Herpes Viruses Flashcards
List the herpes viruses that infect humans.
o Herpes simplex Type 1 (HHV-1) = 50-70% of adults
o Herpes simplex Type 2 (HHV-2) = 20-50% adults (very low in children)
o Varicella-Zoster Virus (HHV-3) = 85-95%
o Epstein-Barr Virus (HHV-4) = 80-95%
o Human Cytomegalovirus (HHV-5) = 40-70%
o Human Herpes virus 6 (HHV-6) = 95% by age 5
o Human Herpes virus 7 (HHV-7) = 95% by age 12
o Kaposi’s Sarcoma Associated Herpes Virus (HHV-8) = <3% adults; very low in kids
Identify the tissues tropisms that separate these viruses into two broad groups
3 subfamilies:
o Alpha Herpesviruses: HSV-1, HSV-2, VZV
o Beta Herpesviruses: HCMV, HHV-6, HHV-7
o Gamma Herpesviruses: EBV, HHV-8
Separated in 2 groups based on tropism (sites of latency):
o Neurotropic = alpha group
o Lymphotrophic = beta and gamma groups
Discuss how herpes viruses are transmitted and their clinical course
• Herpes viruses = widespread
• Highly probable = everyone is latently infected with at least 3-4
• Spread primarily by close contact (kissing, sex)
o Exception: VZV = also can be transmitted by aerosol
All = very high rate of asymptomatic infection
o > 50% of the population will shed virus in the absence of symptoms over the span of 1 year
o > 50% of primary infections occur without symptoms
o Silent reactivations are also very frequent
Initial infection:
o Epithelial cells infected = localized viral replication
o Progeny virus taken up by sensory nerves
o Loaded onto microtubules → neuron (retrograde transport)
o Genome enters nucleus → circularizes and interacts with host histones
o Forms chromatin-like structure
IF:
• Non-permissive state: genome remains inactive (latency)
• Permissive: viral gene expression activates → infection begins
Reactivation triggers: HSV 1 and 2 • Stress • Ultraviolet light • Steroid hormone increases • Trauma to latently infected ganglia • Decreased immune function Other herpes viruses • Not clear • Reduced immune function clearly important • Stress probably important
Anterograde transport of new virions back to synaptic termini
o Released = can infect epithelial cells at same place initially
Recurrent lesions = come back at same place as initial infection
o Neurotropic viruses able to travel via axons of sensory nerves
HSV 1 & 2: Diseases
Primary diseases:
Gingivostomatitis
• Initial pain or tingling → erythematous spot → vesicle formation → ulceration → eventual healing
• Vesicle fluid = highly infectious
• Saliva also contaminated
Keratoconjunctivitis
• Leading cause of blindness due to infection in US
• Conjunctivitis → corneal epithelial cells = viral replication → virus kills cells
• Latent virus can reactivate = damage accumulates
• Clouds cornea, new blood vessel growth → blindness
Cutaneous herpes (Herpes Gladiatorum)
• Ulcers on cheeks
• Common in wrestlers
Genital Herpes
• Men: clustered ulcers on penis shaft
• Women: ulcers on external genitalia or walls of vagina or cervix; can spread to perineum from vaginal secretions
• More severe in immune compromised = extensive spread
Encephalitis (HSV-1)
• Leading cause of sporadic encephalitis in US
• Initial generalized symptoms: malaise
• Progresses: CNS involvement (confusion, coma)
• Mortality rate:
• 70% if not treated
• 30% if treated with antivirals
• See temporal lobe necrotic lesions
Asceptic meningitis (HSV-2)
• Self-limiting
• Rarely a concern
Neonatal herpes (primarily HSV-2)
• Highly lethal (70% untreated; 30% with treatment)
• Virus disseminates since infant has immature immune system
• Highest risk: infants born to mothers who acquire primary infection during pregnancy
Recurrent diseases: o Herpes labialis (cold sores) o Keratoconjunctivitis o Cutaneous herpes o Encephalitis o Genital Herpes = Reactivation of genital ulcers o Asceptic meningitis
HSV 1 & 2: Diagnosis
Usually made by appearance of lesions
Culture can be done = shell vials with IF staining being replaced by PCR
Tzanck stain
• Material scraped from ulcer = stained
• Typical viral cytopathology is observed
Encephalitis: PCR on cerebrospinal fluid = “gold standard”
• Also: neurological symptoms useful (ex: lethargy, confusion, inability to sit upright)
Varicella Zoster Virus: Transmission
Transmission = aerosol and contact with fluids from vesicles
o Causes disseminated infection → seeds skin and internal organs
o Seed skin → ulcer formation, can scab over
o Rash is vesicular (fluid filled) not macular
Highly infectious, 90% attack rate in family members
o Over 90% of population seropositive before vaccine became available
Varicella Zoster Virus: Clinical Diseases
Cause of chicken pox
Reactivation of infection → Zoster (Shingles):
o Rash appearing on specific dermatomes
o Painful sensation → macular rash → vesicles → ulcers that eventually scab over
Post-herpetic neuralgia
• Very painful
• Can last for months after
• Refractory to analgesic agents
Incidence increases with age
o 10 to 20% of the population will get shingles
Diagnosis:
o Basis of characteristic rash
Human Cytomegalovirus: Diseases
Primary Infections
Heterophile negative mononucleosis
• Symptoms: fever, malaise, sore throat, lymphadenopathy, hepatitis
• Self-limiting disease
• Eventually clears
Hepatitis
Congenital cytomegalic inclusion disease
• In infants due to congenital infection
• Leading cause of birth defects in U.S.
