Lecture 12 - Herpes Viruses Types 1 & 2 Flashcards
What are herpes viruses classified based on?
Based on their structure
What are herpes viruses composed of?
- Core
- Capsid
- Tegument
- Envelop
How do herpes viruses mature?
By budding through the inner lamella of the nuclear membrane
Other name for herpes type 2?
Genital herpes
Number of new Herpes type 2 cases/year?
1 M new cases/year
What do herpes viruses use the nucleus of the infected cell for?
- Transcription and replication of DNA
2. Assembly
What are the 4 types of herpes virus-cell interactions? Describe each.
- Lytic infection: causes mucoepithelial cell death and results in a subclinical or clinically apparent infection
- Persistent infection: in lymphocytes and macrophages
- Latent infection: in neurons with later reactivation of a presumably intact virus genome resulting in a productive infection in mucocutaneous or ocular sites
- Transformation: infected cells survive and exhibit the ability to multiply and immortalize B lymphocytes
What 2 herpes viruses cause cell transformation? What are they associated with?
- EBV
- HHV-8
Associated with human cancers
3 subgroups of herpes viruses? Describe each and their members.
- α-herpesviruses: short replication cycle, cytopathic, broad host cell range, latency in sensory ganglia => HSV types 1 & 2, VZV
- β-herpesviruses: narrow host range, relatively long replication cycle, less cytopathic to cells than α-viruses, latency in monocytes and neutrophils => cytomegalovirus, HHV types 6 and 7
- γ-herpesviruses: very restricted host range (mainly lymphoid cells), capable of transforming (immortalizing) host cells, relatively non-cytopathic, latency in B & T lymphocytes => EBV and HHV-8
2 features of herpes viruses?
- They encode enzymes (DNA polymerase) that promote viral DNA replication and that are good targets for antiviral drugs
- They are ubiquitous except HHV-8 => cell-mediated immunity is required for resolution with limited role for antibody
Symptoms of HSV-1?
Most primary HSV-1 infections are asymptomatic, but when symptomatic can cause a primary gingivostomatitis in males or a vulvovaginitis in females
8 triggers of HSV recurrence?
- UV-B radiation (skiing, tanning)
- Fever (hence the name “fever blister”)
- Emotional stress (e.g. final examinations, big date)
- Physical stress, trauma (irritation)
- Menstruation
- Foods: spicy, acidic, allergies
- Immunosuppression
- Respiratory disturbance
How are herpes infections transmitted?
In saliva, in vaginal secretions, and by contact with lesion fluid => orally and sexually and by placement into eyes and breaks in skin
- HSV-1 is generally transmitted orally
- HSV-2 is transmitted sexually
Who is at risk for HSV infections? 4
- Children for HSV-1
- Sexually active people for HSV-2
- Physicians, nurses, dentists, and those in contact with oral and genital secretions => herpetic whitlow
- Immunocompromised and neonates (esp. with infected birth canal): at risk for disseminated, life-threatening disease
Where in the world is HSV found? When?
Virus is found worldwide with no seasonal incidence
5 lab diagnostic test for HSV infections?
- Direct microscopic examination of cells from base of lesion => Tzanck smear shows multi-nucleated giant cells and Cowdry type A inclusion bodies
- Cell culture => HSV replicates and causes identifiable CPE in most cell cultures
- Assay of tissue biopsy, smear, or vesicular fluid for HSV antigen => Enzyme immunoassay, immunofluorescent stain, and in situ DNA probe analysis are used
- HSV type distinction
(HSV-1 vs. HSV-2) => type-specific antibody, DNA maps of restriction enzyme, SDS-gel protein patterns, and DNA probe analysis are used - Serology => not useful except for epidemiology
How do herpes viruses avoid antibodies?
