HIV and Inflammaging Flashcards
What are the drivers of ageing?
chronological; inflammatory; infectious; environmental
What personal characteristics influence ageing?
sex and ethnicity; occupation; educational attainment; wealth
What is the Hayflick limit?
replicative limit of cells
What is cellular senescence?
stress-induced irreversible proliferative arrest and resistance to both mitogenic and oncogenic stimuli
What are the actions of mTORC1 in normal cells?
dependent translation in ageing cells-accumulation of unfolded proteins and ER stress; stimulates mitochondria- increases ROS; oxidative damage to DNA and proteins; inhibits autophagy
What happens when autophagy is inhibited?
reduces turnover of cellular components, promotes accumulation of damaged forms
What is the effect of mTORC1 on stem cells?
promotes stem cells exhaustion and tissue ageing through hyperproliferation or senescense
What is the result of incerased stem cell senscence?
postmitotic cells are no longer replaces dying cell so overall performance of hte tissue is degraded
What happens when mTORC1 is inhibited?
lifespan extension ins multiple organisms
What are the ways of inhibiting mTORC1?
genetic inactivation of mTORC1; dietary resitrction and rapamycin
What is mTORC1?
serine-threonine kinase
What disorders have mTORC1 dysregulation?
cancers and genetic disorders
When is inhibition of mTOR used clinically?
in transplantation and cancers
What stimulate MTORC1 and 2?
mitogens; growth factors and nutrients
What is the senescence phenotype?
cell cycle arrest; resistnace to mitogens and oncogenic transformation
What is the senescence-associated secretory phenotype?
vesicles from the golgi apparatus- secreted cytokines and chemokines that are released and impinge on surrounding cells (paracrine signalling)
Waht are the stress triggers for cellular senescence?
telomere erosion; unresolved DNA damage; lysosomal stress; unresolved unfolded protein response; oncogene activation; culture shock; ROS
What are hte biomarkers of cellular senscence?
SAbeta-gal; elevated expression levels of p16INK4A and hypophosphorylated nuclear retinoblastma protein; telomere damage; SASP; SAHFs
What is SAbeta-gal?
senscence-associated beta-galactosidase
What are SAHFs?
senscence-associated heterochromatic foci
What is the action of p16INK4A?
cyclin-dependent kinase inhibitor which prevents CDK4 and CDK6 from assmebling into functional holoenzymes with their allosteric regulators and the binding prevents import of active kinases into the nucleus and the phosphorylation of nuclear retinoblastoma protein
What does the cyclin-dependent kinase inhibitor 2A (CDKN2A) -CDKN2B encode?
3 tumour suppressor proteins
What does the CDKN2A gene encode?
both p14ARF and p16INK4A
What is the function of hypophosphorylated form of RB?
sequesters E2F transcription factors preventing them from coorindately activating a suite of genes required for DNA replication
What is the function of p14ARF?
prevents p53 polyubiquiylation and facilitates p53 activation
What happens when CDKN2A-CDKN2B are silenced or deleted?
abrogates the tumour-suppressive functions of RB and p53 to facilitate cellular self-renewal
What does the term exon refer to?
both the DNA sequence within a gene and the corresponding sequence in RNA transcripts
What is an alternative reading frame?
transcription of a coding sequence can start at different nucleotides of the first or later codon resulting in 2 polypeptides with no sequence similarity
What is increased p16INK4A a marker of in HIV patients?
T cell ageing in HIV patients, marker goes down when treat HIV
What is the funciton of hte p53 transcription factor?
regulates genes commonly induced by cellular stress
What is SAbeta-gal a marker of?
lysosomal stress
What is the difference in grwoth arrest between senescence and quiescence?
senescence is permanent whereas quiescence is transient and mitogen responsive
What is the difference in metabolism between senscence and quiescence?
metabolism in senscence is high whereas in quiescence its low - reduced ribosomal RNA and protein synthessi
What is the function of a telomere?
protect chromosome ends during cellular replication and shortens with each cellular division until cells become senescent
What is the function of telomerase?
