T cell responses to OIs in HIV Flashcards
What is an opportunistic infection?
infections that are more frequent or more severe because of immunosuppresssion in HIV-infected persons
What is the general function of lymphocytes in hte lymph nodes?
response to tissue associated antigen
What is the general function of lymphocytes in the spleen?
response to blood antigen
What is the general function of lymphocytes in MALT?
response to antigen at mucosal surfaces
What is the function of NKTs?
recognise glycolipids via CD1 molecule
What receptors for NKTs express?
TCR and NK1.1
What are anchors in MHC?
invariant residues that bind to allele-specific pockets of Mhc
What happens when T cells meet antigen and are activated?
shift into proliferative state- clonal expansion; cytokine production and differentiation into effectors- T cell subset
What does the uncoating of the viral capsid release?
the pre-integration complex
What is the pre-integration complex routed to nucleopores via?
microtubular network
When integrated into the genome what does the 5’LTR act as?
any eukaryotic promoter
When integrated into the genome what does the 3’LTR act like?
the polyadenylation and termination site
Where do viral structural and enzymatic proteins localise to in the plasma membrane?
lipid rafts
What protein facilitates the viral assembly?
negative effector- Nef
What does gag stand for?
group-specifc antigen
What does gag recruit to allow virions to be released?
components of multivesicular bodies
what is the main risk factor for OI?
CD4 count
Why does HAART protect against OI?
allows restoration of pathogen and HIV specific T cells, and the memory T cell pool which is composed of T cells specific for opportunistic pathogens
Why is there a reduction in HIV-specific CD4 and CD8 effector T cells with HAART?
decrease in HIV-RNA load
what type of immunity is required for PCP?
cell mediated
What is the lung injury in PCP associated with?
inflammatory response not just pathogen burden
Why do HIV patients not have an increase in all infections?
get infections that rely upon cell-mediated immunity
What cell type are essential for clearance of PCP?
Cd4 - SCID mice injected with CD4 have lowest pathogen burden and highest inflammation, Cd8 cells cannot lcear PCP
Which cells contribute to the respiratory compromise seen with PCP?
Cd8 cells and neutrophils- mice without had no lung impairment, and when CD4 were knocked out, there was the decrease in lung function
What happens when there is Cd4 and Cd8 depletion in mice with PCP?
infection but normal lung compliance and respiratory rate
What happens with CD4 deficiency in PCP?
PCP is not lceared, CD8 dominates with inflammation
What does immune reconstitution of CD4 cells allow with PCP?
cd4 infiltrate with intense inflammation but eventual pathogen clearance
What is the rationale of PCP treatment?
reduce pathogen burden with anti-PCP antibiotics- co-trimoxazole; control inflammatory response with steroids; treat HIV
What type of virus is CMV?
beta human herpes virus type 5
What is the seroprevalence in US of CMV in the over 80s?
90%
How does the priamry injfection with CMV in healthy individuals initate?
replication in the mucosal epithelium
Which cells does CMV disseminate into?
monocytic cells of myeloid lineage
What happens when latently infected monocytes differentate into macrophages?
initiation of productive infection
What is released by activated cells infected with CMV?
virus particles of virus-associated dense bodies
How big is the CMV-specific T cells response in health individuals?
10% of peripheral CD4 and Cd8 cells are CMV-specific
What happens to pateitns with very low CD4 coutns infected wi th CMV?
CMV retinitis–blindness
What are CD4 T cell responses predominantly against in CMV?
viral protein pp65
What are CD8 cell repsonses predominantly against in CMV?
viral protein IE-1
What is protective immunity to CMV associated with?
CMV-specific T cells that express IFN-g and IL-2 and have a CD8 early maturational phenotype
What T cells are important for CMV control?
Cd8
What protein causes gradual down-regulation of MHC-II in TB infected macrophages?
19kDA protein
What is the function of CD4 T cells in TB infection?
produce IFN-y and IL-2, maintain CD8 CTL repsonses; inhibit growth in macropahges
What demonstrates that IFN-y is the main macropahge and monocyte activator?
IFN-y receptor polymorphisms
What is the function of CD8 cells in TB infection?
restrict MTC growth, produce IFNy and TNFa; lyse MTB infected cells
What is the function of IL-2 produced by Th cells?
stimulates Th cells and CD8 cells
What is the effect of HIV on TB?
increases reactivation of latent TB infection; increases MTB infection and re-infection
What happens to the percentage of T cells specigic to MTB during reconstitution using ARt?
decreases (more overall T cells) but a bigger response to TB as actual numbers increase
What is the prognosis of PCP correlated with?
markers of inflammation rather than organism numbers
Why was P.carinii cahnged to P.jirovecci?
