Viral Pathogens: Classification, Biology, Diseases II

Question 1

HIV is tropic for what?

Answer 1

CD4 positive T-cells

Question 2

what is viral load?

Answer 2

no. viral RNA genomes per ml blood

Question 3

explain what happens in a “typical” course of HIV-1 infection

Answer 3

as the course of HIV goes on, you get fewer CD4 positive T-Cells, and more viral RNA

HIV process is quite quick – immediate viral replication, there is a peak and a clear decrease in CD4 T-cells

HIV doesn’t kill you immeadiately, but over the course of years you get fewer and fewer and fewer CD4 T-cells – so by 10 years you basically have undetectable levels of T-cells and huge numbers of RNA copies of the genome

at the end point, you have the clear onset of HIV symptoms – typically fatigue, organ failure, increase in opportunistic infections, and then death

virus replication is chronic, more and more opportunity to be transmitted between people.

depletion of CD4 T cells during infection ultimately leads to immunodeficiency (AIDS) and mortality (via opportunistic infections)

Question 4

Depleting the number of CD4 T cells is a bad thing for the host but a good thing for the virus – why is it good?

Answer 4

viruses must evade immune responses, and some immune responses are mediated by specific cells of the immune system, eg. CD4 cells

HIV is taking out the cells that would normally recognise and kill it.

depleting CD4 T cells means inhibition of immune cell function - allows HIV replication to progress and it also means other pathogens can infect too.

Question 5

why is replication in immune cells good for the virus?

Answer 5

it hides the virus from immune cells and inhibits immune cell function

Question 6

2 types of CD4 T cells?

Answer 6

permissive (95%) and non permissive (5%)

Question 7

explain how HIV affects permissive and non permissive CD4 T cells

Answer 7

PERMISSIVE
-evasion of a double stranded DNA response
-foreign DNA enters cell, and is recognised by the nucleus as being foreign
-activation of caspase 3 and apoptosis
-quite good cell death of permissive T-cells
So, loss of T-cells can occur via this natural cell death, apoptotic cell response.

NON PERMISSIVE
-virus enters but cannot fully replicate
-cell senses foreign nucleic acid – detected by IFI16 DNA sensor which activates the immune response through mechanisms
-activation and production of innate anti-viral responses, immune-inflammatory responses and inflammasome responses
Not apoptosis BUT pyroptosis – during this, you not only get cell death, but excretion of all the immune factors into the extra cellular environment during cell death – acts as a warning for nearby cells that there is an infection.

Question 8

the inflammation caused due to HIV is good for the virus - why?

Answer 8

IFI16 is involved, and release of of pro-inflammatory cytokines and cellular contents

inflammation brings more healthy CD4 T cells which the virus can affect - positive feedback mechanism that allows the virus to infect new cells again and again

inflammatory state hypercharges the immune system, so much so that you get migration of neutrophils and monocytes into the infected area, causing more inflammation

exhaustion of the immune system and number of functional T cells over time. HIV directly affects via infection, but indirectly affects via inflammation.

Question 9

Inhibition of immune cell function allows what?

Answer 9

other pathogens to replicate in virus infected hosts and, thus, disease occurs: Opportunistic infections of HIV associated pathogens.

Question 10

lowering in the number of CD4 T cells over time causes what?

Answer 10

an immunodeficiency state (means there not necessarily anything surveying the virus within the individual)

Question 11

HIV associated pathogens - name some

Answer 11

Colonisation of opportunistic pathogens:

Virus - Herpes simplex virus (HSV), Kaposi’s sarcoma herpesvirus (KSHV)

Bacteria - Mycobacterium tuberculosis, Salmonella

Fungus - Candida

Parasite - Toxoplasma gondii

Question 12

cancer has 2 possible routes of infection - what are they?

Answer 12

(i) primary infection – never been exposed to that pathogen before, you get exposed to it and it colonises. Primary infection can be resolved (typically by immune suppression) and infection moves to sites in the host that the immune system does not access. In these sites the virus resides without replicating: latency
(ii) reactivation from latency - occurs upon immunodeficiency, leads to cancer

Question 13

how are HIV sufferers exposed to HSV and where does HSV go?

Answer 13

via the skin

HSV gets into the infected host and into the nervous system. There is not good immune surveillance within the nervous system, and this is largely because a lot of immune cells don’t access the blood brain barrier. The virus can move along up into the dendrites and CNS.

So for example, vaginal transmission or genital transmission of HSV means the virus can travel up the CNS brain stem up into the brain. The virus can sit there, not replicating, ready for immunodeficiency.

Question 14

why is there not good immune surveillance in the nervous system?

Answer 14

because a lot of immune cells don’t access the blood brain barrier

Question 15

how does the virus ends up sensing that you don’t have an immune system left?

Answer 15

not really sure

we think the interaction of the immune system with the cells is sending a constant message to the latent viruses in the CNS. When the signal stops coming, the virus will reactivate from latency, and travels back down to the site of infection

Question 16

KSHV - method of infection

look at diagram slide 59

Answer 16

KS progenitor cells become de novo/primary infections, leading to latent infection of B cells. KSHV gets into B-cells and the immune system can’t see it. Virus is not replicating/replicating at a very low level.

Cellular/viral cue causes reactivation from latency. Then there are lytic effects, positive feedback scheme involving reinfection of cells.

Some types of B-cells are permissive, some are not. The B-cells themselves have to be cued in some way to let cancer through.

Uncontrolled production of B cells and cancer, during which you get an inflammatory response.

KS lesion – cells are replicating again and again, and inflammatory molecules are being produced. These molecules produces more latent transformed cells. We have ways to combat this – preventing HIV replication or KSHV within B cells.