By cell-to-cell spread (syncytia formation)
Describe the mechanism of the establishment of a latent HSV infection. 5 steps
- Multiplication at portal of entry
- Cell-mediated immunity keeps the virus localized
- Virus travels via sensory nerves
- Main sensory ganglion cell in trigeminal ganglion
- Virus enters inactivated state within sensory cell body
Describe the mechanism of the activation of a latent HSV infection followed by recurrence of disease. 4 steps
- Inactive form of virus is in a main sensory ganglion cell
- Triggers activate the virus, which travels along a neuron => tingling, itching, or burning sensation
- Virus to mucous membranes innervated by the sensory nerve
- Multiplication results in inflammatory response with cell-mediated immunity => localized infection
What people have HSV-2? Include percentages. 4
- College freshmen: <1%
- Mid-high SES: 15-20%
- Low SES: 40-60%
- Prostitutes: 80%
What is herpetic whitlow? Who is at risk?
HSV infection on fingers
At risk:
- Babies with hands in mouth
- Dentists, physicians, nurses
Clinical course of primary genital herpes?
- Sexual contact
- 5 day incubation period
3a. Local symptoms: pain, itching, dysuria
3b. Systemic symptoms: malaise, fever, headache
3c. Tender lymph nodes
3d. Virus shedding - Healing
Which lasts longer: primary or recurrent genital infections with HSV-2?
Primary (25 days vs 10 days)
What is a prodrome?
“Pre-outbreak” signs and symptoms of a recurring herpes infection
Are lesions more significant in primary or recurrent genital infections with HSV-2?
Primary
Are local and systemic symptoms seen in both primary and recurrent genital infections with HSV-2?
Only in primary infection
Can shedding HSV infections be asymptomatic?
YUP
Attack rate for HSV-2? What does this mean?
75%
Rate of transmission upon high risk exposure
What is important to note about recurrent HSV-2 infections?
They become less painful over time
3 modes of control of HSV infections?
- Antiviral drugs
- Healthcare workers should wear gloves to prevent herpetic whitlow
- Patients with active genital lesions should refrain from intercourse until lesions are completely reepithelialized
Different treatments for Type 1 and Type 2 HSV infections?
NOPE
3 FDA-approved antiviral treatments for HSV 1 and 2 infections?
- Acyclovir: low bioavailability
- Famciclovir: is converted to penciclovir and has improved bioavailability
- Valacyclovir (aka Valtrex): the L valine ester of ACV with improved oral bioavailability
What is Abreva? How does it work?
Only non-prescription cold sore medicine approved for oral herpes by the FDA to shorten healing time and duration of symptoms
10% docosanol => changes the cell membrane around healthy cells => modified cell membrane acts as a barrier to the virus, making it harder to infect these cells
What is Varicella Zoster?
- Primary infection: Varicella aka chicken pox
2. Recurrent infection: Zoster aka shingles
Where does initial viral replication take place with VZV infection? How does it spread?
Respiratory tract => infects epithelial cells and fibroblasts and can form syncytia and spread directly from cell to cell and by viremia to skin
What is the advantage of cell-to-cell spread of a viral infection?
Avoids antibodies
Describe chicken pox lesions. What to note?
Lesions come in successive crops: macules, papules, vesicles, and crust
NOTE: stages may be seen all at once => polymorphic
Essential immunity in controlling infection with VZV?
Cell-mediated immunity
Is VZV infection ever life-threatening?
YUP - in the immunocompromised
What does Zoster result from?
Depression of cell-mediated immunity
In what patients is Zoster seen?
In people over 60 yo
Where does VZV establish latent infections?
Neurons: usually dorsal root and cranial nerve ganglia
How are Zoster and chickenpox transmitted?
Direct contact for both
Also respiratory droplets for chickenpox
Attack rate of chickenpox?
90% (highly infectious)
Where do chickenpox skin lesions usually begin? Then what?
Usually begins on scalp and then moves to check, back, stomach, arms, and legs
Number of blisters due to chicken pox?
Up to 500
In what patients do complications due to chickenpox occur?
Children under 1 and over 15 yo
Can pregnant women transmit chickenpox to fetus?
YUP if in first trimester
Mortality rate of neonates with chickenpox?
35%
Describe the time course of chicken pox.
- Infection in mucosa of upper respiratory tract
- Viral replication in regional LNs
- Primary viremia
- Viral replication in liver, spleen, and other organs
- Secondary viremia
- Fever
- Infection of skin and appearance of vesicular rash
Incubation period of chickenpox?
