35.4 Virus Replication Flashcards
What are viruses?
Obligate IC parasites with a unique mode of replication
What is the ‘eclipse phase’?
The disappearance of the EC, infectious virus while the IC replication occurs.
For HIV-1, state the:
- Virus attachment proteins
- Cellular receptors
- Virus attachment proteins -> GP120
- Cellular receptors -> CD4 (and co-receptors CXCR4, CCR5)
For SARS-CoV-2, state the:
- Cellular receptors it binds to
ACE2
What are some co-receptors on host cells that HIV-1 binds to?
Chemokine receptors CXCR4 and CCR5.
Explain the relationship between the distribution of cellular receptors for a virus and its tissue-tropism.
The cellular receptors on host cells determine which cells the virus can bind to using its attachment proteins.
By what process are viruses taken into host cells?
Endocytosis, which is usually dependent on receptor binding.
How does HIV penetrate its host cells?
pH-independent envelope fusion
Describe the virus attachment protein and host cell surface receptor involved in binding and entry of influenza.
- Virus attachment protein -> Haemagglutinin (HA)
- Host cell surface receptor -> Sialic acid (on glycoproteins and glycolipids)
Influenza is taken up into host cells and is then is an endosome. How is its genome released from the endosome?
- There is gradual acidification of the endosome due to entry of H+
- Two things must now happen
First, the viral envelope and endosome membrane must fuse:
- Acidification causes major structural rearrangement of the haemagglutinin
- This exposes the fusion peptide, a part of the haemagglutinin that enables fusion between the virus envelope and the endosomal membrane
- This allows a pathway to be created, ready for the release of the vRNP complex
Secondly, the vRNP complex must be released:
- H+ ions from the endosome enter the virion via the M2 ion channels (Note: Influenza B has an BM2 membrane channel protein instead)
- This acidification of the virion leads to release of the vRNP complex from the virion
Summarise how HIV-1 enters cells.
- HIV-1 has glycoproteins in the envelope that enable binding and entry: gp120 and gp41
- gp120 binds to CD4 on T cells and macrophages
- This triggers a conformational change in gp120 that enables it to bind to CCR5 (on T cells and macrophages) or CXCR4 (on naive T cells)
- This in turn leads to even more conformational changes that allow the gp41 to extend out in an alpha helical arrangement -> They ‘harpoons’ the plasma membrane, causing pore formation
- The capsid can enter the cell due to membrane fusion
Is entry of HIV-1 into cells dependent on acidity?
No, it is dependent on binding of receptors on the virus to host cell receptors.
Describe the tropism of HIV-1 and why this is the case.
- CCR5 (R5) viruses are the transmitted type of HIV-1
- They can enter activated/memory CD4+ T cells and also macrophages/dendritic cells since they present CD4 and CCR5
- However, CXCR4 (X4) viruses evolve in ~50% of infected people, where they gain the ability to enter naive CD4+ T cells also, since they present CD4 and CXCR4
- This typically happens in individuals who progress to AIDS
What does subversion of cell metabolism allow viruses to do?
To manufacture virus components. E.g. poliovirus effects on protein synthesis.
What is poliovirus’ effect on protein synthesis?
Similar to Baltimore class IV viruses
*engages with host cell CD155 receptors on epithelial cells and motor neurons to enter an endosome
* RNA-dependent RNA polymerases (3Dpol) are used within vesicles to amplify the levels of +ssRNA
*transported to the ribosomes for translation to the single polypeptide sequence.
- relies on an important internal ribosome entry site (IRES) at the 5’ end of the mRNA-equivalent, allowing it to mimic the circular, modified mRNA that eukaryotes use for translation and thus recruit the molecular machinery.
What do RNA viruses require for nucleic acid replication?
viral RNA polymerase. These polymerases can be found in the virion of negative-strand viruses.
What do retroviruses need for replication?
Reverse transcriptase and integrase. Theses are important drug targets (see HIV anti-viral therapy).
How is release of a virus different depending on the type?
*Budding of the enveloped viruses (HIV/EBV)
*Cell lysis to release the naked viruses (Polio)
What is involved in nucleic acid replication that can be drug targets?
Viral polymerases and other viral enzymes
What causes the high variation in HIV?
Reverse transcriptase-mediated HIV genome mutation
What contributes to immune escape?
Promotion of amino acid variation by genetic diversity (makes it difficult for specific immune response)
How is replication associated to antigenic shift and drift in influenza?
mutation and genetic reassortment and recombination
What is the role of viral proteases in maturation?
Maturation is the conformational and stabilising changes driven by proteolytic cleavages (proteases hydrolyse specific sites in polypeptide chain) required to reach full infectivity.
*Capsids initially assembled in the cell are in an immature, non-infective state.
*In poliovirus, HIV
*it is a drug target.
