Download a. Herpes Simplex Type 1

CHAPTER 14
Herpesviruses
The human herpesviruses belong to Herpesviridae family which are large, enveloped,
double stranded DNA, viruses and produce infections ranging from painful skin and
genital ulcers to chickenpox to encephalitis to Kaposi’s sarcoma. There are eight
members of the family that infect humans, including two herpes simplex viruses (HSV-1
and HSV-2), cytomegalovirus (CMV), varicella–zoster virus (VZV), Epstein–Barr virus
(EBV), human herpesvirus-6 (HHV-6), human herpesvirus types 7 and 8 (HHV-7, HHV8; Table 14–1). In addition a simian herpesvirus, herpes B virus, has occasionally caused
human disease.
GROUP CHARACTERISTICS
I. VIROLOGY
1. The DNA core is surrounded by an icosahedral capsids
2. Over the capsid is a protein-filled region called the tegument
3. Outside of the viral particle is covered by a lipoprotein envelope derived from the
nuclear membrane of the infected host cell
4. Morphology similar among herpesviruses but genomic sequences differ
5. Can infect nondividing cells
6. Herpes simplex 1 and 2, as well as varicella-zoster viruses, are in the  subfamily
7. Cytomegalovirus, HHV-6, and HHV-7 are in the  subfamily
8. EBV and HHV-8 are in the  subfamily.
9. Herpes simplex has widest range of cell tropism
10. Viral latency and disease reactivation typical for all herpesviruses
A. Replication
1. HSV generally causes lytic infection in epithelial cells and latent infection in
neuronal cells
2. Glycoproteins in the HSV envelope interact with cellular receptors to result in
fusion with the cell membrane
3. Fusion delivers the capsid and DNA case into the cytoplasm, where it migrates to
the nucleus, and the genome is circularized
4. Transcription of the large, complex genome is sequentially regulated in a cascade
fashion.
