Viral Pathogens: Classification, Biology and Disease II Flashcards
Course of HIV
Primary infection
Latent period
AIDS
Throughout the course of a HIV-1 infection:
- fewer CD4+ T cells
- more viral load (virus replicating)
What leads to AIDS?
The inexorable depletion of CD4+ T cells during infection ultimately leads to immunodeficiency (AIDS) and mortality (via opportunistic infections)
How do viruses evade the immune system?
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
Types of T cells the HIV virus attacks
Non-permissive CD4+ T cells
Permissive CD4+ T cells
Non-permissive CD4+ T cells
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
Permissive CD4+ T cells
T cells in which the virus produces DNA from its RNA genome.
Response to HIV Virus in Permissive CD4+ T cells
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
How does the HIV evade the immune system in permissive CD4+ T cells?
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
Which T cells does the HIV virus mostly encounter?
Non-permissive CD4+ T cells
Response to HIV in non-permissive CD4+ T cells
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
Pyroptosis
Programmed cell death that elicits an inflammatory response because there is excretion of immune factors/pro-inflammatory cytokines from the cell into the environment
Why is there excretion of immune factors during pyroptosis?
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
How does the inflammation from pyroptosis affect the virus?
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
HIV Associated Pathogens
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
Opportunistic viral infections in AIDS
Herpes simplex virus (HSV) and Kaposi’ sarcoma herpesvirus (KSHV)
What are HSV and KSHV also involved in?
Cancer
Routes of infection by HSV and KSHV
Two possible routes of infection, either:
- Primary infection
- Reactivation from latency
Primary infection
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
When does reactivation from latency occur?
Upon immunodeficiency
HSV exposure in HIV sufferers (immunocompetence)
- 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
Why does the HSV virus enter the nervous system?
because immune surveillance there isn’t good as immune cells can’t cross blood brain barrier
What triggers HSV reactivation?
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
Effect of unchecked HSV infection
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.
KSHV exposure in HIV
- 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
Viral Oncogenesis of AIDS
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
Treating viral oncogenesis of AIDS- Kaposi’s sarcoma
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
Viruses that cause cancer
· 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
