Medical Microbiology: Viral Pathogens: Classification, Biology, Diseases - II

Question 1

Why might a virus infect a host cell?

Answer 1

• Host cell contains factors required for the virus to replicate
• Infection of host cell allows for the viral transmission and pathogenesis

Question 2

Describe the typical course of HIV-1 infection

Answer 2

• As the course of HIV goes on you get FEWER CD4+ T-cells and you get MORE viral RNA - this means that the virus is replicating
• Infectious process of HIV is quite quick - 6 weeks after initial infection there’s a massive peak of HIV RNA copies accompanied by a large decrease in CD4+ T-cells
• After initial large drop in CD4+ T-cells over the next 10 years you see a more gradual decrease in the no. of CD4+ T-cells
• 10 years after infection there’s undetectable levels of CD4+ T-cells and large numbers of HIV RNA copies
  
  • At this “end point” is where you begin to see onset of HIV symptoms e.g. fatigue and organ failure
  • This leads to increase in opportunistic infection which leads to death

Question 3

Why doesn’t HIV-1 deplete all CD4+ T-cells during the first phase of infection?

Answer 3

• Because if HIV-1 depleted all CD4+ T-cells rather quickly it would decrease its ability to transmit itself as it wouldn’t have a host cell to use in order to replicate itself

Question 4

What is the advantage of HIV-1 replicating within CD4+ T-cells?

Answer 4

• Viruses must evade immune responses.
• Some immune responses are mediated by specific cells of the immune system, e.g. CD4+ T-cells
• These immune cells recognize and kill cells infected by virus so by replicating within, and decreasing the no. of T-cells, HIV-1 is decreasing the chance of it being killed by the immune system

Question 5

How do HIV-1 cells evade immune responses?

Answer 5

• HIV-1 replicates in the immune cells whose function is to recognize and kill infected cells (CD4+ T-cells)
• Replication in immune cells hides the virus from immune cells and inhibits immune cell function
• Inhibition of immune cell function allows other pathogens to replicate in virus infected hosts and, thus, disease occurs

Question 6

What are Non-permissive and permissive T-cells?

Answer 6

• Non-permissive T-cells (5% of cells): T-cells in which HIV-1 can’t fully replicate
• Permissive T-cells (95% of cells): T-cells in which HIV-1 can replicate

Question 7

What effect does HIV-1 have on permissive T-cells?

Answer 7

1. HIV-1 fuses with T-cell membrane and allows it to enter T-cell
2. HIV-1 uses reverse transcription to produce dsDNA from its dsRNA genome
3. dsDNA from HIV-1 enters nucleus but because nucleus has protection mechanisms in place dsDNA is recognised as foreign
4. This results in activation of T-cell enzyme Caspase-3
5. Caspase-3 is a mediator of apoptosis and so its activation results in cell death of the T-cell

• NOTE: HIV-1 is mostly able to shut down this immune response in permissive T-cell
• This is due to presence of viral proteins such as: Vpr, Vif and Nef

Question 8

What effect does HIV-1 have on Non-permissive T-cells?

Answer 8

1. HIV-1 fuses with T-cell membrane and allows it to enter T-cell
2. Incomplete reverse transcription occurs so only some dsDNA produced from RNA genome
3. Incomplete reverse transcripts are detected by the IFI16 DNA sensor
4. This results in activation of the innate antiviral response and the inflammatory response
5. This leads to assembly of the IFI16 inflammasome which activates Caspase-1
6. Caspase-1 causes pyroptosis causing cell death and excretion of immune factors which acts as a warning to cells around it that infection is occuring

Question 9

Explain why there’s such a large loss of CD4+ T-cells during HIV-1 infection

Answer 9

• Release of pro-inflammatory cytokines and cellular contents from non-permissible T-cells due to pyroptosis causes inflammation
• This results in the recruitment of healthy CD4+ T-cells to area of inflammation which allows for HIV-1 particles to infect more CD4+ T-cells (psoitive feedback loop)
• Inflammation also results in the migration of neutrophils and monocytes to the area of inflammation (supercharging of the immune system)
• Neutrophils and monocytes act on CD4+ T-cells which results in release of more pro-inflammatory cytokines leading to even more inflammation
• As already mentioned more inflammation allows for HIV-1 to infect more healthy CD4+ T-cells as they migrate to area of inflammation

Question 10

What are some of the HIV ssociated pathogens?