5. Genomic concatemers are cleaved and packaged into preassembled capsids in the
nucleus
6. Three classes of mRNAs produced
7. Coordinated gene expression
8. After synthesis capsid proteins are transported to the nucleus where their
assembly with DNA takes place
9. The envelope is acquired from the inner lamella of the nuclear membrane
10.Most herpesviruses, except CMV, shut down host cell metabolism
HERPES SIMPLEX VIRUS
I. VIROLOGY
1. HSV-1 and HSV-2 are distinct epidemiologically, antigenically, and by DNA
homology
2. Individual strains differ by restriction endonuclease techniques
II. HERPES SIMPLEX DISEASE
A. EPIDEMIOLOGY
1. No animal reservoirs
2. High seroprevalence among humans, which increases with age
3. Infection with HSV-2 linked to sexual activity
B. PATHOGENESIS
a. Acute Infections
1. Both HSV-1 and 2 replicate in the mucoepithelial cells and later
establish a latent infection in the neurons (sensory ganglion cells
2. Infection produces inflammation and giant cells
3. Virus can infect and spread in axons and ganglia
b. Latent Infection
1. Latent infection of nervous tissue by HSV does not result in the death of
the cell
2. No synthesis of early or late viral polypeptides in latent infection
3. Reactivation can be precipitated by sun exposure, fever, or trauma
C. IMMUNITY
1. Some cross-protection between HSV-1 and HSV-2
2. Neutralizing antibodies directed against HSV envelope glycoproteins important
in preventing exogenous reinfection
3. Antibody-dependent cellular cytotoxicity (ADCC) may limit early spread
4. Cytotoxic T lymphocytes destroy HSV-infected cells
III. HERPES SIMPLEX: CLINICAL ASPECTS
A. MANIFESTATIONS
a. Herpes Simplex Type 1
1. Infection with HSV-1 is usually, but not always, “above the waist.”
2. Vesicular lesions become pustular and then ulcerate
3. Primary infections often asymptomatic
4. Recurrent cold sores usually unilateral
5. Virus in saliva with asymptomatic reactivation
6. Herpetic whitlow mimics bacterial paronychia
7. Herpetic corneal and conjunctival infection can cause blindness
8. Herpes encephalitis may be reactivation
9. Encephalitis typically localized to temporal lobe
10. Rapid diagnosis allows antiviral therapy
b. Herpes Simplex Type 2
1. Both HSV-1 and HSV-2 can cause genital disease, and the symptoms and signs
of acute infection are similar for both viruses
2. Seventy percent of first episodes of genital HSV infection in the United States
are caused by HSV-2
i. Primary Genital Herpes Infection
1. Multiple painful vesicopustular lesions
2. Systemic symptoms and adenopathy common
ii. Recurrent Genital Herpes Infection
1. Prodromal paresthesias and shorter duration
ii. Recurrent episodes common; may involve shedding without lesions
c. Neonatal Herpes
1. Transmission of virus during delivery through infected genital secretions from
the mother
2. Severe neonatal herpes is associated with primary infection of a seronegative
woman at or near the time of delivery
3. Some infants show disseminated vesicular lesions with a widespread internal
organ involvement others have involvement of the central nervous system only
4. High mortality if disseminated
B. DIAGNOSIS
1. Grow rapidly in many cell culture systems
2. HSV-1 and HSV-2 distinguished by type-specific monoclonal antibodies
3. Enzyme immunoassay, immunofluorescence, and PCR all used for rapid
diagnosis
C. TREATMENT
1. Acyclovir or prodrugs can decrease duration of acute and recurrent disease
PREVENTION
1. Avoiding contact with individuals with lesions reduces the risk of spread
2. Acyclovir has been shown to reduce asymptomatic shedding and transmission
of genital herpes, especially from males to females
3. Caesarean section may be performed to avoid neonatal infection
VARICELLA–ZOSTER VIRUS
I. VIROLOGY
1. Same general structural and morphological features as herpes simplex but
contains its own envelope glycoproteins and is therefore antigenically different
2. Slower growth and narrower range of infected cell types
II. VARICELLA–ZOSTER DISEASE
A. EPIDEMIOLOGY
1. VZV infection is ubiquitous
2. The virus is highly contagious, with attack rates among susceptible contacts of
75%.
3. Chickenpox acquired by respiratory route, usually before adulthood
4. Communicability greatest before rash onset
B. PATHOGENESIS
1. Respiratory spread leads to infection of the contact patient’s upper respiratory
tract followed by replication in regional lymph nodes and primary viremia
2. Secondary viremia results in skin lesions
3. Viruses isolated from chickenpox and from zoster (or shingles) are identical
4. Varicella virus latent in sensory ganglion cells; reactivation produces zoster
C. IMMUNITY
1. Circulating antibody prevents reinfection; cell-mediated immunity controls
reactivation
2. Aging associated with increasing risk of zoster
III. VARICELLA–ZOSTER DISEASE: CLINICAL
ASPECTS
A. MANIFESTATIONS
1. VZV produces a primary infection in normal children characterized by a
generalized vesicular rash termed chickenpox or varicella.
2. Lesions appear in different stages of evolution one of the features used to
differentiate varicella from smallpox
3. Chickenpox lesions are widespread and pruritic
4. Severe disease in immunocompromised patients
5. Reactivation to zoster most common in elderly
6. Follow sensory nerve distribution
7. Postherpetic neuralgia after zoster
8. Dissemination with visceral infection in immunocompromised persons
B. DIAGNOSIS
1. Diagnosis usually clinical
2. Rapid confirmation by immunofluorescent staining
C. TREATMENT
1. Acyclovir is recommended in healthy patients over 18 years of age and
immunosuppressed patients
2. Acyclovir may be used to treat herpes zoster in immunocompetent adults, but
has only a modest impact on the development of post-herpetic neuralgia
3. Famciclovir or valacyclovir are more convenient and may be more effective.
D. PREVENTION
1. Passive immunization for immunocompromised
2. Live vaccine is safe and effective
3. Adult live vaccine now recommended for >60 years age group
4. Need for isolation of cases in hospital
CYTOMEGALOVIRUS
I. VIROLOGY
1. In addition to nuclear inclusions CMV produces perinuclear cytoplasmic
inclusions and enlargement of the cell (cytomegaly)
2. Based on genomic and phenotypic heterogeneity, innumerable strains of CMV
exist
II. CYTOMEGALOVIRUS DISEASE
A. EPIDEMIOLOGY
1.
2.
3.
4.
CMV is ubiquitous
High infection rates in early childhood and early adulthood
Present in urine, saliva, semen, and cervical secretions
Viral latency in leukocytes
B. PATHOGENESIS
1. CMV DNA in monocytes
2. Immune-mediated tissue damage
C. IMMUNITY
1. Both humoral and cellular immune responses are important in CMV infections
2. CMV infection of monocytes results in dysfunction of these phagocytes in
immunocompromised patients
3. Vascular endothelial cells can be infected and support viral latency
III. CYTOMEGALOVIRUS: CLINICAL ASPECTS
A. MANIFESTATIONS
1. Infants with symptomatic illness have defects such as hepatosplenomegaly,
jaundice, anemia, thrombocytopenia, low birth weight, microcephaly, and
chorioretinitis
2. Serious disease of fetus may develop with primary maternal infection
3. Perinatal infection asymptomatic or relatively benign
4. CMV pneumonia, visceral, and eye infections in immunocompromised patients
B. DIAGNOSIS
1. CMV can be grown readily in fibroblast cell lines after 3 to 14 days
2. DNA detection by PCR or antigen detection useful to find viremia
3. Thus, the isolation of CMV from urine of immunosuppressed patients with
interstitial pneumonia does not constitute evidence of CMV as the cause of that
illness
4. Histologic detection of inclusions in lung, gastrointestinal tissues is useful
a. Diagnostic procedures in specific clinical settings:
1. Congenital infection. Virus culture or viral DNA assay
2. Perinatal infection. Culture-negative specimens at birth but positive
specimens at 4 weeks or more after birth suggest natal or early postnatal
acquisition
3. CMV mononucleosis in nonimmunocompromised patients.
Seroconversion and presence of IgM antibody specific for CMV are the
best indicators of primary infection
4. Immunocompromised patients. Demonstration of virus by viral antigen,
DNA, or culture in blood documents viremia
C. TREATMENT
1. Ganciclovir has been shown to inhibit CMV replication; prevent CMV disease in
AIDS patients and transplant recipients; and reduce the severity of some CMV
syndromes
2. Foscarnet, a second approved drug for therapy of CMV disease, is also efficacious
3. Cidofovir, a nucleotide analog, is approved for therapy of retinitis but its use is
limited due to nephrotoxicity
D. PREVENTION
1. Use of CMV seronegative blood donors decreases risk
EPSTEIN–BARR VIRUS
I. VIROLOGY
1. Etiologic agent of infectious mononucleosis and certain lymphomas
2. Cultivated only in lymphoblastoid cell lines
3. EBNA, VCA, and EA represent stages of viral replication
II. EPSTEIN–BARR VIRUS DISEASE
A. EPIDEMIOLOGY
1. EBV can be cultured from saliva of 10 to 20% of healthy adults
2. Most cases of infectious mononucleosis are contracted after repeated contact
between susceptible persons and those asymptomatically shedding the virus
3. Widespread asymptomatic infection; disease most common in young adults
B. PATHOGENESIS
1. Although EBV initially infects epithelial cells and
2. Enters B lymphocytes by means of envelope glycoprotein binding to a surface
receptor CR2 or CD21
3. Infects B cells causing polyclonal B-lymphocyte activation with benign
proliferation
4. Encodes proteins associated with immortalization of B cells
5. Lymphomas can develop in immunocompromised patients
C. IMMUNITY
1. Heterophile antibodies, are a heterogeneous group of predominantly IgM
antibodies long known to correlate with episodes of infectious mononucleosis
2. The “atypical” lymphocytosis associated with infectious mononucleosis is caused
by an increase in the number of circulating activated T cells
3. In rare cases, the initial EBV-induced proliferation of B cells is not contained, and
EBV lymphoproliferative disease ensues
III. EPSTEIN–BARR VIRUS: CLINICAL ASPECTS
A. MANIFESTATIONS
1. Infectious Mononucleosis - Primary infection asymptomatic or expressed as
infectious mononucleosis characterized by fever, malaise, pharyngitis, tender
lymphadenitis, and splenomegaly
2. Lymphoproliferative Syndrome - Lymphoproliferative disease occurs,
especially in immunocompromised persons
3. Burkitt’s Lymphoma - thought to result from an early EBV infection that
produces a large pool of infected B cells
4. Nasopharyngeal Carcinoma - Endemic NPC in southern China; suggests
environmental or genetic cofactors
5. AIDS Patients - several distinct additional diseases may occur, including hairy
leukoplakia of the tongue, interstitial lymphocytic pneumonia, and lymphoma.
B. DIAGNOSIS
1. Atypical lymphocytosis common in acute infection
2. Heterophile antibodies nonspecific but appear early
3. IgM antibody to VCA or high IgG antibody to VCA with negative anti-EBNA
suggest, primary infection
4. Virus isolation is impractical for routine diagnosis
TREATMENT
1. Treatment of infectious mononucleosis is supportive
PREVENTION
1. Immunization of humans not available
OTHER HERPES VIRUSES
I. HUMAN HERPESVIRUS-6
A. Virology
1. Identified in cultures of peripheral blood lymphocytes from patients with
lymphoproliferative diseases
2. Replicates in CD4+ T lymphocytes
B. EPIDEMIOLOGY
1. Infection common in infancy
C. MANIFESTATIONS
1. Etiologic agent of exanthem subitum (roseola) in infants aged 6 months to 1
year
2. Characterized by fever for 3 days, followed by a faint maculopapular
3. Reactivation common in immunosuppression
4. Latent infection of T cells
D. DIAGNOSIS
1. Primary infection can be documented serologically
2. PCR used to detect viremic infection
E. TREATMENT
1. Definitive therapy has not been established, but HHV-6 appears to be
susceptible in vitro to ganciclovir and foscarnet
II. HUMAN HERPESVIRUS-7
1. Originally isolated from CD4+ T lymphocytes
2. Can cause exanthem subitum (roseola)
III. HUMAN HERPESVIRUS-8
1. Most closely related to EBV
2. Associated with Kaposi’s sarcoma
3. Infects B lymphocytes