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Dr Richard Hunt

MBIM 650 lectures 67-68

Mercutio (to Romeo) in Romeo and Juliet by Shakespeare:

O'er ladies lips, who straight on kisses dream,
Which oft the angry Mab with blisters plagues,
Because their breaths with sweetmeats tainted are:
Sometime she gallops o’er a courtier’s nose, 
And then dreams he of smelling out a suit; 
And sometime comes she with a tithe-pig’s tail 
Tickling a parson’s nose as a’ lies asleep....

For the complete text of this speech, go here


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 means 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 25 families in the Herpetoviridae but only six of them are known to infect 
man with any regularity (table 1 and 2, figure 1)


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)


class.jpg (34227 bytes) Classification of Herpes viruses


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).

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?


Herpes Virus Structure - General

dna15.jpg (136017 bytes) Herpes Virus structure. Between the nucleocapsid and the membrane is the ill-defined tegument herpescapsid.GIF (123144 bytes)  Herpes Simplex Virus-1 A-capsid from 400kV Spot-scan Electron Cryomicroscopy © 1994 Zhou et al. Baylor College of Medicine 
herpes.gif (48070 bytes) Herpes simplex virus. Negative stain. Copyright Dr Linda M Stannard, University of Cape Town, South Africa, 1995 (used with permsssion) herpes2.gif (9908 bytes) 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)
herpes2.gif (9908 bytes) 3-D computer reconstruction from cryo-electron micrographs of herpes simplex virus capsids. Rotating image.  National Institutes of Health herpes2.gif (9908 bytes) Herpesvirus (entire particle) solved by cryo-electron microscopy and image reconstruction
MPEG version
hsv-3bc.gif (36962 bytes) 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) hsv-envc.gif (12892 bytes) 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)

FIGURE 2 - Herpes virus structure

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.

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

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

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


genomes1.jpg (45528 bytes) 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.

FIGURE 3 - Genomes of herpes viruses


Herpes virus replication


Movie: Replication of herpes
(requires Flash)

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.

herpeslay.jpg (111723 bytes) Expression of immediate early, early and late genes of herpesviruses

FIGURE 4 - Herpes virus gene expression

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).

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).

herpes-exo.jpg (127159 bytes)  Stages in the exocytosis of herpes virus from the nucleus, in which the virus core is assembled, to the plasma membrane

FIGURE 5 - Maturation of herpes viruses


Herpes simplex Virus (HSV) (figure 6)


Animations of Herpesvirus Capsids

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.jpg (32705 bytes) Herpes Simplex Virus (TEM
x169,920) Copyright Dr Dennis Kunkel (used with permission)
hsv1.jpg (55659 bytes) Transmission electron micrograph of herpes simplex virus. Some nucleocapsids are empty, as shown by penetration of electron-dense stain. CDC/Dr. Erskine Palmer 

FIGURE 6     Herpes simplex virus - Electron micrographs

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.


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)

Figure 7


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.

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.

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.



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: Information Box) 

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:  Information Box) 



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.


bodysites.jpg (47018 bytes)  Site at which HSV-1 and HSV-2 cause disease in humans

Figure 8


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 Adewdrop 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)


latency.jpg (21015 bytes) 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 coldsore.jpg (59517 bytes) Herpes simplex lesion of lower lip, second day after onset.  CDC/Dr. Herrmann 
coldsore2.jpg (484719 bytes) Herpes simplex 1: Cold sores © Bristol Biomedical Image Archive. Used with permission herpging.jpg (447649 bytes) Herpetic gingivitis  © Bristol Biomedical Image Archive. Used with permission
hsv-gingstom.jpg (24853 bytes) Gingivostomatitis looks different from a cold sore, occurs only once and is usually so mild as to go unnoticed. However, when florid, gingivostomatitis may be accompanied by severe pain and fever. Whether of not there are noticeable symptoms
associated with primary infection, latency is established in the sensory nervous system and recurrences (cold sores) may occur thereafter. © Australian Herpes Management Forum

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.

Herpes whitlow
This disease of persons who come in manual contact with herpes-infected body 
secretions can be cause 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).

whitlow.jpg (279893 bytes) Herpetic whitlow on the wrist  © Bristol Biomedical Image Archive. Used with permission

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):. 