5 days
Contagious period of chickenpox?
Days 10-17
Who is at risk for VZV infections?
- Children 5-9 for mild classic disease
- Teens and adults for more severe disease with potential pneumonia
- Immunocompromised patients and newborns for life-threatening pneumonia, encephalitis, and progressive disseminated varicella
- Immunocompromised patients and elderly for recurrent disease
Seasonal chickenpox incidence?
Later winter/early spring
Seasonal incidence of shingles?
NONE
Is VZV found worldwide?
YUP
4 modes of control for VZV infections?
- Antiviral drugs are available
- Immunity is lifelong but may wane in the elderly population
- Varicella-zoster immunoglobulin is available for the immunocompromised exposed to virus, as well as newborns of mothers showing symptoms within five days of birth
- For chickenpox, a live attenuated vaccine (Oka strain) is available since 1995 and is 85% effective (recommended for children 12-18 months old)
- Shingles vaccine
Lab diagnosis techniques for VZV infections? What are these similar to?
Similar to HSV
- Direct microscopic examination of cell scrapings of the base and margins of vesicles
- Tzanck smear shows intranuclear inclusion bodies or multinucleated giant cells
5 antiviral drugs for VZV infections? Describe each.
- Acyclovir (Zovirax)
- Famciclovir: used for post-herpetic neuralgia (PHN)
- Valacyclovir (Valtrex): used for PHN
- VZIG (Varicella-zoster immune globulin): shown to prevent varicella in susceptible normal children if given within 72 hr of exposure
- ZIP (Zoster immune plasma)
What % of people who live to 85 yo develop shingles?
50%
Describe the shingles vaccines.
Zostavax given to adults 60+ contains a weakened form of the chickenpox vaccine and reduces rate of shingles by 50% and PHN by 66%
How is the cytomegalovirus acquired? So what does this mean for transmission?
- Blood
- Tissue
- Most body secretions: including urine, saliva, semen, cervical secretions, breast milk, and tears
TRANSMISSION:
- Orally
- Sexually
- Blood transfusions
- Tissue transplants
- In utero
- At birth
- By nursing
Immune response against cytomegalovirus infection?
CMI required for resolution and contributes to symptoms
Symptoms caused by cytomegalovirus infection?
Generally subclinical, unless CMI is suppressed which allows for severe presentation
What cells are infected by cytomegalovirus?
Epithelial cells and others
Where does the cytomegalovirus establish latency? 3
- T cells
- MOs
- Other cells
4 types of CMV infections? Describe each.
- Congenital: most serious when infection occurs during first trimester
- Natal: causes no disease in healthy full-term babies, asymptomatic in most cases
- Mild and asymptomatic infection: in children and in adults
- Symptomatic infection: in children and in adults can cause heterophile-negative mononucleosis
Most prevalent viral cause of birth defects?
CMV infections
How to diagnose congenital CMV?
Presence of fetal IgM
How is congenital CMV best documented?
By isolating the virus from the neonate’s urine during the first week of life
What can primary infection with CMV cause in pregnant mothers?
- Abortion
2. Cytomegalic inclusion disease
3 symptoms of congenital CMV?
- Hepatosplenomegaly
- Thrombocytopenia
- Microcephaly with severe mental retardation
What 4 viruses cause infectious mononucleosis syndromes?
- EBV
- CMV
- Viral hepatitis
- Toxo-plasmosis
Clinical findings of infectious mononucleosis syndromes due to EBV infection?
- Severe sore throat
- Severe lymphadenopathy
- Severe lymphocytosis
- Severe atypical lymphocytes
- Severe heterophile antibodies
Clinical findings of infectious mononucleosis syndromes due to CMV infection?
- Mild lymphadenopathy
- Severe Lymphocytosis
- Severe atypical lymphocytes
3 lab diagnostic tests for CMV infections?
- Cytology and histology: “Owl’s eye” inclusion body, antigen detection, in situ DNA probe hybridization
- Cell culture: cytological effect in human diploid fibroblasts, and immunofluorescence detection of early antigens
- Serology: primary infection
Does CMV infection cause lifelong infection?
