Viral infections and anti-viral drugs Flashcards
what are examples of common viral infections?
Common cold
Flu
Bronchitis
Pharyngitis
Herpes (coldsores)
Chickenpox
Shingles
Conjunctivitis
Gastroenteritis/ Norovirus
MMR (less common now, vaccination)
SARS-CoV-2 (COVID-19
what are the possible routes of transmission?
- airbrone/droplets - influenza, MMR
-contact via non-living surfaces - common cold, influenza
-faceal-oral - rotavirus, hepatitis A, poliovirus
-insect bites - dengue , west nile, yellow fever
contact with lesions - herpes simplex, varicella zoster
sexual contact - HIV, hepatitis B, herpes
blood - HIV, Hep B and c
blood and body fluids - ebola, epsteib- Barr
mother to child - HIV, rubella, zika
how are viruses classified ( virus classification)
- Genetic material
- Mode of replication
- Structure and symmetry of capsid
- Presence / absence of envelope
What is Baltimore classification and examples
Groups I-VII (Baltimore classification)
(I – dsDNA, II – ssDNA, III – dsRNA, IV – (+)ssRNA,
V – (-)ssRNA, VI – ssRNA-RT, VII – dsDNA-RT)
Group 1 - HSV -1
Group 2 - Parovirus
Group 3 - Rotavirus
Group 4 - SAR-CoV-2
group 5 - Rabies
Group 6 - HIV
group 7 - HBV
DNA viruses
Replicate in host nucleus
Normally not incorporated into host genome
Examples: herpes, varicella-zoster, adenovirus
RNA viruses
Replicate usually in cytoplasm
Reproduction depend on sense / antisense RNA
Examples: rotavirus, enterovirus, rhinovirus,
rubella virus, rabies virus
how is Baltimore classification
how the virus makes mRNA- they are grouped according to that
what are antiviral drugs and their targets?
Antiviral drugs target different stages in viral life cycles and replication:
Attachment/Entry/Fusion inhibitors: Prevent binding or entry/fusion of virus with host cell, e.g. targeting viral receptors
Uncoating inhibitors: Prevent uncoating of capsid
Nucleic acid synthesis inhibitors: Common examples are nucleoside/tide analogs that block new RNA or DNA synthesis. Others inhibit enzymes required (polymerases or reverse transcriptase). Large number of this category are reverse transcription inhibitors (e.g. for HIV – see Lecture 6 HIV)
Integrase inhibitors: Specifically for retroviruses that rely on host genome integration (e.g. HIV)
Protease inhibitors: Inhibit proteases commonly used for generating viral proteins for assembly of new virions
Release inhibitors: Prevent release of virus from host cell, such as antivirals used for influenza
Other non-direct methods include immune modulation
what are examples of antiviral drugs?
Entry inhibitors:
Nucleic acid synthesis inhibitors
Nucleoside/-tide reverse transcriptase inhibitors (NRTIs/NtRTIs))
Integrase inhibitors:
Protease inhibitors/Inhibitors viral assembly:
Exit/Release inhibitors:
Entry inhibitors:
Enfuvirtide or Maraviroc – inhibits HIV binding/fusion with cells
Nucleic acid synthesis inhibitors
Nucleotide/side analogues
Aciclovir - herpes viruses and VZV (nucleoside analog, inhibits HSV DNA polymerases); Ganciclovir – CMV disease
Ribavirin –life-threatening RSV and PIV infections
Sofosbuvir (HCV, NS5B Polymerase inhibitor)
Remdesivir (SARS-CoV-2, nucleotide prodrug)
Nucleoside/-tide reverse transcriptase inhibitors (NRTIs/NtRTIs))
Zidovudine (AZT) – HIV (nucleoside analog)
Tenofovir alafenamide – HIV
Non-nucleoside reverse transcriptase inhibitors (NNRTIs)
Efavirenz (HIV)
Integrase inhibitors:
e.g. Bictegravir (HIV)
Protease inhibitors/Inhibitors viral assembly:
e.g. Atazanavir (HIV)
Voxilapravir (HCV)
Exit/Release inhibitors:
Zanamivir (Relenza) and Oseltamivir (Tamiflu) – block neuraminidase on flu viruses
Others:
Amantadine/rimantadine antagonist M2 channel of virus, prevent viral shedding and replication (once used influenza)
Via immune system – IFN-a, vaccines
what group is present if it is an RNA
OH
what group will be present if it is DNA
H
what makes a structure nucleoside
without phosphate
what makes a structure nucelotide?
with phosphate
mono/di/triphosphate
explain nucleic acid synthesis?