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).

eczma.jpg (479746 bytes) Mother with cold sore on lip holding baby with eczema herpeticum   © Bristol Biomedical Image Archive. Used with permission

Figure 11


Genital herpes


Management of Genital Herpes Simplex Infection in Pregnancy

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.

herp-penis.jpg (15823 bytes)  Genital herpes on the penis  © Australian Herpes Management Forum penile_GH.jpg (50654 bytes)  Genital herpes on the penis  © Australian Herpes Management Forum
primaryvulval.jpg (50216 bytes) 
Classical primary genital herpes affecting the vulva. This clinical picture is seen in a minority of cases  © Australian Herpes Management Forum

Figure 12



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


perianal_GH.jpg (39315 bytes) Misdiagnosed perianal herpes. This woman also has severe secondary
Staphylococcal infection  © Australian Herpes Management Forum

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 

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).


hsv-liver.jpg (547929 bytes) Neonatal herpes simplex infection of the liver © Bristol Biomedical Image Archive. Used with permission

Figure 14


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.

hsvplaque.jpg (555427 bytes) Herpes simplex 1, Human Plaque Assay. Cells grown on African green monkey cells. Phase contrast image.  © Bristol Biomedical Image Archive. Used with permission herpes-hist.jpg (495891 bytes) Herpes simplex 1: Histological stain. Note the multinucleate cell with dark staining inclusions.  © Bristol Biomedical Image Archive. Used with permission

Figure 15


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.


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


chickenpox-em.jpg (26406 bytes) Transmission electron micrograph of varicella- zoster virions from vesicle fluid of patient with chickenpox CDC/Dr. Erskine Palmer  vzv-em.jpg (63107 bytes) 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 16


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 via the cranial nerve.

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? Information Box) 

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%.


chickenpox1.jpg (83878 bytes)   chickenpox3.jpg (11010 bytes)  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 chickenpox2.jpg (73961 bytes) 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
shingles_vesicles.jpg (6006 bytes) 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

 Figure 17



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.


CDC - Shingles
Medinfo - Shingles
Dematology Forum - Shingles and Chickenpox
NIAID Factsheet  - Shingles
Shingles - Australian Herpes Management

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 (Bell's Palsy: 
Information Box)
and Ramsay-Hunt syndrome (Ramsay-Hunt: Information Box) 
(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.


shingles.jpg (16833 bytes) Typical isolated rash in shingles CDC shingles_umbilical.jpg (12678 bytes) In severe cases of shingles, the lesions coalesce, forming a disfiguring carpet of scabs and sometimes the rash leaves permanent scars   © Australian Herpes Management Forum
shingles_chest.jpg (25101 bytes) Shingles affecting the left side of the trunk zoster1.jpg (286508 bytes)  shingles2.jpg (16655 bytes) Recurrent varicella zoster on the right side of the face © Bristol Biomedical Image Archive  © Australian Herpes Management Forum
shingles-trunk.jpg (10269 bytes) 
Severe atypical episode of shingles affecting the trunk of a person with impaired immunity. Note that the distrubution of the lesions rersembles a 'sword belt'. Hence the name zoster   © Australian Herpes Management Forum
zoster_disseminated.jpg (7261 bytes) Disseminated lesions affecting multiple dermatomes  © Australian Herpes Management Forum
shingles_ophthalmic.jpg (9615 bytes) Facial shingles. The ophthalmic division of the trigeminal nerve is the dermatome involved. © Australian Herpes Management Forum shingles_L1.jpg (14491 bytes) Shingles affecting the right L1 dermatome © Australian Herpes Management Forum
Ramsey-Hunt.jpg (10322 bytes)  Ramsay-Hunt syndrome causing a right-sided facial palsy. Paralysis is more obvious in cases of shingles involving the face. It is caused by an extension of the disease process to motor regions of the spinal cord or brainstem. In a minority of cases, the areas of paralysis and rash do not coincide. For instance, rash on the neck and lower part of the face, involving the trigeminal and cervical nerves, may be associated with paralysis of the facial nerve and loss of taste. This distribution of rash and combination of motor and sensory symptoms cannot be explained by involvement of a single nerve ganglion or a mixed motor and sensory nerve trunk. Rather, it must be the result of a wider, if still local, spread of virus in the central nervous system. © Australian Herpes Management Forum Ramsey-Hunt_ear.jpg (11992 bytes) Ramsay-Hunt syndrome affecting the ear showing blistering of the external ear canal © Australian Herpes Management Forum
zoster_pain.gif (6117 bytes) The most common and widely feared complication of shingles is persistence of pain in the affected area of the body after the rash has healed. This is often called post-herpetic neuralgia, which may be very severe and prolonged, particularly in older patients. Unfortunately it can be very resistant to treatment but, by treating shingles with an antiviral agent within 3 days of the rash appearing, it may be possible either to reduce the likelihood of developing prolonged pain or, put another way, reduce the overall duration of pain associated with the condition.  © Australian Herpes Management Forum

