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Overview
Two of the three enveloped DNA virus families- the Herpesviridae and the
discussed later]
The Herpesviridae and the Poxviridae are both structurally and genetically
there is less dependence on host cell-supplied functions with a correspondingly greater number of virus-coded functions involved in viral replication
Overview
This latter fact contributes to the greater success in
developing antiviral drugs against these viruses (more virus-specific enzymes that can serve as targets for
Overview
The one highly virulent member of the poxvirus family,
variola (the cause of smallpox), is the only human pathogen that has been successfully eradicated.
This success serves as a model for attempts to control
HERPESVIRIDAE
Cytomegalovirus (CMV)
Varicella Zoster Virus (VZV) Human herpes virus 6 (exanthum subitum or roseola infantum)
HERPESVIRUSES
Capacity to persist in host indefinitely in nucleus of the cell Every vertebrate species has at least one host specific herpes virus Varicella zoster and herpes simplex viruses establish latent infections in neurons reactivation
Herpesvirus Virion
1. 2. 3. 4.
Herpesvirus Virion
Spherical 150- 250 nm Icosahedral
Enveloped ds DNA linear 124-235 kbp More than 35 proteins in virion Envelope:8nm spikes viral glycoproteins.Fc receptors. Replication nuclear, bud from nuclear membrane Infection: Lytic, latent and recurrent
Herpesviruses
Set up latent infection following primary infection.
Persist indefinitely in infected host Reactivation are more likely to take place during periods of
immunosuppression.
Both primary infection and reactivation are likely to be more serious in immunocompromised patients. Some are cancer causing
A. Structure of herpesviruses
Herpesvirus virions consist of an icosahedral capsid enclosed in a lipoprotein envelope. Between the envelope and the capsid lies an amorphous proteinaceous material (tegument) the tegument contains virus-coded enzymes and transcription factors essential for initiation of the infectious cycle, although none of these is a polymerase. Although all members of the family have some genes with homologous functions, there is little antigenic relatedness between species.
Classification of herpesviruses
Herpesvirus Particle
identical
Official name Common HHV 1 Herpes simplex type 1 HHV 2 Herpes simplex type 2 ________________________________________ Varicello HHV 3 Varicella Zoster virus _________________________________________________________ Beta herpevi Cytomegalo HHV 5 Cytomegalovirus Roseolo HHV 6 HHV 6 HHV 7 HHV 7 ____________________________________________________________ Gamma her Lymhocrypto HHV 4 Epstein-Bar virus Rhadino HHV 8 Kapossis sarcoma associated herpes virus
Latency is established in non-neural tissues, primarily lymphoreticular cells and glandular tissues.
Human cytomegalovirus (HCMV) and human herpesviruses types 6 and 7 (HHV-6 and HHV-7) are in this group.
Herpesviruses replicate in the nucleus, following the basic pattern of DNA virus replication . Regulation of herpesvirus transcription is referred to as cascade control, in that expression of a first set of genes is required for expression of a second set, which in turn is required for expression of a third set of genes. [Note: A similar pattern is found in some other DNA virus families in which the genes are referred to as immediate early, delayed early, and late.]
Latency
All herpesviruses can undergo an alternative infection cycle, entering a
3)the frequency of reactivation, 4) and the nature of the recurrent disease are characteristic for each of the herpesviruses, the topic of latency is discussed in the context of the individual virus species
modes of transmission.
onto which they have been inoculated, resulting in production of vesicles or shallow ulcers containing infectious virus.
remains localized
because cytotoxic T lymphocytes recognize the HSV-
B. Clinical significance
A useful generality is that HSV-1 is most commonly found
in lesions of the upper body, and HSV-2 is more commonly the cause of genital tract lesions.
Either can, however, infect and cause similar lesions at the
opposite site
common symptomatic infections of the upper body are gingivostomatitis in young children and pharyngitis or
tonsillitis in adults.