To add new nucleotide need a free hydroxyl on 3’ end of growing strand and 5’ triphosphate group on incoming nucleotide
Polymerase adds incoming nucleotide, releasing pyrophosphate
In viral infection can be viral polymerase or reverse transcriptase
Nucleoside/tide Analogs as Anti-viral Drugs: MoA
ACV: In the cell, gains first phosphate via the viral HSV-1 TK (kinase). Then further 2 phosphates via host kinases to become triphosphate. Lacks 3’ OH for further chain growth – INHIBITION viral DNA polymerase
guanosine and aciclovir - acv
how is respiratory viral infections transmitted?
Transmission via droplets or contact with nasal secretions / saliva
how is respiratory viral infections transmitted?
Transmission via droplets or contact with nasal secretions / saliva
smaller droplet = more contagious
what are the immune defences + non-specific for respiratory viral infections?
Body has non-specific and immune defences:
Respiratory endothelial cells (ECs) covered thick glycocalyx & tracheobronchial mucus (traps viral particles)
Cilliated respiratory ECs move particles from lower to upper respiratory tract, then swallowed
Lung immune response
what are the main respiratory viruses? (4)
Influenza viruses - Elderly most at risk
Rhinoviruses / Coronaviruses*
Both cause common cold
Adults ~ 2-5 colds/yr, Children ~ 4-8 colds/yr
Respiratory syncytial viruses (RSVs)
Major cause of respiratory illness in children
~90% of children by age 2
Serious in elderly, leads to pneumonia / death
Parainfluenza viruses (PIVs)
Cause colds, croup, bronchitis and pneumonia
Can be life threatening in infants
what is the causes of common colds?
Cause: Most by rhinoviruses as well as some coronaviruses (15%), picornaviruses, influenza viruses, PIV, RSV and others.
Coronaviruses HCoV-OC43, -HKU1, -229E and –NL63 can cause mild, cold symptoms. MERS-CoV, SARS-CoV and SARS-CoV-2 can be severe (see next slide)
what is the symptoms of common cold?
Symptoms: fever (children), sore throat, runny nose, sneezing, nasal congestion. Can also have muscle ache, fatigue headache, malaise.
Symptoms due to viruses largely affecting URT (mainly nose and can be throat, larynx, sinuses).
what is the transmission route for common cold?
Transmission: Usually airborne droplets + contact with secretions and fomites.
what is the mechanism of common cold?
Mechanism: Depends on virus. e.g. rhinovirus – binds receptors on ciliated surface of nasal epithelial cells (e.g. ICAM1) followed by receptor-mediated endocytosis. Leads to pro-inflammatory response
how can you prevent common cold?
Prevention: Good hygiene, hand-washing, tissues (sneezing)
no vaccines
what is the treatment for common cold?
Treatment: symptomatic: analgesia & antipyretics. Possible other OTC options
what is SARS-CoV-2
(what is viral spike unit)
Severe Acute Respiratory Syndrome Coronavirus 2, SARS-CoV-2
New coronavirus, related to SARS-CoV, first identified in Wuhan, China, Dec 2019
An enveloped, + sense, ssRNA virus (group IV)
Enters cells via Angiotensin Converting Enzyme 2 (ACE2 receptor) on host cells
ACE2 highly expressed in epithelium of lung + intestine, and lesser extent in other tissues e.g., liver & kidney
Spike protein on surface of the virus important for cell infection
Viral Spike (S) protein has 2 domains: S1 receptor binding domain (RBD), S2 mediates fusion of virus with host membrane
what is the mechanism of SARS-CoV-2
Virus enters host cell by 2 main mechanisms: early/cell surface or late/endocytosis
S protein (S1, RBD) binds to ACE2
Proteolytic cleavage between S1 and S2 by TMPRSS2 (when present) activates the S protein releasing S1 and allowing fusion via S2 and cell surface entry
In absence of TMPRSS2, following binding to ACE2, virus enters via endocytosis
Cleavage in S protein by Furin before exit can prime virus for entry to infect new cells
Several stages of these pathways are possible therapeutic targets
what is the symptoms of covid 19
what is long covid?