YUP
Do CMV/EBV infections cause asymptomatic shedding?
YUP
What patients are at risk for CMV infections?
- Babies of mothers who seroconvert during term are at high risk for congenital defects
- Sexually active people
- Blood and organ recipients
- Burn patients
- Immunocompromised patients
CMV seasonal incidence?
NONE
Is CMV found worldwide?
Yup
1 mode of control for CMV infections?
Screening potential blood and organ donors
2 antiviral treatments for CMV infections? Issue though?
- Ganciclovir: reduces viral shedding and is the drug of choice for severe CMV infections like pneumonia, chorioretinitis, or colitis in AIDS patients and organ graft recipients
- Foscarnet (phosphonoformic acid): reduces viral shedding.
ISSUE: after prolonged usage of Ganciclovir, resistant CMV mutants appear => Foscarnet is the second line drug when this happens
In what patients do most EBV infections occur? Symptoms for these?
Most infections occur in early childhood and are asymptomatic
The general population is approximately 90% seropositive to EBV
Intimate oral contact required for transmission (saliva)
What can EBV infection of adolescents and adults lead to?
Infectious heterophile positive mononucleosis
What % of pop is seropositive for EBV?
90%
Transmission for EBV infection?
Intimate oral contact with saliva (kissing disease), or sharing of items such as toothbrushes or cups
What EBV infections can lead to severe disease?
Infection of post-transplant patients and immunodeficient patients
How to test for heterophile antibodies caused by EBV infection? For what patients is this test helpful? When will this test be positive?
Monospot test: IgM antibodies agglutinate sheep, horse, and bovine RBCs but not guinea pig RBCs => excellent indicator of EBV infection in adults but not reliable in children and in infants
Usually positive by two weeks
Does EBV cause lifelong infection?
YUP
Face symptom of EBV infection?
Macular rash
Is the attack rate of EBV infections higher on college campuses?
NOPE
% of household transmission with children for EBV infection?
20%
What patients are at risk of EBV infection?
- Children, who may be asymptomatic or have mild symptoms
- Teenagers and adults: at risk for infectious mononucleosis
- Immunocompromised people: at highest risk for life-threatening neoplastic disease
Is EBV found worldwide? What to note?
YUP
Associated with African Burkitt Lymphoma and with nasopharyngeal carcinoma in China
EBV infection modes of control?
NONE
Disease mechanism of EBV infection? 4
- Virus in saliva initiates infection of oral epithelial cells and spreads in lymphatic tissue
- There is productive infection in epithelial cells
- Virus promotes growth of B cells (immortalizes)
- T cells kill and limit B cell outgrowth, promote latency in B cells, and are required for controlling infection (antibody role is limited) => T cell response (lymphocytosis) contributes to symptoms of infectious mononucleosis
4 ways of diagnosing EBV infection?
- Symptoms
- Complete blood count: hyperplasia and atypical lymphocytes (Downey cells, T-cells)
- Heterophile antibody (transient)
- EBV- antigen specific antibody
symptoms of EBV infection?
- Mild headache
- Fatique
- Fever
- Triad: lymphadenopathy, splenomegaly, exudative pharyngitis
- Hepatitis
- Ampicillin-induced rash
2 variants of HHV-6?
6A and 6B
Disease caused by HHV-6 and 7? 2 names
Exanthem subitum aka roseola infantum
How is HHV-6 infection transmitted? What is this similar to?
Close contact or respiratory means and similar to HCMV
Treatment for HHV-6 infection? What is it resistant to?
Ganciclovir, foscarnet, and resistant to ACV
Incidence of HHV-6 and 7?
Population is 45 to 100% seropositive by age 2
Which is found in saliva in higher frequency: HHV-6 or 7?
HHV-7
3 diseases associated with HHV-8 infections?
- Kaposi’s sarcoma-associated herpesvirus (KSHV)
- Castleman’s disease, a rare lymphoproliferative disorder often associated with KS
- Peripheral effusion lymphoma.
Treatment for HHV-8 infections? What is it resistant to?
Foscarnet, cidofovir (toxicity), resistant to ACV