Figure 18


Both chicken pox and shingles are diagnosed by their characteristic appearance 
but a definitive diagnosis can be made by culture of the virus from the lesions 
(a difficult procedure) followed by detection of specific antigens. The characteristic 
appearance of cells in biopsy specimens of skin lesions can also be used.


As with HSV, acyclovir (or other nucleoside analogs) can be useful, particular in 
preventing dissemination in immunosuppressed patients. Varicella immunoglobulin 
can also be used. Normally, however, only supportive care is used in children who 
quickly recover if they mount an adequate cell-mediated response.


There is a live attenuated vaccine virus and this is used in the United States. It leads 
to antibody production and cell-mediated immunity. It can be used post-exposure.


chickenpox-cases.jpg (78371 bytes) Varicella cases and states reporting, United States, 1972-1996.  CDC/Barbara Rice 

Figure  19


Epstein- Barr Virus

Epstein-Barr virus is the causative agent of Burkitt=s lymphoma in Africa, 
nasal pharyngeal carcinoma in the orient and infectious mononucleosis in the west. 
It was first discovered as the causative agent of Burkitt=s lymphoma and it was later 
found that patients with infectious mononucleosis have antibodies that react with 
Burkitt=s lymphoma cells.

Receptors for the virus

The virus only infects a small number of cell types that express the receptor for 
complement C3d component (CR2 or CD21). These are certain epithelial cells 
(oro- and naso-pharynx) and B lymphocytes. This explains the cellular tropism of the

Semi-permissive replication

B lymphocytes are only semi-permissive for replication of the virus and infection 
may either be latent or the cells may be stimulated and transformed by the virus. 
When lymphocytes are latently infected the cell contains a few unintegrated copies
(episomes) of the virus genome which are replicated every time the cell divides. 
In this case the early immediate genes are expressed including the EBV nuclear 
antigens. In addition, two latent membrane proteins, a protein designated LP (a 
DNA-binding protein) and two small RNA molecules are expressed. The membrane 
proteins are oncogenes.

Permissive replication

In contrast, epithelial cells permit complete lytic replication of the virus. Epithelial 
cells allow the expression of the ZEBRA protein which activates early genes resulting
in expression of the polymerase and DNA replication. Subsequently, capsid proteins
and the membrane glycoproteins are made.


i) Transformation of B cells
The virus is replicated in pharyngeal epithelial cells, shed into the saliva and is taken
up by CD21+ B lymphocytes. These cells are normally short-lived, dying by 
apoptosis. This is a natural process that allows cells to be generated for a particular
process and then removed when no longer needed. Although B cells do not show 
any histological alterations as a result of EBV infection, they are stimulated to divide 
and are protected from undergoing apoptosis; thus, the cell becomes transformed 
and high levels of monocytes are seen in the bloodstream. Transformation of the 
B cell changes the interaction of the cell with other components of the immune system
. HLA markers, CD23 blast antigen and certain adhesion proteins are expressed. 
The presence of the virus results in the expression of an analog of interleukin-10 
(IL-10) which inhibits gamma interferon secretion. This results in the inhibition of T cell
responses and promotes growth of the B cells and IgG secretion. The virus also 
causes the cells to produce other cytokines including IL-5 and IL-6.