PCP cannot be transferred from mammalian species to another-therefore PCP is species specific-mutliple unique speecies, jirovecci is the name for P. carinii of human origin
What suggest that PCP results from new infection rather than reactivation of latent infection?
no evidence for latency has ever been demonstrated, mouse models have shown that latency does not develop, latency suggested by early seroconversion and disease later in life; humans with recurrent episodes of PCP have variation in isolates of PCP
Before the AIDS epidemic, which pateitns got PCP?
oncological
What initially suggested that PCP clinical manifestations are the restul of host immune repsonse?
PCP occured after cessation of steroids; onset of clinically reocnisable PCP followed engraftment with bone marrow receipients
What is thought to be the cause of mortality being much higher in non-AIDs patietns vs AIDs with PCP?
non-AIDs patients are more able to mount an immune reposnse to PCP than AIDs patietns which exacerbates clinical manifestations– e.g patients with connective tissue diseases have an even higehr mortality (diseases assoc. with inflammation)
What suggests that it is not pathogen burden which results in higher mortality in non-AIDs patietns with PCP vs AIDs?
AIDs patietns have a higher organism burden but minimal thickening of the alveolar wallls and less infiltration whereas non-aIDS had higher pathogen numebrs; btu more wall thickening; more mononuclear infiltration and diffuse lung damage and interstitial fibrosis
What experiment in mice helped show the importance of the immune response in PCP?
SCID mice with PCP demonstrated rapid deterioration and death when infused with functional lymphocytes
Which type of Th effector response is capable of protecting afainst PCP?
both Th1 nad Th2 - although the consequence of polarisation for the severity of lung injury isn’t known
depletion of what type of cell is necessary to make mice susceptible to the developmetn of PCP?
Cd4 cells
What happens to mice deplted in Cd4 t cells with PCP?
develop intense inflammation; hypoxia and decreased dynamic lung compliance- associated iwth TNFa and chemokines; infiltration of Cd8 and neutrophils
What happens to mice depleted of both Cd4 and CD8 cells with PCP compared with Cd4 depletion only?
dramatically reduced lung inflammation and relatively normal lung function despite having a similar P.carinii burden
What is the role of Cd8 cells in PCP?
contribute to pulmonary injury but do not have a significant role in clearance of PCP in absence of Cd4s; beneficially suppress the CD4 response
What is immune restoration disease?
after immune reconstituation, the immune response restored is immunopathoglogical and causes disease
What are CD25 postiive T cells?
Tregs
What are the 3 key cytokines involved in the protection against PCP?
IL-1; TNF-a and IFNy
What happens when PCP infected SCID mice are depleted of IL-1 or TNFa?
when they are reconstituated they are unable to clear PCP
What is the function of IFNy in PCP?
isnt crucial for protection- depletion does not interfere with recovery, but is important in overall protective response by enhancing macrophages function; mice deficient in IFNy have prolonged inflammatory reponses
What happens in TNFa knock out mice?
unable to clear infection; have reduced level of pulmonary inflammation despite reduced pathogen numbers when CD4 cells are also depleted; associated with CD8 dependent lung injury
Therefore what is the overall role of pro-inflamamtory cytokines?
requried for control of PCP but contribute to lung injury when an effective immune repsonse is not possible (eg when CD4 cells are knocked out)
What happens when IL-6 is depleted in PCP infected mice after reconstitution?
exacerbated inflammatory response
What is thought to be the reason that depletion of IL-6 results in increased inflammation?
IL-6 downregulates TNF-a which enhances inflammatory responses
What is surfactant?
am macromolecular complex of lipids and proteins that is responsible for maintaining reduced surface tension in the alveoli
Which surfactant proteins are part of the collectin family thorugh their lectin-binding activity?
SpA and SpD
What happens to mice deficient in Spa or SpD with PCP?
enhanced inflammatory repsonse and lung injury as well as increased pathogen coutns
What is the alveolar epithelium composed of?
type I and type II pneumocytes
What is the function of type II pneumocytes?
secretory cell in the alveolus and are required for surfactnat, protein and phospholipid production; express PRRs
What is hte first event after exposure to PCP?
direct activation of type II pneumocytes that results in NFkB activation and release of inflammatory signals
What is the course of infection in CD4 depleted patietns with PCP?
