-specific antibodies can distinguish between HSV-1 and HSV-2.

Virus can be isolated from biopsy specimens, that is from the lesions, and grown on tissue culture cells where it forms characteristic cytopathic effects (plaque) including multinucleated cells (figure 15). The presence of anti-HSV antibodies in the patient can be used to form a diagnosis of the primary infection but recurrence is not usually accompanied by a rise in antibody levels.

HSV chemotherapy

There are a variety of nucleoside analog drugs used to treat herpes infections, many of which are of high specificity since they take advantage of the activation of the drug by a viral enzyme, thymidine kinase (see chemotherapy section). The fact that the drug is only activated in herpes-infected cells (because only here is the rather specific viral thymidine kinase expressed) means that these drugs show few side effects.

The best known of the nucleoside analogs is acycloguanosine (acyclovir) but there are other approved drugs including famciclovir and valacyclovir. All of these nucleoside analogs suffer from the appearance of resistant herpes mutants although resistant strains of the virus are usually less virulent than the wild type. It should be noted that these drugs act against the replicating virus (they are incorporated into the DNA as it is copied) and therefore they are ineffective against latent virus.

Since once the virus infects, the patient has it for life, the best option is to avoid infection by not coming in contact with the virus. This is particularly important for health care providers. However, this is not always possible as many patients with active viral replication are asymptomatic. Patients with genital herpes should avoid intercourse when they have the prodromal itching symptoms or an active lesion.





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CDC chicken pox and shingles
Varicella-Zoster Virus (also known as Herpes Zoster Virus, Human Herpes Virus-3) (figure 16)

Zoster means girdle from the characteristic rash that forms a belt around the thorax in many patients (figure 18). The structure of Varicella virus is very similar to Herpes Simplex virus although the genome is somewhat smaller

Diseases caused by Varicella-Zoster virus

This virus causes two major diseases, chicken-pox (Varicella), usually in childhood, and shingles, later in life. Shingles (Zoster) is a reactivation of an earlier varicella infection.

Chicken Pox

This virus is highly infectious (figure 19) and even if we do not remember getting it, more than 90% of the population of the US has antibodies against varicella proteins. In the household of an infected patient, 90% of contacts who have hitherto not had the disease will get it (unless vaccinated). It is spread by respiratory aerosols or direct contact with skin lesions. As with HSV, infection is via mucosa, this time in the respiratory tract.

Why chicken pox?


During the 10-12 day prodromal stage, the virus in the respiratory mucosa infects macrophages and pneumocytes. At this stage, there are no symptoms. The virus spreads from the lungs to lymphocytes and monocytes and to the reticulo-endothelial system. Here, at about 5 days, a second viremia occurs and the virus travels to the skin, mouth, conjunctiva, respiratory tract and, indeed, to epithelial sites throughout the body. Here the virus leaves the blood vessels and first infects sub-epithelial sites and then epithelial sites forming papulae containing multinucleated cells with intracellular inclusions. The virus reaches the surface and is shed to the exterior of the respiratory tract about 12-14 days after the initial infection. It takes a little longer (a few days) for the virus to reach the surface of the skin when the characteristic papulae (rash) appear. At this stage the patient will likely have a fever for a few days (up to 39 degrees). There are various periods between the initial infection and the occurrence of the papulae that are diagnostic of chicken pox but the average is about two weeks with range of 10 to 23 days (figure 17). Spreading of the disease can be from virus in the respiratory tract (by a cough) or from contact with ruptured papulae on the skin containing infectious virus. Thus the contagious period starts at about 12-14 days after the initial infection.

For some reason, the rash is most pronounced on the face, scalp and trunk and less on the limbs. The disease is more severe in older children and adults. This is particularly the case in immunocompromised patients (AIDS, transplantation etc) where the disease may linger for several weeks and the fever may be more pronounced. The spread of the virus may lead to problems in the lungs, liver and to meningitis. In this case mortality may be up to 20%.

Complications

Pneumonia can be associated with a varicella infection (about 15% of adult patients) and may be fatal.

Although most children recover rapidly from the disease, there are some complications. These include fulminant encephalitis and cerebellar ataxia. It is possible that some of these complications may be Reyes syndrome. It has been suggested that the latter may be cause by aspirin used in chicken pox infections. Other rare complications of chicken pox are traverse myelitis, Guillian Barre syndrome and aseptic meningitis.



Congential Varicella syndrome

Major problems may be caused by infection in utero during the first trimester. This is congenital varicella syndrome which leads to scarring of the skin of the limbs, damage to the lens, retina and brain and microphthalmia.

Infection of the mother, who presumably has not previously been infected and therefore does not have anti-varicella antibodies, at around the time of birth can lead to the infection of the infant. Since the infant will not have maternal antibodies against varicella and has immature cell-mediated immunity, it may succumb to the disease with a mortality rate of up to 35%. If the mother becomes infected near to term, both she (before delivery) and her infant (immediately after delivery) should be treated with varicella immune globulin. Most infants, however, get maternal antibodies trans-placentally and are protected from the disease.

Figure 16
Transmission electron micrograph of varicella- zoster virions from vesicle fluid of patient with chickenpox CDC/Dr. Erskine Palmer

Negative stain of varicella zoster virus � Dr S. McNulty, Queens University, Belfast. Image must not be used for commercial purpose without the consent of the copyright owners.