burkitta.jpg (19017 bytes) Burkitt's Lymphoma The Johns Hopkins Autopsy Resource (JHAR) Image Archive.  leukoplakia.jpg (470910 bytes) Oral hairy leukoplakia of tongue in AIDS © Bristol Biomedical Image Archive

Figure 20


burkitt-hist.jpg (582564 bytes) Burkitt;s lymphoma histological stain. Notice the large multinucleated cells
 © Bristol Biomedical Image Archive. Used with permission

Figure  21



Burkitt=s lymphoma
The association between Epstein-Barr virus and Burkitt=s lymphoma has long been established. This is a tumor of the jaw and face found in children (figure 20). The tumor cells show evidence of EBV DNA and tumor antigens and patients show a much higher level of anti-EBV antibodies than other members of the population. Tumor cells are monoclonal and show a very characteristic translocation between chromosomes 8 and 14. This brings the c-myc next to the gene for the immunoglobulin heavy chain. As a result, the oncogene is next to the promotor for a gene that is highly expressed in B lymphocytes resulting is elevated transcription of c-myc. It should be noted that this translocation is not seen in infectious mononucleosis patients. Biopsy tissue shows large multinucleated cells (figure 21). Further evidence that implicates EBV in Burkitt=s lymphoma is the observation that EBV can transform B lymphocytes in culture and can produce B cell lymphomas in primates.

This lymphoma is endemic in equatorial Africa but only occurs rarely elsewhere. Why this is so is unclear but there is probably a genetic reason possibly involving an association with malaria. Persons who are resistant to malaria appear to be susceptible to progression to the lymphoma.

Nasopharyngeal cancer
This disease, which occurs in a number of areas (south China, Alaska, Tunisia, east Africa), is also associated with EBV. There may be a genetic predisposition to the development of EBV cancers in these populations or there may be an environmental cofactor involved. The disease is a tumor of the epithelium of the upper respiratory tract and the cells contain EBV DNA. The titer of anti-EBV antibodies alter as the tumor progresses.

Oral hairy leukoplakia
This EBV-associated disease results in lesions in the mouth and has increased in frequency recently as it is an opportunistic infection of HIV-infected patients (figure 20).

ii) Infectious mononucleosis


CDC - Mononucleosis

The primary infection is often asymptomatic but the patient may shed infectious virus 
for many years. Some patients develop infectious mononucleosis after 1-2 months of
infection. The disease is characterized by malaise, lymphadenopathy, tonsillitis 
(figure 22), enlarged spleen and liver and fever. The fever may persist for more than 
a week. There may also be a rash. The severity of disease often depends on age 
(with younger patients resolving the disease more quickly) and resolution usually 
occurs in 1 to 4 weeks.

Although infectious mononucleosis is usually benign, there may be complications. 
These include neurological disorders such as meningitis, encephalitis, myelitis and 
Guillain-Barrè syndrome.  (Guillain-Barrè Syndrome: Information Box) Secondary 
infections, autoimmune hemolytic anemia, thrombocytopenia, agranulocytosis, 
aplastic anemia may also occur. As noted above a chronic syndrome may also 
occur. The symptoms are similar to those reported for chronic fatigue syndrome (headaches, sore throat and low fever) but EBV is probably not the cause of chronic 
fatigue syndrome.

In infectious mononucleosis, infected B cells are also transformed. The infected 
B cells proliferate and activate suppressor CD8 T cells. These T cells differ from 
normal T cells in appearance and are known as Downey cells. The T cells increase
in number in the circulation and may account for up to 80% of the white blood cells. 
This T cell response results in enlarged lymph glands (and enlarged liver and 
spleen). The activation of the T cells limits the proliferation of B cells and the disease 

If cell mediated immunity is suppressed, resolution of the disease may not occur. 
Uncontrolled viral replication may lead to a severe syndrome with B cell lymphoproliferation, leukopenia and lymphoma. In patients with T cell deficiency 
X-linked lymphoproliferative disorder may occur. Transplant patients and AIDS 
patients who are also immunosuppressed may exhibit post-transplant 
lymphoproliferative disorder


mono.jpg (65950 bytes) Tongue and palate of patient with infectious mononucleosis. CDC/Emory U./Dr. Sellers

Figure 22



A large proportion of the population (90-95%) is infected with Epstein-Barr virus and 
these people, although usually asymptomatic, will shed the virus from time to time 
throughout life. The virus is spread by close contact (kissing disease). Infection is 
associated with socioeconomic factors and in developing countries, seropositivity is 
observed at an earlier age than in developed countries. Up to 80% of students 
entering college in the US are seropositive for the virus and many of those that are 
negative will become positive while at college. The virus can also be spread by 
blood transfusion.