Symptoms of COVID-19: fever, persistent cough, loss of taste/smell*, fatigue, muscle ache, shortness of breath and others including GI symptoms –
* original ‘key’ symptoms. Later variants: headache, sore throat, blocked/runny nose, nausea/vomiting, loss appetite…
Symptoms can be mild to severe and many with the virus can be asymptomatic
Long COVID: wide range symptoms, e.g., fatigue, SOB, insomnia, muscle ache…
what is the transmission route of covid
Transmission: Droplets. Prodromal illness typically 2-10d. 1 of 7 coronaviruses that affect humans. Aerosols? Fomites?
what is the prevention of covid?
Prevention: Good hygiene, hand-washing, PPE (including face masks), physical distancing measures, vaccination* [self-isolation, quarantine]
what is the diagnosis of covid 19
Nasopharyngeal swab and RT-PCR testing for the viral RNA (by PCR/NAAT) or for antigens using lateral flow tests/rapid antigen tests
- Serological tests of blood to detect antibodies raised against the virus (see Dr Edwards lectures) – can show if someone has had the virus
what is the treatment and management of covid 19
no one specific treatment
often based on symptom management
- vaccinations
Corticosteroids (anti-inflammatories):
Dexamethasone (or hydrocortisone or prednisolone) – see Dr Edwards immune system teaching
Monoclonal antibodies (as anti-inflammatory therapy):
Tocilizumab, sarilumab - recombinant, humanised anti-IL-6R mAbs, block IL-6 signalling to reduce inflammation)
Monoclonal antibodies (neutralising antibodies – target SARS-CoV-2 binding):
Sotrovimab, Casirivimab and imdevimab – see Dr Edwards immune teaching
Anti-virals: Remdesivir, nirmatrelvir and ritonavir (Paxlovid), and molnupiravir
Other therapies:
Baricitinib - inhibitor JAK (JAK1/2, immunomodulatory, May 2022, off-label)
Low MWt heparin (VTE, venous thromboembolism)
Also O2 [low-flow O2, high-flow O2, CPAP or mechanical ventilation]
Some simple symptom management in community e.g., paracetamol/ibuprofen for fever/symptoms that would benefit, honey or linctus for cough.
who are the risk group for covid 19
At risk groups examples
High risk: transplant & cancer patients, severe lung conditions, some at higher risk of infection (immunosuppressed), serious heart condition & pregnant.
Other vulnerable groups: Elderly, lung condition, heart disease, diabetes, liver or chronic kidney disease, CNS disorders, obesity, pregnancy, at higher risk of infection due to condition or medication
Plus other risk factors…
what are the vaccinations which are available for covid 19 and who are able to get vaccinated
A number of vaccines now available, vary between country and age/risk groups
Include:
Adenovirus-based (e.g. Oxford/Astra-Zeneca, Janssen/Johnson&Johnson),
RNA-based (Pfizer/BioNTech^, Moderna^),
Inactivated virus (e.g. Sinovac, Sinopharm, Valneva),
Protein sub-unit (e.g. Novavax*)
DNA-based (ZyCoV-D)
Who gets vaccinated?: Currently
5yr+ get 1st and 2nd dose
16yrs+, and some 12-15 yrs can get 3rd dose
5yrs+ with severely weakened immune system, get 3rd dose before any booster dose (4th)
Some people, including 50yrs+, those at higher risk, pregnant, frontline health and social care workers, Carers (16-49) and household contacts of immunocompromised, will get Autumn booster (2022)
what are examples of monoclonal antibodies and their moa
Monoclonal Antibodies: Tocilizumab, sarilumab, sotrovimab
Tocilizumab: against IL6-R (blocks pro-inflammatory response)
Sarilumab: against IL6-R (blocks pro-inflammatory response)
Sotrovimab: neutralising antibody* against SARS-CoV-2 (binds spike RBD)
Casirivimab and imdevimab: neutralising antibodies* against SARS-CoV-2 (binds spike RBD)
what are examples of antivirals and their moa
Antivirals: Remdesivir, nirmatrelvir and ritonavir (Paxlovid), and molnupiravir
Nirmatrelvir* + ritonavir (Paxlovid): A 3C-like protease inhibitor (b/ritonavir)
Remdesivir: prodrug (protide), adenosine nucleoside analogue, delayed chain termination
Molnupiravir: prodrug of synthetic nucleoside (similar to cytidine). Induces mutations in RNA replication
Remdesivir anti-viral drug – IV only
IV 100mg daily 5-10 days (200mg loading dose)
This is an adenosine nucleotide prodrug
Refer to slides on nucleoside/tide analogs
Gets converted to remdesivir triphosphate (active) and
Inhibits RNA-dependent RNA polymerase (RdRp) – causes delayed chain termination
Molnupiravir anti-viral drug – oral (capsule)
This is a prodrug resembles cytidine
When metabolised to a triphosphate (active) form (NHC-TP)
gets incorporated into new RNA and causes mutations
that leads to lethality
how many times of influenza virus is there
Types: 3 - A, B and C (and many subtypes)
A found in humans and animals, B/C only humans
2 different types surface protein: haemaglutinin (H) and neuraminidase (N)
H and N undergo slight changes over time so also classified into subtype e.g. H1N1 etc.
H/N changes make Influenza A a threat - acquired immunity less effective against different sub-type
Influenza C uncommon, B less severe infections A, B/C less prone changes
Pandemics since 1900:
how long can symptoms of influenza last?
Can be shed before symptom onset and for up to 7 days after onset
Infectious before symptoms develop and for a week afterwards
how long can influenza a and b last on surface
Influenza A & B survive on surfaces for up to 48h
Shown to transfer onto hands 24 hours after inoculated
Common issue most viruses
what is the treatment options for influenza
Self-limiting in healthy patients, complications:
Secondary chest infection → pneumonia (elderly)
Bronchitis, ear infections, sinus infections
Worsen underlying condition
Antibiotics may be prescribedto treat secondary bacterial infections
GPs may prescribe antivirals (Zanamivir or Oseltamivir) at risk patients (NICE guidelines). Otherwise treatment is for symptoms (e.g. analgesia/antipyretics)
vaccinations (prevention)
who are the risk group which gets influenza jab
Vaccination “Flu jab” for at risk groups:
aged 65+
ages 50-64 yrs (cont’d - was introduced subject to availability in 2020-21)
those in long-stay residential care homes
children aged two to fifteen (31st Aug 2021), (2-11 in 2019, 2-10 2018)
those 6 months – <65yrs in clinically vulnerable groups such as:
chronic heart /chest complaint, incl. asthma
chronic kidney or liver disease
diabetes
immunocompromised
pregnant women
close contact of immunocompromised (2020-21 also those living with COVID shielder)
all frontline health and social care workers
Carers (since 2020-21)
what were the influenza vaccine which were used in each of the age groups
In UK 2021-22 season, vaccines in use were:
6mo-2yr: QIVe
2yr-17yr: LAIV (QIVc if contraindicated);
18-64yr: QIVc or QIVr (QIVe alternative);
65+yr: aQIV or QIVc/QIVr if aQIV unavailable (change from 2020-21, aTIV)
how is gastrointestinal infections transmitted?
Transmission usually faecal-oral
>1012 rotavirus particles/g stool
Children and adults often asymptomatic
Rotavirus still excreted up >50 days after diarrhoea stopped
bodys preventions to GI infections and preventions
Stomach acidity inactivates some viruses (e.g. rhinovirus)
Bile salts, proteolytic enzymes, secretory IgA all protect against GI viruses
Destroy virus lipid envelopes
GI viruses tend to be non-enveloped
In general, prevention by good hygiene
what is Rotaviruses
Most common cause of viral gastroenteritis, especially in children
7 species: A-G, dsDNA
‘A’ most common, ~90% childhood infections
Have triple protein coat – resistant to acid pH
Produce enterotoxin causes diarrhoea, vomiting and slight fever
> 100 million cases/yr; >200,000 deaths/year; most in developing countries, <5yrs old
what is the transmission route of rotavirus?
Transmission
Fecal-oral (and contaminated surfaces)
2 day incubation
what is the symptoms of rotavirus?
Symptoms
Watery diarrhoea, vomiting
Fever, abdominal pain
what is the treatment of rotavirus
Treatment
Self-limiting (2-8 d)
Manage symptoms: re-hydration
what are the vaccines available for rotavirus?
Vaccines
For babies – Rotarix (2 mo, 3 mo)
Refer to Immunisation schedule (L1)
what is the transmission route for norovirus?
Transmission: Faecal-oral, person-to-person and contamination, highly contagious (within 12-48 hrs contact get symptoms)
Diarrhoea
Projectile vomiting major transmission (airborne)
3 x 107 particles in an aerosol during vomiting attack
May cause up to 50% of gastroenteritis worldwide
Attaches to host receptors on intestinal epithelial cells and endocytosis
what are the symptoms of norovirus?
Symptoms: Diarrhoea, nausea, vomiting, stomach pain
what is the treatment for norovirus?
Treatment
Self-limiting (1-3 days)
Hygiene
Re-hydration
Susceptible populations as before
what are the symptoms for hepatic- hepatitis A?
Symptoms: often mistaken flu: fever, nausea, diarrhoea, fatigue,
loss appetite
what is the diagnosis of hepatitis A
Diagnosis: Increased levels serum transaminase (ALT)
Affects liver: Usually acute, seldom chronic – virus replicates in heptocytes and GI epithelial cells, released into blood and bile
Usually no permanent liver damage – any damage usually from cell-mediated immune response
Occasionally complications
Most serious if already infected HepB/C
what is the treatment for hepatitis A?
Treatment: Rest, avoid fatty food & alcohol
Immune response confers protection
against further infection (IgM ~6months,
IgG life)
what is the vaccine for hepatitis A?
Vaccine
e.g. Avaxim, protection for >10 years (not part routine schedule UK, risk low)
what is varicella-zoster virus?
Herpes virus VZV, also called herpes zoster, human herpes 3
Primary infection causes Chicken pox (varicella) - usually self limiting
what is the transmission route of varicella-zoster virus
Airborne particle inhalation or direct contact lesions. Initially multiplies URT epithelium (inhalation), then into T-cells/blood and then to skin
what is the symptoms of varicella-zoster virus
Typical rash (begin as red spots, these blister then scab)
More general symptoms can include e.g., fever, fatigue
what is the complications of varicella-zoster virus
Encephalitis, pneumonia, infection in lesions
what is the treatment of varicella-zoster virus
Calamine lotion, paracetamol (oral aciclovir if severe, <24hrs rash)
what is shingles?
Shingles (zoster): Rash and pain for 3-5 weeks
Rash usually on one side of torso (but can be elsewhere), blisters
Can lead to long-lasting problems - Neuralgia
what is the treatment of shingles?
Treatment: antivirals - Aciclovir, famciclovir, valaciclovir, pain management
what is the vaccine for shingles?
Vaccines: Zostavax (zoster, UK schedule, Shingrix if contraindicated
what are the symptoms of measles?
Symptoms: High fever, cough, coryza and conjunctivitis. Later red rash over the body
what are the symptoms of mumps?
Symptoms: Low grade fever, muscle pain, headache, malaise. Later one or both parotid salivary glands swell.
Can cause male sterility and deafness
what are the symptoms of rubella
Symptoms: Rash (starts on face), not as read as measles. Also possibly fever, joint pain, sore throat, fatigue, swollen lymph nodes.
Can cause congenital defects if caught during pregnancy
how are mmr spread?
All highlight contagious, spread by aerosols/droplets, no specific treatments
how is mmr prevented
MMR vaccination available (~12 mo then 2nd dose later)
There is a version with VZV (MMRV) but not routine in UK
what is the cause of warts
Cause: Small growths caused by human papillomavirus (HPV, L10)
how is warts transmitted?
Contagious: skin contact, towels / other objects
Can spontaneously resolve after few months but can last for years
what are the diff type of warts and where do they affect
Common (Verruca vulgaris)- raised with rough surface, common on hands
Filiform (see image)- thread-like, most common on the face, near the eyelids and lips
Flat wart (Verruca plana)- small, smooth, flattened, flesh coloured, common face/neck/hands
Plantar wart (Verruca pedis)- hard, can be painful, often multiple black dots, often on pressure points
Periungual warts- around nails
what is the treatment of warts?
Treatment: Keratolysis (OTC)
Typically topical salicylic acid, also topical preparations of silver nitrate or glutaraldehyde/formaldehyde
Cryosurgery - Liquid nitrogen to wart, falls off
If serious, surgery (remove surrounding tissue) or laser