Figure 17

This person has chickenpox rash. Some of the sores are red spots and some are blisters. The red spots will become blisters and new red spots will form CDC

Each spot starts as a 2-4 mm diameter red papule which develops an irregular outline (rose petal) as a small vesicle appears on the surface. This 'dew drop on a rose petal' appearance is very characteristic of chickenpox. � Australian Herpes Management Forum

This is a classic case of chickenpox of the newborn. The infant contracted chickenpox at birth from her infected mother. A severe skin infection has developed on the face and neck and, without treatment, this infection could spread throughout the body and cause serious illness or even death Courtesy of the American Academy of Pediatrics, Pennsylvania chapter - Immunization Action Coalition

Thirty year old female with chicken pox. There is a general rash over the entire back.
Images � Lewis Tomalty, Queens University, Kingston, Ontario K7L 3N6 Canada and The MicrobeLibrary


WEB RESOURCES

CDC - Shingles

Medinfo - Shingles

Dematology Forum - Shingles and Chickenpox

NIAID Factsheet - Shingles


Shingles
After the infectious period, the virus may migrate to the ganglia associated with areas in which the virus is actively replicated. The virus may then be reactivated under stress or with immune suppression. This usually occurs later in life. The recurrence of varicella replication is accompanied by severe radicular pain (figure 18) in discrete areas, those innervated by the nerve in which latent infection has occurred. A few days later chicken pox-like lesions (figure 18) occur in restricted areas (dermatome) that are innervated by a single ganglion. New lesions may appear in adjacent dermatomes and even further afield. Reactivation can affect the eye via the trigeminal nerve (uveitis, keratitis, conjunctivitis, ophthalmoplegia, iritis) and the brain via the cranial nerve VII and VIII (Bell's Palsy and Ramsay-Hunt syndrome (figure 18)). The skin lesions are somewhat different from those in chicken pox, being restricted to small areas of the skin, usually in the thorax (figure 18). They are small and close together. They are maculopapular with an erythematous base and usually heal in about two weeks. Reactivation can lead to chronic burning or itching pain called post-herpetic neuralgia which is seen primarily in the elderly. The pain may last well after the rash has healed (even months or years). Often associated with post-herpetic neuralgia is increased sensitivity to touch (hyperesthesia).

Patients with AIDS often exhibit multi-dermatomal recurrence of varicella infection. There is also a chronic verricous form in some AIDS patients.

Bell's Palsy
Ramsay-Hunt Syndrome

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quote:

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Originally posted by seekhelp:
The point is DON'T KISS BOYS. lol.

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I kiss girls so I guess I am safe .

Before getting on antibiotics I had mouth sores every month and on antibiotics I get none at all. It keeps the lyme infection from wreaking such a big havoc on my immune system that the viruses can no longer come out and play. Antibiotics work better at controlling the sores than zovarix which helped, but required really high dosages to work.
 

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Posted by sparkle7 (Member # 10397) on :
 
Bob - could you post any studies/info about transfer factor & DNA correction.

I think transfer factor is a valid substance to take. I just don't know if any of the products really work. One senator was able to cure his Lyme by making his own transfer factor with a pregnant cow by injecting his blood into the cows udder. The colustrum contained a personal transfer factor which he credited to giving him back his health. I'm kind of skeptical of the actual products that are available. I am taking apolactoferrin, though.

I really couldn't find alot of information about transfer factor & how it can help us. Most of the non-technical info was on websites that sell products.

FYI -

Universal Oral Vaccine: The Immune Milk Saga

by Anthony di Fabio

http://www.tldp.com/New%20Articles/Universal%20oral%20vaccine%20Part%203.htm

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radfaraf - I don't understand how abx could help with a virus... I guess it's something that worked for you, though. It's hard to tell why we may be getting herpes outbreaks alot. Could be a number of factors...? It mainly has something to do with the nerves from what I have read. UV light & stress are big factors.
 

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Posted by sparkle7 (Member # 10397) on :
 
fucoidan-

http://www.vrp.com/articles.aspx?ProdID=2149

Scientists have conducted an extensive array of in vitro and animal studies that have found fucoidan exhibits powerful inhibitory action against herpes and HIV viruses. Furthermore, newer, human research is confirming what these in vitro and animal studies have found in the past. Other studies have delved into a number of immune-enhancing characteristics of fucoidan, indicating it may be of particular benefit for immune support during the cold and flu season.

Moreover, studies indicate fucoidan may improve cardiovascular health, reduce non-ulcer-related indigestion, control allergic reactions and even inhibit the prions (denuded, ancient, pre-viral DNA/RNA particles) responsible for the sheep version of ``mad cow disease.''
 

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Posted by lymie_in_md (Member # 14197) on :
 
Sparkle if you google "dna repair colostrum" you'll get all you need about how colostrum corrects or repairs DNA. Colostrum containing a number of transfer factors. Also through supposition of DNA from correcting autoimmune situations which can be shown through blood tests.

Another method is from stem cells, such as replacing all your blood with stem cell generated blood.
 

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Posted by sparkle7 (Member # 10397) on :
 
Thanks Bob. I think I'm going to create a new thread on this. It's interesting stuff.
 

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Posted by Pinelady (Member # 18524) on :
 
For those that do try fresh whole straight from the moo.

Know if you do not heat treat it, or freeze it---

it should be used in 2 days--you can make some great mozzarella.
 

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Posted by sparkle7 (Member # 10397) on :
 
Pinelady - Raw milk is not easy for many people to find. This is why I'm a bit skeptical of the transfer factors & the other milk products. I don't see how it can still be active in a dried powder form. Maybe I'm wrong...?

There's a place near me that sells raw milk but it's not colostrum. I guess I'd have to contact the dairy to see if they have some.
 

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Posted by Pinelady (Member # 18524) on :
 
sparkle watch for the milk trucks that pick it up from the farmers in the refrig. gas looking semi's.

If that don't help you can call the dairies and see who they buy their milk from.

Just tell them you are looking for some dairy cows.
 

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