In infectious mononucleosis, blood smears show the atypical lymphocytes (Downey 
cells). There are also serological tests available. Heterophile antibodies are 
produced by the proliferating B cells and these include an IgM that interacts with 
Paul-Bunnell antigen on sheep red blood cells.



Unlike herpes simplex virus, there are no drugs available to treat Epstein-Barr virus.
This may reflect the absence of a thymidine kinase encoded by this virus (drugs 
such as acyclovir that are active against herpes simplex are activated by the viral 
thymidine kinase). A vaccine is being developed.





Cytomegalovrius dynamic images

Cytomegalovirus has the largest genome of all herpes viruses and appears only to replicate in human cells. Its name derives form the fact that, like other herpes viruses,
it can form multinucleated cells (syncytia) with characteristically staining inclusions. 
Some cells such as macrophages and fibroblasts support a productive infection 
while a latent infection is set up in several cell types including T lymphocytes and 
stromal cells of the bone marrow. There is only one serotype.

Cytomegalovirus infection is found in s significant proportion of the population. As 
with Epstein-Barr virus (also spread in saliva), seropositivity increases with age. By 
college age, about 15% of the US population is infected and this rises to about half 
by 35 years of age. The virus is spread in most secretions, particularly saliva, urine, vaginal secretions and semen (which shows the highest titer of any body fluid). 
Cytomegalovirus infection is therefore sexually transmitted. It can also spread to a
  fetus in a pregnant woman and to the newborn via lactation, though there is some 
doubt about the importance of milk transmission. In the hospital, the virus can also 
be spread via blood transfusions and transplants. In third world countries with more 
crowded conditions, the virus is found in a much higher proportion of the population 
than in western countries.

Cytomegalovirus causes no symptoms in children and at most mild disease in 
adults (but see below). The virus first infects the upper respiratory tract and then local
lymphocytes. Circulating lymphocytes then spread the virus to other lymphocytes 
and monocytes in spleen and lymph nodes. The virus finally spreads to a variety of
epithelial cells including those of salivary glands, kidney tubules, testes, epididymis 
and cervix. Infection is usually asymptomatic (sub-clinical) but glandular fever is 
sometimes seen in young adults. The virus can inhibit T cell responses. The virus 
elicits both humoral antibodies and cell-mediated immunity but the infection is not 
cleared. Cell-mediated immunity, not humoral antibodies, controls the infection The 
importance of cell-mediated immunity stems from the possibility of spread from cell 
to cell. Although suppressed, the virus may later reactivate, particularly in cases of immunosuppression; indeed, infection by the virus can, itself, be immunosuppressive

Congenital disease
There are two instances in which cytomegalovirus can cause serious disease. 
During a primary infection of the mother, the virus can spread via the placenta to the 
fetus and congenital abnormalities can occur; in fact, this virus is the most common 
viral cause of congenital disease. Up to one in forty newborns in the United States 
are infected by the virus. Abnormalities include microcephaly, rash, brain 
calcification and hepatosplenomegaly. These may result in hearing loss (bilateral or
unilateral) and retardation. As might be expected, when reactivation occurs in a 
pregnant mother (usually reactivation in the cervix), the symptoms are less severe 
because of the mothers seropositivity. In this case, congenital abnormalities are rare.

Besides infection in utero, infants may be infected perinatally. As noted above, one 
tissue in which cytomegalovirus can set up a latent infection is the cervical epithelium
and immunosuppression associated with pregnancy can lead to reactivation. About
50% of children born to such mothers are infected and can themselves shed virus 
within a few weeks. Also breast epithelium can harbor latent virus that may be 
similarly reactivated leading to infection of the infant. In neither case is there usually 
a problem and the infant remains asymptomatic.

