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How does viral attachment work?
Initial non-specific adhesion—low affinity and reversible, not strictly needed but helps increase likelihood of finding and binding receptor
Specific viral binding—low affinity but one particle binds multiple receptors leading to high avidity. Initiates entry
Where are viral receptor binding proteins usually located
Non-enveloped: part of capsid proteins, typically in canyons or protrusions
Enveloped: dedicated integral membrane glycoproteins for binding, protrude from envelope
What are the two main ways for viruses to be taken up into cells?
Macropinocytosis—non-specific uptake, cellular drinking
Receptor-mediated endocytosis
What is the most common route of entry?
Endocytosis but some can directly penetrate plasma membrane
May have preferred endocytic pathway, may use multiple
What are the three identified endocytic pathways?
Clathrin-dependent
Caveolin-dependent
Clathrin and caveolin independent
What happens to the virus in the endosome?
Endocytic vesicle rapidly fuses with an early endosome (pH 6.5-6.0)
Fuse with late endosome (pH 6.0-5.0)
Mature into lysosomes (pH 5.0-4.5) which is inhospitable due to pH and degradative enzymes—if virus doesn’t escape before this stage will be degraded
pH continuously dropping, but also constantly getting closer to nucleus—need to time exit just right
What is the most common signal for viruses to exit the endosome?
Low pH
What is penetration?
Breaching the endosomal membrane and releasing viral capsid or genome into host cytoplasm
How does penetration work for non-enveloped viruses?
Membrane lysis or pore formation
Pore formation leads to spool of genome escaping rather than whole capsid
How does penetration work in enveloped viruses?
Membrane fusion: viral and host membranes merge, allowing the interior of the viral particle to be released
Viral fusion protein is what facilitates fusion
What can viral fusion proteins be triggered by?
Fusion protein binding to a co-receptor
Low pH of endosomes
Host protease cleavage
Combination of the above
How does membrane fusion work?
Fusion proteins undergo conformational changes when triggered leading to extension and anchoring in endosomal membrane, and then folding back on self to pull membranes closer together
Membranes now merge in hemifusion intermediate
Eventually fully merge, leading to pore formation
Where do RNA viruses usually replicate? Where do DNA viruses usually replicate?
RNA: cytoplasm
DNA: nucleus
How can viruses reach their destination for replication?
Use actin filaments and myosin
Microtubule transport
Can either transport while in an endosome eg Influenza A using microtubules, or have the capsid interact directly eg Adenovirus and dynein
What is uncoating?
Process of releasing the viral genome from its capsid
What are some methods of uncoating?
Proton channels in Influenza allow protons from acidic late endosome to diffuse in, leading to capsid disassembly
Host ribosomes may bind and disassemble viral capsid proteins after entering cytoplasm, eg Semliki Forest virus
Pore in endosome where genome is spooled out
What structure in the nucleus facilitates transport of proteins and RNA in and out?
Nuclear pore complex
Most viruses too large to pass through
What are some ways viruses can enter the nucleus?
RNA embedded in viral protein containing a nuclear localization signal (Influenza)
Bind to nuclear pore complex and inject viral DNA through pore with intact capsid (HSV-1)
Disassemble capsid at nuclear pore complex to let viral DNA enter through pore (Adenovirus)
Parvovirus might bind to complex and disrupt membrane to enter as very small?
What is susceptibility?
If virus is susceptible to cell type, cell can support binding and entry
What is permissibility?
Cell contains appropriate machinery to support viral replication once virus has entered cell
