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SEM 4: Medical Microbiology > Viral Pathogens I > Flashcards

Viral Pathogens I Flashcards

1
Q

What is a virus?

A

An infective agent that typically consists of a nucleic acid molecule in a protein coat, is too small to be seen by a light microscopy, and is able to multiply only within the living cells of a host.

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2
Q

Structure of viruses

A
  • Single stranded RNA or DNA
  • Double stranded RNA or DNA with complementary base pairing
  • RNA genomes can be linear and segmented. For example, more than one RNA per capsid.
  • DNA genomes can be linear or circular.
  • All of these configurations of viruses cause different diseases in different ways.
  • Difficult to group viruses based on disease they cause but on how their genomes are put together.
  • Eventually all viruses will make RNA that will then be used to make proteins and more viruses.
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3
Q

Structure of HIV virus

A
  • 2 RNA strands encapsulated by a protein capsid.
  • Lipid bilayer and protein spikes (envelop glycoproteins) on the cell surface which helps entry into the cell
  • Multiple enzymes that are key for its function; integrase; reverse transcriptase and protease.
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4
Q

Organisation of the HIV genome

A
  • Similar to the retrovirus genome organisation
  • Many specific genes but also similar genes as ALV which is a retrovirus
  • ALV polyproteins: GAG, POL and Env
  • Extra HIV polyproteins: TAT, Rev, Vif, Nef, Vpu, Vpr.
  • HIV infects humans and therefore it has to combat the strongest immune system
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5
Q

Why does ALV have some different genes to HIV?

A

ALV infects birds which have a weaker immune system compared to humans. HIV infects humans so needs a stronger system.

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6
Q

Function of GAG

A

Group specific antigen

responsible for making the matrix, capsid and nucleocapsid of the virus

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7
Q

Function of Pol

A

Viral enzyme responsible for making protease, reverse transcriptase and integrase.

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8
Q

Function of Env

A

Envelope glycoprotein responsible for making the surface and the transmembrane.

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9
Q

Function of TAT

A

potent activator of viral transcription

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10
Q

Function of Rev

A

Mediates unspliced RNA nuclear export

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11
Q

Function of Vif

A

Critical regulator of virus infectivity

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12
Q

Function of Nef

A

Immune modulator, T cell activation and virus spread

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13
Q

Function of Vpu

A

Immune modulator and virus spread

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14
Q

Function of Vpr

A

Cell cycle and virus nuclear import

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15
Q

Genomic RNA and provirus of HIV

A
  • HIV is a retrovirus that needs RNA to be reverse transcribed into DNA.
  • The HIV RNA molecule at the top is not all linear in the virus, it is jumbled up and contains specific sites such as RRE.
  • DNA to RNA via transcription and RNA to DNA via reverse transcription.
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16
Q

Describe the (HIV) retrovirus entry into the cell

A
  1. The HIV virus attaches onto a cell by binding to its receptor. It does this through the HIV-1 Env containing glycoproteins sticking out of the surface. One of these is gp120 glycoprotein molecule and a smaller gp41 molecule. These are able to recognise and bind to cellular receptors on the cells.
    1a. The cellular receptor for HIV-1 is CD4; a glycoprotein found on the surface of immune cells such as T cells. If there is CD4 glycoprotein present, then the gp120 from the virus and CD4 will bind.
  2. There are many different types of T cells, and all have CD4 receptors. This is why T cells also have core receptors (CoR) which the virus is able to recognise.
  3. Once all of this is recognised by the virus, then a 6 helix bundle formation occurs. This is the meshing of the 2 membranes together, the viral membrane and the T cell membrane. Therefore, the virus is able to enter the cell.
  4. HIV is therefore tropic for CD4 expressing cells such as T cells and macrophages. The loss of which results in immunodeficiency and AIDS.
17
Q

Describe intracellular trafficking of (HIV) retrovirus

A
  1. The virus travels to the site of replication and replicate itself. Whilst travelling from the plasma membrane to the nuclear membrane, the virus undergoes some advantageous changes.
  2. It undergoes an uncoating step where it loses the capsids and remains the RNA genome covered by the enzymes and the nuclear capsid protein.
  3. It also undergoes reverse transcription via reverse transcriptase so the RNA molecule is converted to DNA.
  4. It travels down a microtubule complex, so it is not floating around the cell, it is travelling in a directed manner to the nucleus of the cell from the plasma membrane.
  5. There are different intracellular trafficking pathways and the virus needs to select which pathway. This is done via capsids which come in with the virus and choose the microtubule and pathway taken.
  6. So once the capsid guides the pathway taken, it will reach the nuclear pore complex (NPC) which will allow the virus to enter the cell.
  7. Once this happens, it will attach to the Nup protein which guides it even further into the nucleus.
18
Q

Reverse transcriptase

A
  • Moves from the plasma to nuclear membrane.
  • A heterodimer of P66 and P51 subunits enzyme that is bound to the RNA molecule in the capsid.
  • Catalytic properties are in P66 subunit and P51 served structural role and lacks RNAse H domain.
  • The enzyme displays 3 distinct enzymatic activities:
    • > RNA dependent DNA polymerase so only recognises RNA and not DNA.
    • > Has a RNAse H domain which cleaves RNA intermediates
    • > DNA dependent DNA polymerase
19
Q