The lesions typically consist of vesicles and shallow
ulcers, which are often accompanied by systemic symptoms such as fever, malaise, and myalgia.
(CNS) it can cause encephalitis, which, if untreated, has a mortality rate estimated to be 70 percent.
Survivors are usually left with neurologic deficits.
oropharynx
however, based on the frequency of antibody in the population,
vagina, or penis .
Systemic symptoms of fever, malaise, and myalgia may also be more
infecting the newborn during birth is estimated to be thirty to forty percent (neonatal herpes).
Because such infants have no protective maternal antibody, a disseminated
Latency
In latently infected cells of the ganglia HSV-1 in
cells.
Reactivation:
Several factors, such as hormonal changes, fever, stress and
Immunosuppression , are known to induce reactivation and replication of the latent virus
The newly synthesized virions are transported down the axon to
the nerve endings from which the virus is released, infecting the adjoining epithelial cells.
Characteristic lesions are thus produced in the same general
Reactivation:
The presence of circulating antibody does not prevent this recurrence,
Reactivation:
HSV-1:
The frequency of oropharyngeal symptomatic recurrences is variable, ranging from none to several a
year.
The lesions occur as clusters of vesicles at the border of the lips (herpes labialis or cold sore fever blisters) and
Herpes labialis
Reactivation:
HSV-2:
Reactivation of HSV-2 genital infections can occur with considerably greater frequency (for example, monthly) and is often asymptomatic, but still results in viral shedding. Consequently, sexual partners or newborn infants may be at increased risk of becoming infected resulting from lack of precautions against transmission. The risk of transmission to the newborn is much less than in a primary infection
because considerably less virus is shed and there is maternal anti-HSV antibody in the baby.
This antibody also lessens the severity of the disease if infection does occur.
Immunity
New born-passive immunity up to 6 months 6 mo-2 yr-highly susceptible Transplacental antibodies infection Primary infection antibodies +virus
important.
Diagnosis
Light microscopy-intranuclear inclusions
Electron microscopy ? Antigen detection Virus culture-HSV 1, HSV 2 easiest to culture typical CPE Serology Antibodies-4-7 d after infection CFT/ IHA/ELISA/RIA
can be used to distinguish between the two types and among strains of
each subtype.
Treatment
The guanine analog, acycloguanosine (acyclovir), is selectively
effective against HSV because it becomes an active inhibitor of DNA synthesis only after initially being phosphorylated by the HSV thymidine kinase .
The drug of choice for any primary HSV infection, it is
especially important in treating herpes encephalitis, neonatal herpes, and disseminated infections in immunocompromised patients.
Treatment
Other drugs effective in treating herpes simplex infection include
oral acyclovir.
Penciclovir is active against HSV-1 and HSV-2, and against VZV. None of these drugs can cure a latent infection, but they can
Prevention
Prevention of HSV transmission is enhanced by avoidance
importance; however, genital infection of the mother is difficult to detect because it is often asymptomatic.
Prevention
When overt genital tract lesions are detected at the time of delivery,
measures to prevent physical transmission following birth are also important. A vaccine is not currently available
Varicella-Zoster Virus
VZV has biologic and genetic similarities to HSV, and is
mononuclear leukocytes.
epithelial cells become infected, resulting in the characteristic, virus-containing vesicles of chickenpox that appear from 14 to 21 days after exposure.
From one to two days before the appearance of the exanthem the
transmission.
Clinical significance
In contrast to HSV infections, the primary and recurrent
individual
Both can have severe complications in
immunocompromised patients.
Clinical significance
Primary infection (varicella, or chickenpox):
In a normal, healthy child, the incubation period is most commonly
from 14 to 16 days.
The first appearance of exanthem is often preceded by one or two days
development.
While the first crop of lesions is evolving, new crops appear on
immunocompromised patients.
Varicella pneumonia is the most common of the serious
complications
contract the more severe adult form of varicella, and may affect the fetus or neonate as well.
More commonly, a fetus infected near the time of delivery
Clinical significance
Recurrent infection (herpes zoster, or shingles): Due to the disseminated nature of the primary infection, latency
is established in multiple sensory ganglia, the most common ones are trigeminal and dorsal root ganglia.
Unlike most of the herpesviruses, asymptomatic virus shedding
is rare.
Herpes zoster results from reactivation of the latent virus, not
infected individuals.
The most striking feature of herpes zoster is that distribution of
the clustered vesicular lesions is dermatomal (affecting the area of skin supplied by cutaneous branches from a single spinal nerve). Acute inflammation of sensory nerves and ganglia It is very painful lesion Unilateral (one side of the body) vesicular lesion is common Healing occurs with scarring
Herpes zoster
Laboratory identification
Laboratory identification
Cell tissue cultures inoculated with a sample of vesicle fluid show
from the base of vesicles with the stains described above, or by doing in situ hybridization with VZV-specific DNA probes.
Treatment
Acyclovir- is the drug of choice
Oral acyclovir reduces the time course and acute pain of
Prevention
Susceptible individuals for example, neonates,
nonimmune healthy adults, and immunocompromised children who have been exposed to chickenpox or to
zoster.
Cytomegalovirus (CMV)
CMV is structurally and morphologically identical to other
Animal CMV strains do not infect humans. Giant cells are formed, hence the name Cytomegalo
CMV is transmitted by a variety of modes. Early in life it is transmitted across the placenta, within the birth canal,
saliva.
Later in life it is transmitted sexually; it is present in both semen and
cervical secretions.
It can also be transmitted during blood transfusions and organ
transplants.
CMV infection occurs worldwide, and more than 80% of adults have
disease
abnormalities result infection of the fetus occurs mainly when a primary infection occurs in the pregnant woman.
Reactivation of CMV from the latent state in cervical cells can result in infection of the newborn during passages through the birth canal.
inhibiting T cells.
Host defenses against CMV infection include both
Clinical Findings
Hepatosplenomegaly is very common. Cytomegalic inclusion disease is one of the leading causes of mental retardation in the United States.
Infected infants can continue to excrete CMV, especially in the urine, for several years.
Clinical Findings
In immunocompetent adults, CMV can cause heterophil-negative mononucleosis, which is characterized by fever, lethargy and the presence of
abnormal lymphoctyes in peripheral blood smears.
Systemic CMV infections, especially pneumonites and hepatitis, occur in a high proportion of immunouppressed patients,e g. those with renal and bone marrow transplants.
In AIDS patients,CMV commonly infects the intestinal tract and cause interactable diarrhea.
CMV also cause retinitis in AIDS patients, which can lead to blindness.
Laboratory Diagnosis
called shell vials coupled with the use of immunoflurescent antibody, which can make a diagnosis in 72 hours.
If available, PCR-based assays that detect viral nucleic acids are also useful.
Laboratory Diagnosis
The inclusion bodies are intranuclear and have an
diagnostic.
PCR-based assays for CMV DNA or RNA in
tissue or body fluids, such as spinal fluid are also very useful.
Treatment
Granciclovior is moderately effective in the treatment of
Prevention
There is no vaccine. Ganciclovir can suppress progressive retinitis in AIDSpatients. Infants with cytomegalic inclusion disease who are shedding
negative.
If possible only organs from CMV antibody-negative donors
DNA synthesis, and nuclear antigen (EBNA), which is located in the nucleus bound to chromosomes, are sometimes diagnostically helpful as well.
EBV
Two other antigens, lymphocyte-determined membrane antigen
antigen.
During kissing.
The saliva of people with a reactivation of a latent infection as
well as people with an active infection can serve as a source of the virus.
In contrast to CMV, blood transmission of EBV is very rare.
worldwide;
More than 90% of adults in the United states have antibody.
asympromatic.
Early infection tends to occur in individuals in lower
socioeconomic groups.
The frequency of clinically apparent infectious
mononucleosis, however, is highest in those who are exposed to the virus later in life. Eg, college students
?lymphoid tissue) and then spreads to the blood, where it infects B lymphocytes.
Cytotoxic T lymphocytes react against the infected B cells.
The T cells are the atypical lymphs seen in the blood smear.
EBV remains latent within B lymphocytes. A few copies of EBV DNA are integrated into the cell
genome;
Many copies of circular EBV DNA are found in the
infection,
whereas the IgG response is best for revealing prior infection Lifetime immunity against second episodes of infectious
antigen.
Clinical Findings
Infection mononucleosis is characterized primarily by
Clinical Findings
In addition to infectious mononucleosis, EBV causes two other diseases.
Hairy leukoplakia
Laboratory
Isolation and Identification of Virus
Nucleic acid hybridization is the most sensitive means of detecting EBV in
patient materials.
EBER RNAs are abundantly expressed in both latently infected and
lytically infected cells and provide a useful diagnostic target for detection
of EBV-infected cells by hybridization.
Viral antigens can be demonstrated directly in lymphoid tissues and in
nasopharyngeal carcinomas
EBV can be isolated from saliva, peripheral blood, or lymphoid tissue
Laboratory
Serology
Common serologic procedures for detection of EBV antibodies include ELISA tests, immunoblot assays, and indirect immunofluorescence tests
Early in acute disease, a transient rise in IgM antibodies to viral capsid antigen occurs,
Then replaced within weeks by IgG antibodies to this antigen, which persist for life.
Slightly later, antibodies to the early antigen develop that persist for several months.
Several weeks after acute infection, antibodies to EBNA and the membrane antigen arise and persist throughout life
Treatment
infectious mononucleosis.
Acyclovir has little activity against EBV, but
Burkitts lymphoma was the production of EBV by the lymphoma cells in culture.
In fact, this was how EBV was discovered by Epstein and Barr in 1964.
lymphocytes in vitro.
following primary infection and are reactivated from time to time, especially during periods of immunosuppression.
HHV-6 infection is firmly associated with roseola infantum. It had also been associated with neurological manifestations
transplant recipients such as fever, graft vs host disease, liver and CNS manifestations
However such associations are very difficult to prove since
remains unclear.
HHV-7 is not associated conclusively with any human disease.
infection Reactivation T- lymphotropic human viruses HHV 6- discovered in 1986, grows well in CD4 Other cells like B cells too support growth Oropharynx saliva-transmission HHV-6-Early life-roseola infantum sixth disease persists for life reactivation in pregnancy-encephalitis? neurological manifestations
HHV 8
A new herpesvirus, designated human herpesvirus 8
specimens.
KSHV is lymphotropic and is more closely related to
HHV 8
The KSHV genome (about 165 kbp) contains numerous
genes related to cellular regulatory genes involved in cell proliferation, apoptosis, and host responses (cytokines,
HHV 8
KSHV is not as ubiquitous as other herpesviruses;
About 5% of the general population in the United States
infection.
It appears to be sexually transmitted among men who have sex with men, who have a higher seroprevalence (30 60%).
Infections are common in Africa (> 50%), with infections acquired early in life by nonsexual routes, possibly
HHV 8
KSHV is shed in saliva independent of the subject's
immune status.
Viral DNA has also been detected in breast-milk samples
in Africa.
The virus can be transmitted through organ transplants
HHV 8
Viral DNA can be detected in patient specimens using
PCR assays.
Direct virus culture is difficult and impractical. Serologic assays are available to measure persistent
antibody to KSHV, using indirect immunofluorescence, Western blot, and ELISA formats.
HHV 8
Foscarnet, ganciclovir, and cidofovir have activity against
KSHV replication.
The rate of new Kaposi's sarcomas is markedly reduced in
HIV-positive patients on effective antiretroviral therapy, probably reflecting reconstituted immune surveillance against KSHV-infected cells.