Viral Pathogens: Classification, Biology and Disease II

Question 1

Course of HIV

Answer 1

Primary infection
Latent period
AIDS

Throughout the course of a HIV-1 infection:

• fewer CD4+ T cells
• more viral load (virus replicating)

Question 2

What leads to AIDS?

Answer 2

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

Question 3

How do viruses evade the immune system?

Answer 3

Viruses replicate inside immune cells who function is to recognise and kill infected 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 4

Types of T cells the HIV virus attacks

Answer 4

Non-permissive CD4+ T cells

Permissive CD4+ T cells

Question 5

Non-permissive CD4+ T cells

Answer 5

T cells in which the virus cannot fully replicate. It gets to a particular point of replication and does not replicate any further. Therefore, you don’t necessarily see a virus coming out of the cell

Question 6

Permissive CD4+ T cells

Answer 6

T cells in which the virus produces DNA from its RNA genome.

Question 7

Response to HIV Virus in Permissive CD4+ T cells

Answer 7

Virus produces DNA from its RNA genome. Mechanisms in the cell recognise DNA elements as foreign invaders to shut down that invasion. This recognition activates host cell protein caspase-3 which mediates apoptosis →cell death

For the most part in the permissive cell, the virus is able to shut down this response

Question 8

How does the HIV evade the immune system in permissive CD4+ T cells?

Answer 8

The virus recognises the machinery which mediates apoptosis in HIV infected cells (e.g. caspase-3 pathway) and evades the immune system

But, some of this activation of caspase-3 does occur and you do indeed get cell death of permissive T cells

Question 9

Which T cells does the HIV virus mostly encounter?

Answer 9

Non-permissive CD4+ T cells

Question 10

Response to HIV in non-permissive CD4+ T cells

Answer 10

Virus gets into the cell but there isn’t full replication of the genome.

Foreign nucleic acid (DNA or RNA) is detected by IFI16 DNA sensor in the cell. This sensor, via a number of mechanisms, activates the immune response:

1) Activation of innate antiviral and inflammatory response
2) IFI16 inflammasome assembly
3) Caspase-1 activation → pyroptosis

Question 11

Pyroptosis

Answer 11

Programmed cell death that elicits an inflammatory response because there is excretion of immune factors/pro-inflammatory cytokines from the cell into the environment

Question 12

Why is there excretion of immune factors during pyroptosis?

Answer 12

To warn other surrounding cells that there is some form of infection
-however this immune response could be deleterious to the health of other cells

Question 13

How does the inflammation from pyroptosis affect the virus?

Answer 13

Direct effect:
The inflammation is advantageous for the virus, because it recruits more healthy CD4+ T cells, meaning more infection can take place (positive feedback)

Indirect effect:
Inflammation hypercharges immune system
-migration of neutrophils and monocytes into infected area
-more inflammation through cell death and release of pro-inflammatory cytokines

Both direct and indirect effects cause loss of CD4+ T cells, causing our immune deficiency state which is advantageous to the virus

Question 14

HIV Associated Pathogens

Answer 14

Because HIV AIDS sufferers are chronically immunodeficient, they are open to any number of opportunistic infections which cause mortality

Virus

• Herpes simplex virus (HSV)
• Kaposi’s sarcoma herpesvirus (KSHV)

Bacteria

• Mycobacterium tuberculosis
• Salmonella

Fungus

• Candida
• Cyprococcus neoformans

Parasite

• Cryptosporidium
• Toxoplasma gondii

Question 15

Opportunistic viral infections in AIDS

Answer 15

Herpes simplex virus (HSV) and Kaposi’ sarcoma herpesvirus (KSHV)

Question 16

What are HSV and KSHV also involved in?

Answer 16

Cancer

Question 17

Routes of infection by HSV and KSHV

Answer 17

Two possible routes of infection, either:

• Primary infection
• Reactivation from latency

Question 18

Primary infection

Answer 18

when you are exposed to the pathogen for the first time and it colonises you

Primary infection can be resolved typically by immune suppression, and the infection moves to sites in the host that the immune system does not access. In these sites, the virus resides without replication → virus latency

Question 19

When does reactivation from latency occur?

Answer 19

Upon immunodeficiency

Question 20

HSV exposure in HIV sufferers (immunocompetence)

Answer 20

• HSV infect epithelial cells of skin
• Virus replicates
• Virus moves into nervous system
• Virus enters neurites and travels into dendrites and CNS
• immune system cannot access these areas, and the virus resides in these areas without replication (virus latency), ready for reactivation upon immunodeficiency

Question 21

Why does the HSV virus enter the nervous system?

Answer 21

because immune surveillance there isn’t good as immune cells can’t cross blood brain barrier

Question 22

What triggers HSV reactivation?

Answer 22

SUGGESTED:
-immune system is constantly sending a message to the latent infectious viruses, but when the signal is no longer there during immunodeficiency, the viruses will reactivate and move to an area where it can productively replicate

Question 23

Effect of unchecked HSV infection

Answer 23

An unchecked HSV infection can cause neuronal pathologies, where the virus is replicating within neuronal dendrites, and the cell death leads to very serious CNS disease and mortality.

Question 24

KSHV exposure in HIV

Answer 24

• De Novo infection of KS progenitor cells which leads to latent infection of B cells
• In HIV patient, viral or cellular cue triggers reactivation. This could be because there is constant interactions between B and T cells, however loss of T cells in HIV removes signal which prompts reactivation signal for the virus
• Reactivation leads to lytic, productive, cytopathic and immunogenic effects
• Positive feedback loop where we see re-infection of new cells

Question 25

Viral Oncogenesis of AIDS

Answer 25

KSHV:

• De novo infection of KS progenitor cells
• Latent infection of B cells
• Inflammatory cytokines/AIDS trigger B cell reactivation
• This cause lytic/productive infection, and cells become oncogenic (MOA not understood)
• Oncogenic cells undergo uncontrolled proliferation resulting in KS lesions
• This produces more inflammatory molecules, which produce more latent transformed cells (reactivation) via positive feedback

Question 26

Treating viral oncogenesis of AIDS- Kaposi’s sarcoma

Answer 26

Anti-Retroviral Therapy (ART)
-stops HIV replication, which would stop the inflammatory response, and therefore no reactivation of B cells

Ganciclovir
-direct acting antiviral drug which prevents replication of KHSV within B cells and a number of different cells

Question 27

Viruses that cause cancer

Answer 27

· Human papilloma viruses (HPVs)- Papilloma virus, circular dsDNA genome→skin cancer

· Epstein-Barr virus (EBV)- Herpes virus, linear dsDNA genome → lymphoma

· Hepatitis B virus (HBV)- Hepadnavirus, circular dsDNA genome → carcinoma

· Hepatitis C virus (HCV)- Flavivirus, ssRNA → carcinoma

· Human herpes virus 8 (HHV-8)- Herpes virus, linear dsDNA genome → lymphoma

· Human T-cell lymphotrophic virus-1 (HTLV-1)- Retrovirus, RNA-DNA genome → leukaemia/lymphoma

· Merkel cell polyomavirus (MCV)- Polyomavirus, dsDNA genome → carcinoma