STI: viruses Flashcards
Describe the features of the papilloma virus
Papilloma Virus
- dsDNA circular genome
- Only 2 promoters and 8 proteins (E and L proteins)
- Replicates in the nucleus of cells
- Can use the host transcription machinery, including splicing mechanisms
- Physically links itself to a host chromosome
- This occurs in long-lived basal-layer skin cells
- Contributes to persistence
Describe the replication of papilloma viruses
- Very closely linked with process of maturation of skin cells
- Infection of basal cells= Persistence + Evasion of immunity
- DNA amplification in spinous and granular layers
- Viral E proteins induce cell division
- Cause warts - proteins push cell into cell cycle
- Viral E proteins induce cell division
- New virus assembly at stratum corneum layer
- Rapid DNA replication
- Capsid proteins made to generate viral particles
- Shedding at skin surface
Describe the link between HPV and cervcial cancer
- Cervical carcinoma kills >250 000 women/year
- HPV6 first identified - used as a probe in hybridisation to find DNA that is similar but not identical
- Virus particle integrates into host chromosome → E proteins push cell into cell cycle → E6/E6 viral oncogenes take effect →
additional mutations accumulate → uncontrolled cell division → cance
Describe the hpv vaccine
- HPV was the first virus unambiguously shown to be a sole initiating cause of a human cancer
- Once identified, epidemiological studies done to link these HPV types to cancer = ‘high risk’ types
- High risk HPV infections are very prevalent
- Much more common than cervical cancer
- Are generally cleared by immunity- Hypothesis: A vaccine that stops HPV infections will reduce cervical carcinoma rates
Virus-Like Particles
Vaccine based on VLP that express capsid proteins (no nucleic acid!)
- Virus capsids are self-assembling machines
- Can be as simple as a single repeated unit
- Can have multiple units
- For unenveloped viruses, VLPs look like a virus to the immune system
- Superior immunogenicity compared with protein
- The subunits are made in a culture system and are not derived from virus infection
- Very safe!
The Vaccine for Cervical Cancer
- Clinical trials show:
- 100% effectiveness against HPV infection
- 98% against high-grade carcinoma
- Only if recipients are HPV negative
- Where cervical lesions were present at the time of immunization, there was no effect
- The first vaccine to protect against a human cancer
- *Strictly speaking, is an anti-viral not anti-cancer vaccine
HPV Vaccines
- Cervarix (GSK)
- VLPs of HPV types 16 & 18
- These cause 70% of cervical cancer
- Gardasil (Merck)
- VLPs of HPV types 6, 11, 16 & 18
- Gardasil9 (Merck)
- VLPs of HPV types 6, 11, 16, 18, 31, 33, 45, 52 & 58
- Types 6 & 11 cause 90% of genital warts
- On the NIP for age 12-13 yrs
- Girls since 2007, boys added 2013. Gardasil9 since 2018
Dramatically reduced rates of cervical cancer among vaccinated individuals.
List the herpesviruses that infect people
Herpesviruses that Infect People
- Herpes Simplex Viruses 1 & 2
- Cold sores, genital herpes
- Varicella-Zoster Virus
- Chickenpox and shingles
- Cytomegalovirus
- Severe infections in utero and in immunocompromised
- Epstein-Barr Virus
- Glandular fever (IM), associated with several cancers
- Human Herpesvirus 6
- Roseola infantum
- Karposi’s Sarcoma Associated Herpes Virus
- Karposi’s sarcoma
Describe the common features of herpesviruses
- A **large linear dsDNA genome
- Capsid with icosahedral symmetry
- Envelope
- Tegument between capsid & envelope, packed with virus proteins
- released in infected cell as soon as virus gets in: shut off host cell functions so virus takes over
Describe the cellular outcomes of herpesvirus infection
Infection
* Productive infection: cell death, new virus made
* Latent infection: long-term cell and virus survival
- Site of latency differs amongst herpesviruses.
- It is pivotal in each infection.
