HTHSCI 1DT3 Lecture Notes - Lecture 14: Pegylated Interferon, Interleukin 22, Endonuclease
23 Jun 2018
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Importance of immune activation
Immune activation is not observed in non-pathogenic SIV primate infection despite similar levels
of viral replication to that in HIV-1
Markers of cellular immune activation predict disease progression independently of CD4 and
viral load in HIV-1 infection
Increased CD4 T cell count post-HAART is inversely related to levels of immune activation
Increased immune activation may result in actively induced cell death of CD4 T cells and immune
exhaustion / replicative senescence in CD8 T cells:
-Rate of apoptosis in uninfected CD4 T cells is greater than in healthy
controls
Expression of CD38 on CD8s = common marker of immune activation
Causes of immune activation: 1) immune response to HIV-1 (20%) 2) HIV-1 protein
products 3) co-infection with conventional or opportunistic infection 4) microbial translocation
from GI tract = KEY THEORY 5) loss of function of counter-regulatory / immunosuppressive
response
Intestinal immunity & HIV
1) role in transmission of HIV-1
2) role in amplification of HIV infection
3) CD4+ cell depletion
4) Contribution to immune dysfunction
5) Reservoir of viral infection in patients on treatment
1) HIV transmission
Damage / breaks to anorectal mucosa increase HIV transmission
It may be transmitted by M cells
Initial targets of HIV-1 are DCs and memory CD4 T cells; DCs can transfer in tact virions
to draining LNs
2) Amplification of infection
HIV gp120 binds intestinal homing proteins (e.g. alpha4beta7 integrin)
The interaction of homing signals and HIV proteins increases transmission to neighbouring CD 4
T cells and activates CD4s, making it easier for HIV to replicate in them
3) CD4+ cell depletion
CCR5 CD4+ are commoner in the intestine than in the blood and there are more CCR5 molecules
per cell hence there is preferential loss of CCR5s in the gut > the peripheral blood
4) contribution to immune dysfunction
damage to lining of the gut microbial translocation + immune activation
LPS concentration (marker of microbial translocation) is increased in patients with progressive
HIV infections (+ SIV in macaques)
Transmission causes monocyte activation, represented by increased soluble CD14
Microbial translocation (LPS) correlates with percentage of CD38 and T cells hence contributes
to chronic innate and adaptive immune responses
Potential causes of increased bacterial translocation are:
- decreased mucosal IgA
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Document Summary
Immune activation is not observed in non-pathogenic siv primate infection despite similar levels of viral replication to that in hiv-1. Markers of cellular immune activation predict disease progression independently of cd4 and viral load in hiv-1 infection. Increased cd4 t cell count post-haart is inversely related to levels of immune activation. Increased immune activation may result in actively induced cell death of cd4 t cells and immune exhaustion / replicative senescence in cd8 t cells: Rate of apoptosis in uninfected cd4 t cells is greater than in healthy controls. Expression of cd38 on cd8s = common marker of immune activation. Causes of immune activation: 1) immune response to hiv-1 (20%) 2) hiv-1 protein products 3) co-infection with conventional or opportunistic infection 4) microbial translocation from gi tract = key theory 5) loss of function of counter-regulatory / immunosuppressive response. 5) role in transmission of hiv-1 role in amplification of hiv infection.