• Greatest danger = primary infection in a seronegative mother
• Intrauterine infection 55% in primary infection
• Results: jaundice, hepatosplenomegaly, microcephaly, petechial rash, mental retardation, chorioretinitis
• Symptoms more severe when infection is earlier in pregnancy
Reactivation
o No known disease associated with reactivation in immunocompetent people
Human Cytomegalovirus in immunosuppressed patients
About 70% of organ transplant patients have CMV reactivate
• Donor organs can transmit if infected
• Bone marrow transplant → interstitial pneumonia (84% mortality rate)
• Hepatitis in liver transplant patients
• Kidney infection can lead to donor organ failure
CMV retinitis in AIDS patients → blindness
Human Cytomegalovirus: diagnosis
o Laboratory Confirmation Required
o Examine saliva for typical “owl eye” cells in tissues
o Immunostaining for viral antigens in cell or tissue samples = IE antigens give fastest results for culture samples
o PCR can be done
o Virus grows extremely slowly so looking for typical CPE in cultures is not used
Epstein-Barr Virus: Diseases
Infectious monocucleosis (heterophile +) Clinical features: • Fever, sore throat, severe malaise • Tonsular exudate • Petechial spots on palate • Lymphadenopathy, spenomegaly • Heterophile antibodies = specific for sheep RBCs o Due to polyclonal B cell stimulation from virus o Useful diagnostically Diagnosis: • Monospot test • Viral specific antigens
Hepatitis
Encephalitis (rare)
Reactivation
o If immunocompetent host = none known
Epstein-Barr Virus: infection in immunocompromised hosts
Polyclonal and monoclonal lymphoproliferative syndromes (lymphomas)
Oral hairy leukoplakia
• AIDS patients
• Nonpainful white plaque along lateral tongue borders
Epstein-Barr Virus: Cancer
Mechanism:
EBV infects B cells = induces cell proliferation
Allows cells to accumulate mutations in cellular proto-oncogenes
Extends Ig gene rearrangement stage in pre-B cells leading to chromosomal translocations
• All Burkitt’s Lymphoma tumors have C-myc translocations and disregulation
• Normally: c-myc triggers cell division
Leads to malignant transformation
Immune suppression → failure to remove cancer cells
Types: Burkitt’s Lymphoma • Found in central Africa • Affects Children between 6 - 15 yrs. • Solid tumors of jaw and long bones • Some association with Malaria (endemic overlap) Nasopharyngeal Carcinoma • Endemic in Southern China • Usually affects adults • Affects epithelial cells US • American Burkitt’s (rare) • Other solid B cell tumors (lymphomas) Proposed associations • Hodgkin’s disease, GI cancers
Epstein-Barr Virus: Diagnosis
Triad of symptoms relatively unique:
• Aore throat
• Fever
• Lymphadenopathy
Monospot test
• Rapid latex agglutination test for mononucleosis
Heterophile antibodies to sheep red blood cells in patient serum
• Detected by hemagglutination tests
Lymphocytosis (Downey Cells)
• Characteristic cytopathic effect in lymphoid cells in blood
Immunostaining for virus specific proteins helpful in prognosis or if other tests are negative
Culture not routinely available
Biopsies for solid tumors (lymphomas)
HHV-6
Typically acquired at young age (<6-11 years)
Causes Roseola infantum o Mild self-limited febrile illness with mild macular rash o High rate of asymptomatic infection o Transmitted by close contact o No approved antivirals o No vaccine
Serious infections = seen in organ transplant patients
o Due to reactivation of latent virus
o Can lead to transplant failure or lethal dissemination infection
HHV-8: diseases
Primary Infection
o No known disease association
Recurrent Disease
o No known recurrent diseases
Immunocompromised People:
1) Kaposi’s sarcoma
• Tumor of vascular endothelial cells
• Dark purple to brownish lesions
• Seen in: AIDS patients, elderly (men) endemic in Mediterranean region
• Sexually transmitted but also requires immune deficiency
2) Castleman’s Disease
• Infection of internal organs → inflammatory response
HHV-8: diagnosis
Kaposi’s sarcoma lesions are distinctive
• Purple spots on skin
• Multiple spots appear simultaneously
Viral Detection
• PCR
• Immunostaining of biopsies
• Serology
Culture not routinely done
Explain the concept of latency and how it differs between viruses that establish latent infection in different types of cells.