- Most important adaptation
Describe HSV,its tropism and mode of infection, and its prevalence
- Primary infection in the skin
- Spread to peripheral nervous system
- Via Axonal transport in sensory nerves: stays latent in cell bodies
- Infection in primary sensory neurons
- Latency in neurons
- Virus almost silent
- Neurons are long-lived
- Periodic reactivation
- May lead to shedding
- May lead to symptoms
- Latency in neurons
- Neuronal Infection is Key
-
You don’t always know…
- Prevalence in Australia
- HSV-1 = 76%
- HSV-2 = 12% (much higher in some groups)
- Asymptomatic shedding
- Thought to be the most common cause of transmission
- Study example (by virus culture):
- 65% of HSV-2 seropositive women shed virus w/out symptoms
- Over a mean time of 106 days
- 11% shed virus more than 5% of days
- When PCR is used, the rates are much higher
- Estimated to be 4-5% higher
- ALL seropositives shed virus!
- Prevalence in Australia
Describe the opportunistic nature of HSV
- Type 1 and 2 are generally associated with facial and genital infections, respectively.
- This localisation reflects transmission rather than virus tropism…
Examples include:
- This localisation reflects transmission rather than virus tropism…
- Herpes gladiatorum demonstrates the same point
- In wrestlers and rugby players
- Herpetic whitlow - under nail
- Herpes keratitis
- Leads to blindness
Describe the severe manifestations of HSV
Neonatal Herpes
- Acquired during birth
- Infection can disseminate
- Hepatitis, encephalitis…
- Up to 50% mortality unless treated
Herpes Encephalitis
- Occurrence around 1/500,000 annually
- 1/3 primary infection, 2/3 reactivation
- Treat fast…
- 70% mortality without drugs → 30% with treatment
Eczema Herpeticum
- Two common conditions, but a rare complication
- Widely spreading lesions
Describe briefly the outcomes of primary and secondary VZV infection
-
Varicella = Chickenpox
- What you get the first time you meet VZV
-
Latency in Sensory Ganglia
- Zoster = Shingles
- What you get if VZV wakes up
Distinguish between primary and secondary vzv infection
Primary infection (chickenpox) is systemic
- Spread by respiratory route, dissemination to lymph nodes and to skin via infected lymphocytes
- Virus gains access to the nervous system
- Latency is in sensory neurons
Secondary infection: Reactivations lead to neural and skin infection - shingles
- Associated with waning immunity in the elderly
- Characterized by extreme pain due to nerve damage
- More than a single reactivation is uncommon
- Usually maps a particular dermatome as virus lies dormant in a particular ganglion
Describe post herpetic neuralgia
- Shingles is very painful
- Sometimes the pain does not stop after healing = Post-herpetic neuralgia
- Can affect areas not covered by original lesions, due to residual nerve damage
- In one study, the risk was 6% (<55 yo) and 11% (>55)
Describe VZV vaccines
- Based on a tissue culture-derived, classically attenuated strain of VZV (Oka)
- Varivax (CSL/Merck) or Varilrix (GSK)
- Lower dose, for VZV naïve (mostly kids)
- On the National Immunization Program at 18 months
- Breakthrough infection and reactivation occur
- Zostervax
- Higher dose (~15 x higher than Varivax)
- For boosting of immunity to prevent shingles
- Only recommended for people >60
- Varivax (CSL/Merck) or Varilrix (GSK)
- A new recombinant vaccine (glycoprotein E) is looking good in clinical trials for Zoster
- Efficacy was 97% irrespective of age
- Zostervax is 70%, dropping to 40% with age
- US CDC has just recommended the new vaccine
Describe CMV
- Spread via close contact
- In urine, saliva & breast milk
- Infection is systemic
- Many organs
- Many cell types
- Classic histopathology
- ‘Owl’s eyes’ intranuclear inclusions
- BUT usually asymptomatic
- Latency in myeloid progenitors in bone marrow
- CMV DNA found in blood monocytes (1:10,000)
- Reactivations probably frequent
- As in primary infection, these are usually inapparent
- Highly prevalent: 50-80% infected by 40 yo
-
Clinical Issues:
- Primary CMV infections during pregnancy
- Most common cause of congenital defects
- 1 in 750 live births in the USA
- Deafness, blindness, mental retardation, growth retardation
- Severe infections in immunocompromised
- Organ transplant recipients, AIDS patients
- Pneumonia, retinitis
- In transplant patients, there is often a trade-off between organ rejection and controlling CMV infection
- Primary CMV infections during pregnancy
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Clinical Issues:
