Viruses Flashcards
What are the differences between plasmacytoid and myeloid dendritic cells, and how do they confer antiviral resistance?
plasmacytoid dendritic cells (pDC)
- Specialized in producing large amounts of type I interferons (IFN-α and IFN-β) in response to viral infections through Toll-like receptor (TLR) signaling.
- limited antigen presentation
myeloid dendritic cells (mDC)
- Efficient in antigen uptake, processing, and presentation to T cells, promoting adaptive immune responses.
- Produce proinflammatory cytokines and chemokines upon activation through various stimuli, including pathogens and inflammatory signals
How are viral antigens processed and presented?
Protein Degradation:
- Proteasomal Degradation: Proteins, including viral antigens, are degraded by the proteasome in the cytoplasm into smaller peptide fragments.
- Endosomal Degradation: Some viral proteins may also be processed by lysosomal proteases following endocytosis and fusion with lysosomes.
Peptide Loading onto MHC Molecules:
- MHC Class I Pathway: Cytosolic peptides generated by proteasomal degradation are transported into the endoplasmic reticulum (ER) by the transporter associated with antigen processing (TAP).
- Peptide Loading: In the ER, peptides bind to newly synthesized MHC class I molecules, which are then transported to the cell surface for presentation to CD8+ T cells (cytotoxic T lymphocytes, CTLs).
T Cell Recognition and Activation:
- CD8+ T Cell Activation: MHC class I-peptide complexes on infected cells are recognized by CD8+ T cells (CTLs), leading to T cell receptor (TCR) engagement, co-stimulation, and activation of CTLs.
What role do CD4 T cells play in antiviral immunity?
- provide help to CD8 T cells (induce proliferation)
- recruit proinflammatory macrophages
- eliminate infected cells
- provide help to B cells to produce antibodies
How do CD8 T cells tackle infection?
- killing cells through release of perforin and granzymes
- trigger death by Fas binding to FasL on infected cell
- produce soluble factor which cure the cell eg IFN-gamma, TNF-alpha
What role do antibodies play in antiviral immunity?
- opsonisation
- prevent binding to receptors
- prevent endocytosis
- prevent fusion
- activate complement
–> destroy virus and opsonisation
–> destroy virus-infected cells
What is the structure of a coronavirus?
- positive, single stranded RNA genome
- enveloped
- zoonotic viruses
- spherical
- cell entry via various receptors
What is the genome structure of SARS-CoV2?
- read in two large ORFs
- proteases cut large polyproteins into 16 smaller proteins
- 2 are proteases responsible for cleavages that make entry into cells much more efficient
What is unique about the polymerase in SARS-CoV2?
RNA viruses tend to be small as RNA is unstable, which is why they mutate so fast
but cov2 has polymerase w proof-reading activity
What are the receptors necessary for HIV entry?
CXCR4 on T cells
CCR5 on macrophages
these allow fusion of lipid envelope w cell membranes facilitating entry into the cell
antiCXCR4 and antiCCR5 can inhibit viral entry
Why are nucleoside/nucleotide analogues effective at inhibiting viruses?
take advantage of the fact that viral polymerases are not as discriminating as cellular polymerases
but are relatively toxic to humans, can cause mutations, and are potentially carcinogenic
How are non-nucleoside reverse transcriptase inhibitors useful?
rather than binding to the active site of HIV RT, they inactivate by binding elsewhere
However, mutations in RT can allow mutants to escape effects
Why is HIV maturation crucial?
- only mature HIV protease is infectious
- driven by virion protease
this protease is a major antiviral target
eg
- natural substrate for HIV-1 protease is 7 amino acids long
–> Saquinivar (Ro 31-8959) mimics this structure
–> fits into active site and doesnt leave, inactivating the enzyme
What is HAART?
Highly Active Anti-Retroviral Therapy
Uses more than one anti-HIV drug
reduces probability of virus acquiring drug resistant mutation
can dampen down replication of HIV to undetectable levels, so patient can live a normal life
v large drug burden however
What is PrEP?
Pre-Exposure Propylaxis
aimed at HIV-negative individuals who are at a substantial risk
contains two drugs - NRTIs
when taken daily, shown to reduce the risk of HIV infection up to 92%
How do anti-herpesvirus drugs work?
nucleoside analogues
- DNA chain terminating
- activated in infected cells by viral Thymidine Kinase
What are three important features on the influenza virion surface?
Hemagglutinin (HA) - binds to sialic acid on cell surface
Neuraminidase (NA) - cleaves sialic acid allowing release of virus from cell
Matrix protein 2 (M2) - forms pore, allows H+ ions to enter virion - essential for uncoating
What is an example of an influenza drug target?
decreased pH within endosome causes conformational changes in HA allowing it to fuse with the endosome
amantadine can block this fusion as well as bursting out of cell by blocking M2 protein ion channel
How is Hepatitis C treated?
a combination of IFN-alpha and Ribavirin, a nucleoside analogue
60-80% success rate
left untreated, can lead to cancer in the liver
How is EBOV treated?
monoclonal antibodies
eg ZMapp
- cocktail of three mAbs
- recognises conformational epitopes on GP2 or the stem region of the GP trimer
REGN-EB3
- 3 humanised mAbs from mice infected w ebola
- recognise proteins on outside of EBOV particle eg GP which allows virus to enter a cell
secreted GP can act as an antibody decoy
SARS-CoV2 assembles new particles via the endoplasmic reticulum-Golgi intermediate compartment (ERGIC). What are the advantages of this?
- Protection and Budding:
Enclosed Environment: The ERGIC provides an enclosed and protected environment conducive to viral assembly and budding, shielding viral components from degradation by host cell proteases and nucleases. - Incorporation of Viral Proteins:
Post-Translational Modifications: The Golgi apparatus facilitates post-translational modifications, such as glycosylation and palmitoylation, of viral proteins, which may be essential for their proper folding, stability, and functionality in viral assembly and entry.
Protein Sorting: The Golgi apparatus ensures the proper sorting and trafficking of viral proteins to the budding sites on the ERGIC membrane, promoting efficient virion assembly. - Protection from Immune Recognition:
Immune Evasion: Assembling viral particles in the ERGIC may help evade host immune surveillance by concealing viral antigens until the virions are released from the host cell.
Stealthy Exit: The budding and release of enveloped virions from the ERGIC allow the virus to exit the host cell without triggering immediate immune responses, facilitating viral spread and propagation within the host.
What is respiratory syncytial virus (RSV)?
cause of upper respiratory tract infection (URTI)
- common cold in healthy adults
- otitis media in children
cause of lower respiratory tract infection (LRTI)
- viral pneumonia in the elderly and in immune suppressed patients
- bronchiolitis in infants
–> is a big problem is an inability to feed as it requires breathing
How is RSV treated?
no active vaccination
mAbs - monthly palivizumab
- single dose of nirsevimab
does not alleviate bronchiolitis
What is the role of RSV G protein?
binds to CX3CR –> inhibits IFN-I, promotes T2-response
soluble form acts as an immuno decoy –> can bind to CX3CR1 on pDCs and to some lymphocytes, leading to altered chemotaxis and reduced function
–> can bind specific neutralising antobodies
What is the role of RSV F protein?
- binds to nucleolin which facilitates virus internalisation by forming a pore where the nucleocapsid can enter through
- binding to epidermal growth factor (EGF) –> micropinocytosis, promotes fusion
- pre-fusion form is unstable –> refolding
- post fusion form is v stable
- activates the Th2 response
- binds to TLR4 and causes desensitisation of TLR signalling receptors