Neonates may also receive the virus through infected blood transfusions. In this 
case, the amount of virus is much higher and symptoms may occur. These usually 
consist of pneumonia and hepatitis.

Disease in immunosuppressed patients
In patients who have received an organ transplant or have an immunosuppressive
disease (e.g. AIDS), cytomegalovirus can be a major problem. Particularly 
important is cytomegalovirus-retinitis in the eye which occurs in up to 15% of all AIDS
patients. In addition, interstitial pneumonia, colitis, esophagitis and encephalitis are 
seen in some patients.

Most infections are asymptomatic and therefore go undiagnosed. There are 
fluorescent antibody and ELIZA tests. Multinucleated (cytomegalinic) cells with 
characteristic inclusions can be seen in biopsies of many tissues.

Ganciclovir, which inhibits the replication of all human herpes viruses, is usually used,
especially to treat retinitis. Foscarnet is also approved in the US. Acyclovir is not 
effective. A vaccine is being developed but the best way to avoid the virus is to 
restrict contact between infected children and pregnant women. Also since 
cytomegalovirus is sexually transmitted, condoms can limit spread.


Other herpes viruses

Human herpes virus 6


Human herpes virus 6
from Expert Reviews in Molecular Medicine

This virus is found worldwide and is found in the saliva of the majority of adults 
(>90%). It infects almost all children by the age of two and the infection is life-long. 
Again, it replicates in B and T lymphocytes, megakaryocytes, glioblastoma cell 
and in the oropharynx. It can set up a latent infection in T cells which can later be 
activated when the cells are stimulated to divide. Infected cells are larger than 
normal with inclusions in both cytoplasm and nucleus. Cell-mediated immunity is 
essential in control, although infection is life-long, and the virus can reactivate in 
immune-suppression. The receptor for this virus is not known.

Human herpes virus-6 has two forms, HHV-6A and HHV-6B.  The latter causes 
exanthem subitum, otherwise known as roseola infantum. This a common disease 
of young children (in the US >45% of children are seropositive  for HHV-6 by two years
of age) and symptoms include fever and sometimes upper respiratory tract infection
and lymphadenopathy. The symptoms last a few days after an incubation period of 
around 14 days. The fever subsides leaving a macropapular rash on the trunk and 
neck that last a few days longer. In adults, primary infection is associated with a 
mononucleosis. This virus was originally isolated from patients with a 
lymphoproliferative disease and may co-infect HIV-infected T4 lymphocytes 
exacerbating the replication of HIV. Patients with HIV have a higher infection rate 
than the normal population.   HHV-6 has  been associated with a number of 
neurological disorders, including encephalitis and seizures. It has been postulated 
to play a role in  multiple sclerosis and chronic fatigue immunodeficiency syndrome. 

Human herpes virus 7


Human herpes virus 7
from Expert Reviews in Molecular Medicine

This virus binds to the CD4 antigen and replicates in T4 (CD4+) cells and is found in 
the saliva of the majority of the adult population (>75%). Most people acquire the 
infection as children and it remains with them for the rest of their lives. It is similar to 
HHV-6 and may be responsible for some cases of exanthem subitum

Human herpes virus 8

This was formerly known as Kaposi=s sarcoma associated herpes virus and is 
found in the saliva of many AIDS patients. It infects peripheral blood lymphocytes. 
The distribution of the virus may explain why some populations of HIV-infected 
people go down with Kaposi=s sarcoma while others do not. For further details see 
the AIDS/HIV section

Herpes B

This is a simian virus found in old world monkeys such as macaques but it can be 
a human pathogen in people who handle monkeys (monkey bites are the route of transmission). In humans, the disease is much more problematic than it is in its 
natural host. Indeed, about 75% of human cases result in death with serious 
neurological problems (encephalitis) in many survivors. There is also evidence that 
the disease can be passed from a monkey-infected human to another human. 
In vitro
the virus is sensitive to both Acyclovir and Ganciclovir and these are 
recommended for therapy. Their efficacy is unknown



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