prevent DNA cellular repair machinery from accessing ends of chromosomes- maintains telomere length in stem cells nad embryonic cells
What does telomerase work with to maintain telomere length?
telomere bound shelterin protein
What is the biggest effect on leukocyte telomere length?
in association with current smoking
What are the causes of shorter telomere length?
smoking; older age; HIV infection; acute HCV
What is responsible for the association between HIV-positive status and shorter leukcoyte telomere length?
acquisition of HIV and VL
What is the evidence for impairment of the immune system with ageing?
increasing incidence of infection with poorer prognosis; reactivation of chronic infection and reduced anti-tumour immunity
What is the effect of ageing on neutrophils?
impairment of chemotaxis; phagocytosis and superoxide generation; reduced response to survival signals- clearance of inflammation may be impaired
What is the effect of ageing on DCs?
reduced ability to induce T cell proliferation and express co-stimulatory molecules, reduction in autophagy and antigen processing
What happens to maccropahge function with ageining?
reduced expression of MHC-II; antigen presentation and alterations in signalling pathways; defects in TLR function
What cytokine in particular increases from age 50-60?
IL-6
what condition is IL-6 increased in ?
HIV infection
What happens to thymic function with age?
gradual involution with fatty infiltration with increasing loss of function
is the function of the thymuc completely lost?
no- number of recent thymic emigrants reduced greatly with age but still detectable in elderly
What is the result of thymic involution?
reduced naive cell output and reduced clonal diversity–less breadth of immune response
What controls the cell cycle?
CDK molecules and cyclins
How does the percentage of CD69+ DP thymocytes compare in old mice vs young after stimulation for 48 hours?
significantly decrease in old mice
What is CD69?
one of hte earliest activation markers of T cells
What is the difference in the proportion of thymoctes in the G2-M phase of the cell cycle between old and young mice?
increase in proportion of thymocytes in G2-M phase in young vs old
What maintains the T cell pool in adults?
peripheral turnover
What causes oligoclonal expansion of hte peripheral T cell pool?
antigen exposure
what is the effect of persistent antigen exposure e.g chronic viral infection on the peripehral T cell pool?
causes skewing
What do T cells require to induce telomerase?
CD28 costimulation
What are the phenotypic and function changes to peripheral T cell pool with ageing?
loss of costimulatory molecules eg CD28; increased epxression of inhibitory moelcuels eg CTLA4; increased PD-1 associated with chronic viral infection
How does the proportion of naive Tregs change with age?
reduces - increased differentiation
What is the effect of ageing on germinal centres?
smaller and show reduced functionality- esp. follicular Th cells and DCs; number of GCs reduces iwith age
How does the proportion of circulating memory B and T cells change with age?
increasein proportion
What is the effect of toleromere shortening in the peripheral B cell pool with ageing?
doesn’t seem to be affected- inducible telomerase expression not affected by ageining in humans
What is seen in the immune risk profile?
men especially- redued CD4/8 ratio; human CMV IgG+ and CD8+CD28- T cells
How is CMV infection related to ageing of the adaptive immunity?
late differentiated CD8+ cells accumulate- associated with CMV infection; less effective cellular level but overall greater inflammatory effect
What is the evidence to suggest HIV infection is a pro-ageing phenomenon?
inflammaging- association with peripehral pro-inflam cytokines; premature evolution of frailty phenotype and icnreased inciddence of diseases associated with ageing
What is the effect of HIV on the CD4/CD8 ratio?
low CD4/8 ratio even in HIV suppressed
What markers were associated with increased risk of death in the intermittent ART arm of the SMART study?
hsCRP; IL-6 and D-dimer
What is the frailty phenotype?
shrinking; exhaustion; low activity; weakness; slowness
Which markers of immune activation are independetly assocaited with functional imparment inpatietns receviing ART?
IL-6 and CD8+ T cell activation
What suggests that there is a pro-inflammatory mileu in functionally impaired HIV patients?
high IL-6 and hsCRP and TNF-a
What is a prominent immunological feature of accelerated agining in HIV infection?
inflation of CMV-specific memory T cell rpeosnses to levels associated iwth an immune risk phenotype
Who develops an immune risk phenotype in HIV-negative individuals?