Answer 10

• Viruses
  
  • Herpes simplex virus (HSV)
  • Kaposi’s sarcoma herpesvirus (KSHV)
• Bacteria
  
  • Mycobacterium tuberculosis
  • Salmonella
• Fungi
  
  • Candida
  • Cryptococcus neoformans
• ​Parasites
  
  • Cryptosporidium
  • Toxoplasma gondii

Question 11

A large number of unchecked HIV infections allow other viruses to colonise and replicate. What are the 2 possible routes of infection for these other virsuses?

Answer 11

• Primary infection - Never been exposed to pathogen before so exposure allows virus to replicate
  
  • Can be resolved (typically by immune suppression)
  • However, Infection then moves to sites in the host that the immune system does not access
  • In these sites virus doesn’t replicate: latency
• Reactivation from latency - Occurs due to immunodeficiency as immune system unable to suppress virus

Question 12

Explain how the Herpes simplex virus (HSV) is reactivated from latency due to HIV-1 infection

Answer 12

• HSV infection occurs via infection of epithelial cells (via skin)
• HSV moves into nervous system
• Nervous system doesn’t have good immune system surveillance because most immune cells can’t pass through blood-brain barrier
• HSV then gets into neurons and can move along neurins to access PNS and eventually CNS
• HSV then sits within PNS/CNS and doesn’t replicate (latency)
• Normally because of constant immune system surveillance signals are sent to latent HSV patricles so they know immune system is working
• However, due to immunodeficiency there’s a lack of these signals so latent HSV begins to reactive
• This leads to HSV travelling back to site of infection and replicates

Question 13

Explain how reactivation from latency of KSHV leads to KSHV infection

Answer 13

1. KSHV enters and produces KS progenitor cells
2. This leads to de novo infection (primary infection)
3. De novo infection leads to latent infection of cells in the immune system (B cells)
4. KSHV doesn’t replicate or replicates very slowly within B cells
5. Normally there’s constant B and T cell interaction but due to HIV depletion of T -cells this interaction doesn’t happen
6. This results in KSHV reactiving with B cells
7. Reactivation results in lytic and cytopathic effects

Question 14

Explain how reactivation from latency of KSHV leads to Kaposi’s sarcoma

Answer 14

1. KSHV enters and produces KS progenitor cells
2. This leads to de novo infection (primary infection)
3. De novo infection leads to latent infection of cells in the immune system (Non-permissive B cells)
4. KSHV remains latent within B cells until specific cue occurs (inflammatory signal from cytokines causes reactivation)
5. Once reactivated for some reason some of the cells become oncogenic which leads to uncontrolled cell division of B cells
6. These Oncogenic B cells also produce an inflammatory response resulting in KS lesions (Cancer)

Question 15

What treatments are there for Kaposi’s sarcoma?

Answer 15

• Antiretroviral therapy (ART) - Stops HIV replication which stops inflammatory response that leads to reactivation of latent KSHV-infected B cells
• Gancyclovir ART - Prevents repliaction of KSHV within B cells

Question 16

What viruses are able to cause cancer and what cancers do they cause?

Answer 16

• Human papilloma viruses (HPVs) - skin cancer
• Epstein-Barr virus (EBV) - lymphoma
• Hepatitis B virus (HBV) - carcinoma
• Hepatitis C virus (HCV) - carcinoma
• Human herpes virus 8 (HHV-8) - lymphoma
• Human T-lymphotrophic virus-1 (HTLV-1) - leukemia/ lymphoma
• Merkel cell polyomavirus (MCV) - carcinoma