Latency = characteristic of all herpes viruses
o Primary infection results in viral replication
o Seeding of the target cells for latency then occurs
o Virus replication shuts down in the latently infected cell
o Virus persists as the genome in the cell nucleus
o Infectious virus cannot be detected in the host during latent periods
Periodically = virus reactivates in latently infected cells → releases infectious virus
o Infectious virus can now be detected in the host.
o Result: result in asymptomatic shedding or in recrudescence of disease (eg. cold sores, shingles).
Sites of latency: o HSV-1 and 2: neurons o VZV: neurons o HCMV: monocytes o EBV: resting B cells o HHV-6: CD4+ T cells o HHV-7: CD4+ T cells o HHV-8: unclear (maybe B cells)
Neurotropic vs. Lymphotropic viruses
Neurotropic viruses:
• Neurons do not divide → virus does not have to replicate genome to maintain latent infection
• Result: can shut off expression of all viral proteins
• No viral antigens present = makes it hard for host to target and eliminate infected cells
Express only 1 gene: Latency associate transcript (LAT)
• LAT mRNA is not translated
• Functions as RNA molecule
• Prevents apoptosis of latently infected neuron
Lymphotropic viruses:
• Lymphoid cells do divide → virus needs to pass viral genome to daughter cells
• Needs to express minimal set of genes for replication and segregation
• These 5-6 genes = target for immune system
Result = virus has mechanisms to suppress immune response:
• Prevent MHC antigen expression on infected cell surfaces
• Encode viral cytokines that mimic host IL-4 and IL-10 (immunosuppressive)
• Encode secreted proteins that act as decoy receptors for host cytokines = suppress immune response
• Some viral genes have sequences that prevent degradation
Identify those herpes viruses that cause cancer in humans and briefly explain their role in neoplastic disease.
Epstein-Barr Virus o Burkitt’s lymphoma o Nasopharyngeal carcinoma o American’s Burkitt’s o Other lymphomas
HHv-8
o Kaposi’s sarcoma
Define heterophile antibody and discuss the significance of the terms “heterophile positive” and “heterophile negative” mononucleosis.
Heterophile Abs = specific for sheep RBC’s
o Important diagnostic tool for EBV
o EBV causes polyclonal B cell stimulation → production of Ab’s
o Able to detect Ab’s with sheep blood cells
Lab test = heterophile Ab’s detected by hemagglutination test
o If heterophile positive = EBV infection
List the vaccines & treatment available to prevent herpes virus disease
Vaccines:
• Chicken pox and shingles (same vaccine)
Treatment:
Herpes Simplex 1, 2 and VZV
o Several nucleoside analogs are available
o Trifluorthymidine, Idoxuridine = used topically
o Acyclovir, Valacyclovir, Famciclovir = orally or parentally
HCMV
o Foscarnet or ganciclovir
o Both have toxicity issues
EBV
o Acyclovir, Valacyclovir
HHV-6
o Ganciclovir
o Only in life threatening infections
HHV-7 = ?
HHV-8
o Interferon for virus
o Radiation and cytotoxic drugs for cancer
o Restoration of immune system will control