CMV infected octogenarians
What does the immune risk phenotype mean?
signifies some degree of immune senescene and an elevated risk for all-cause mortality
What is the effect of CMV infection in the elderly?
increases all cause mortality and risk for a number of age-related morbidities
When does the IRP manifest in elderly CMV-potivie individuals?
when levels of immunological paramters in peripheral blood cross a threshold beyond which a number of negative health outcomes increase in likelihood
What largely determines IRP development in the non-HIV infected population?
absolute magnitude of T cell repsonses against CMV
Why are markers assocaited with the IRP elevated by HIV infection?
partially due to the immune response against HIV itself and partially due to accelerated CMV-specific CD8 T cell memory inflation
What is the signfiance of a peripheral blood CD4/8 ratio <1 seen with theIRP?
numerical and functional deficit of helper T cells
What is the significane of an increased fraction of CD57 CD8 T cells with the IRP?
accumulation of CD8 T cells at stage of replicative senescene marked by shorteend telomeres
what is the significance of a decreased fraction of CD28+ CD8 cells with the IRP?
reduced vaccine responsiveness; immunosenesnce
What is the significance of resistance of CMV-specific CD8 T cells to apoptosis?
enrichment of MCV specific CD8 T cells in T cell reperotire
What is a normal CD4/8 T cell ratio?
2
What is the signifnace of reduced in vitro resposne to T cell mitogen concanavalin A with the IRP?
reduced in vivo response to infection
What does the increased mortality assocaited with the IRP likely reflect?
a level of immune dysfunction predisposing to multiple age-associated morbidities
Aside from a costimulatory molecule what else does expression of CD28 relfect about the T cell?
capacity to produce IL-2
Which types of T cells lack CD28?
effector cells and effector memory cells with limited regenerative capccity
Do CMV specific memory T cells provide protection against CMV disease?
No
What type of T cell are most of the oligoclonal T cells populations that airse in octogenarians?
CD8
Why do chronic viruses cause skewing of hte T cell repertoire?
if aren’t eliminated, virus continues to recruit and activate CD8 cells which increases the proportion of virus-specific cells with activated or memory phenotypes
What happens to virus-specific T cells that fial to eliminate or effectively suppress the virus?
acquire a phenotype distinct from effector or memory cells, become dysfunction and often undergo apoptosis
What ar emost of the CMV-specific CD8 T cells reactive against?
2 immunodominant CMV proteins- pp65 and IE-1
What is the reuslt of CMV seropositivity with increased CRP?
increased risk for CVD-related mortality
What are the functional correlates of immunological senescence seen in the IRP?
reduced lymphocyte responses; increased susceptibiltiy to infection and poor vaccine repsonsiveness
What diseases aside from CVD are associated with CMV seropositivity?
T2DM; cognitive deterioration in the elderly and pre-eclampsia in pregnant women
What is the co-infection rate of CMV and HIV?
almost universal
What features of IRP are seen in HIV?
CD4/8 ratio <1 often persist dewspite HAARt; oligoclonal T cell expansions are more common; more CD8 cells have markers or chronic activation and frustration; more CD8 are CD28-CD57+
How does HIV affect the immunological decay associated with CMV and ageing?
exacerbates them- happen much earlier as in a inflammatory environment
What deos the secretosome of CMV-infected endothleial cells contain?
IL-6; IL-8; GM-CSF
What is the function of IL-6 in the endothelium?
induces expression of survivin, a chemokine that promotes endothelial cell survival to ocmpound the abnormal growth of vascualr epithelium
What effect might teh IL-8 released by the CMV secretosome have?
attract neutrophils which may mediate nedothelial cell damage
What happens when PBMCs from persons with strong anti-CMV repsonses were incubated with CMV antigens?
IFNy and TNF were released from the CMV-specific T cells stimulated endothelial cell destruction—CVD assocaited iwth CMV
What suggests that there is some level of smoldering CMV replication causing increased inflammation?
treatment with valganciclovir reduced inflammatory markers in HIV-infected individuals