Retroviral Integration

A
  1. The DNA copy of the viral genome which has entered via intracellular trafficking needs to be integrated into the human cell DNA.
  2. It is integrated via the virus DNA being pasted into the host cell chromatin.
    - > Have a target sequence in the host cell chromatin.
    • > TTAC on both sides at the end of the viral genome
  3. HIV-1 molecule contains an integrase enzyme which travelled with the virus molecule all the way to the nucleus.
  4. Integrase then recognises the target sequences on the viral genome and flips into the host cell chromatin.
  5. This means the virus DNA genome is now integrated within the host cell chromatin.
    - > Nothing from the host cell is deleted, the virus DNA is simply added in the middle. This is now called a provirus.
    - > Able to get viral RNA genome and via transcription, we then get the viral proteins being produced in the body.
20
Q

Funcrion of the viral integrase enzyme

A

It binds both the host and viral DNA.
It copies the same mechanism of the repair mechanism in a host cell when there is a mistake during the replication process of DNA.
1. Integrase wraps the viral DNA around the target host DNA.
2. It brings the target sequences, TTAC from the viral genome in physical contact with the target host genome.
3. Once they come into physical contact with each other, the integrases uses divalent cations to break open the DNA.
4. One strand at a time anneal the viral DNA to the cellular DNA.
5. Once finished, end up with one linear form of provirus.

21
Q

What is the LEDGF/P75: facilitating protein?

A
  • A protein that is picked up by the virus from the cell.
  • The protein binds to the integrase molecule and allows the virus enter the nucleus via the nuclear pore.
  • It also helps facilitate the virus to recognise the target sequences on the host cell chromatin.
22
Q

Gene expression of the retrovirus

A
  • When the virus is fully integrated into the host chromatin, it can be transcribed to make viral proteins in the host body.
  • The transcription is controlled by a number of transcription factors binding to the viral DNA.
  • The virus has evolved to be able to bind all of the transcription factor so that it increases its chance of getting replication of the genome.
23
Q

TAT - TAR interaction of the retrovirus

A
  • The virus needs to be in an area that is being transcribed.
  • It encodes the TAT protein which binds within the TAR element in the viral genome.
  • the binding of these 2 elements leads the RNA polymerase to preferentially go to the viral genome.
  • It then transcribes the viral genome.
24
Q

How are different mRNAs/viral proteins produced?

A
  • The whole provirus DNA will get transcribed.
  • Splicing of the RNA to create different sequences will mean different proteins e.g. singly spliced mRNAs produce different proteins to multiply spliced mRNAs.
25
Q

How are the viral RNAs exported from the nucleus?

A
  1. The virus will make a Rev protein.
  2. Rev will interact with a particular viral structure such as RRE.
  3. The REV RRE interaction will bring about other cellular proteins to preferentially get the RNAs out of the nucleus into the cytoplasm via the nuclear pore. This cellular protein that binds to the REV REE interaction is the Crm1 protein. This dictates which nuclear pore the RNAs will leave via and which way it will move in the cytoplasm.
  4. The cell needs to make sure the RNAs do not leave before they are ready so it does this via REV and RRE interaction. The cell has no way of exporting introns containing viral RNAs, because transcription normally doesn’t contain introns. Therefore, the REV-RRE interaction is what allows the intron containing viral RNAs out of the nucleus.
26
Q

How do the RNAs in the cytoplasm come together?

A
  • The viral RNAs are not linear structures, they have intrinsic structures within it.
  • The viral RNAs contain kissing loop complexes which are loops that can interact with each other.
27
Q

What does the long RNA molecule produce when it undergoes translation?

A

The polyproteins GAG and Pol

28
Q

How is the GAG polyprotein produced?

A

Normally, when the ribosome translates the RNA molecule - this includes the matrix (MA), capsid (CA), nuclear capsule (NC) and P6 components.

29
Q

How is the Pol polyprotein produced?

A

When the ribosome misreads the RNA, you get different proteins. This is called slippery sequence that the ribosome misreads. The different open reading frame will produce the Pol polyprotein. This includes the protease (PR), reverse transcriptase (RT) and integrase (IN) components.

30
Q

How do the polyproteins know how to get to the plasma membrane?

A
  • At the end of the polyproteins, there is the Myr structure.
  • This is created via Myristoylation of glycines in the MA domain of GAG.
  • This mediates association with the plasma membrane.
31
Q

How does budding of the plasma membrane occur?

A
  • The P6 end of the polyprotein is bound to PT(S)AP and YPLTSL which are amino acid residues that are present in any proteins that require to be pushed out of the cell via budding.
  • The binding of the host Tsg101 protein also mediates this process.
  • It also happens in other processes which require budding or breaking off e.g. in cytokinesis for the daugther cells to be produced. The ESCRT machinery mediates this and the virus is able to hijack this so that it can push its one virion out.
32
Q

Virulent identity

A
  • The polyproteins at the membrane get cleaved to produce individual proteins which make up the capsid.
  • As the virus is pushed out of the cell, the virus protease cleaves off the polyproteins to make individual proteins.
  • This is to allow each of the individual viral enzyme to bind the RNA.
33
Q

Immature virions

A
  • Very ordered rays of the polyproteins surrounded by the membrane which has been taken out as the virion buds out of the cell.
34
Q

Mature virions

A

The viral protease has digested the immature polyproteins to produce individual proteins.

SEM 4: Medical Microbiology (15 decks)

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