PCP continues to proliferate and a CD8 dominated response is seen–severe surfactant dysfunction and respiratory failure
What suggests that HIV affects innate immune response to P.carinii?
reduces the ability of macrophages to respond to P.carinii with NFkB activation and IL-8 secretion
When does the clinical disease recognised as PCP manifest after infection?
when organism numbers reach a sufficient level to trigger a T-cell driven inflammatory response
What happens when CD8 cells are deficient but have CD4 T ells in PCP e.g during IRD?
an effective but exaggerated inflammatory response is seen
What is the clinical hallmark of PCP?
hypoxia nad reduced lung compliance
Why would you consider delaying instituion of HAARt in AIDS patient who present with PCP and poor viral control?
immune reconstituion can result in IRD and considerable bystander injury to the lung
What is thought t be the cause of poor lung function in inflammatory responses?
disruption of surfacant activity
What are the histological findings in PCP?
inflammation; oedema; septal thickening; fibrosis; erosion of type I penuocytes; proliferation of type II pneumocytes (surfactant composition abnormalities)
What type of genome does HCMV have?
DNA
What is the most abundant protein in the matrix of CMV?
lower matrix phosphorptein 65 pp65
Waht are the 2 functions of the matrix proteins?
proteins that play a structural role and are important for the assembly of virions and disassembly of the particle during entry and 2-proteins which modulate the host cell response during infection
What surface receptor does CMV use to access a cell?
platelet-derived growth factor a
What happens in response to viral DNA release in the nucleus?
expression of IE-1/IE-2 genes
How can HCMV be transmitted?
saliva; sexual contact; placental transfer; breastfeeding; blood transuffsion; solid-organ transplantation or stem cell transplatation
What cytokine is thought to be a key mediator in the reactivation of CMV?
TNFa by the activation of protein kinase C and NFkB
What is the normal course of primary CMV infection in the immunocompetent host?
usually asymptomatic, but can resutl in a mononucleosis syndrome indistinguishable from EBV
What is the leading cause of infectious deafness ?
congenital CMV
When is the risk and severity of CMV disease in the baby greatest?
if primary infection in a seronegative mother occurs during the ifrst trimester
Why does reactivation of CMV during pregnancy have a lower risk of congenital infection?
preexisting maternal CMV antibodies ahve a protective role against intrauterine transmission
How many HIV patients suffered from CMV disease before HAARt?
40%
What is the CD4 threshold for CMV in HIV?
<100
Why does CMV infection remain a problem in HIV?
can directly or indirectly accelerate progression to AIDs and death
What is CMV retinitis characterised by?
haemorrhagic retinal necrosis
What is the major target for neutralising antibodies to HCMV?
gB (glycoprotein involvedi n cell attachment and penetration)
What is the role of natibodies in CMV infection?
in guinea pigs, passive immmunisation increased survival but did not prevent infection; reduces transmission to fetuses
What is the predominant mechanism by which CMV replication is controlled?
cell mediated immunity
What is the CTL response directed against during the early CMV infection?
antigenic peptides derived from IE-I transcription factor
How does CMV evade the immune response against IE-1 protein?
matrix protein pp65 can phosphorylate the IE-1 protein preventing its prcoessing and presentation on MHC-I
If CMV downregulated MHC-I, how does it evade NK cells?
expresses virus-encoded MHCI homologues, upregualtes HLA-E expression
What suggested that passively restoring CMV cellular immunity could be successful?
adoptive transfer of CD8 cells protected against viral challenge and recovery of CMV specific T cell immunity was associated iwth decreased risk of developing disease after allogenic BMT
What are some of the strategies for adoptic immunotherapy of CMV?
MHC-peptide tetramer enrichment of CMV-specific T cells or invitro stimulation of T cells with CMV viral lysate; recombinant viral vectors or synthetic peptides then following enrichment or in vitro expansion cells are transferred
What was the success of MHC-peptide tetrameric complexes to select CMV-specific T cells from peripheral blood and transfer?
resultedi n massive expansion of virus-specific T cells invivo and induced clearacne of active viral replication in 8/9 stem cell transplant patients
What mayu be a problem with immunodominance by CMV in elderly population?
hindering of responses to other patogens e.g CMV seropositivity is associated with lower success rates for influenza vaccination and a cofactor that enhances progression to AIDS
Which type of T cell are most important in controlling CMV?
Cd8 T cells
How many CD8 t cells in the peripheral blood are CMV specific in the lederly?
upto 40%
What happens to mice depleted of CD4 with CMV?
increased incidence of recurrent CMV infection
What suggests that there may be a changein the natural history of HIV wit hthe introduction of effective treatmetn?
increased CD4 counts at diagnosis of OIs have been noted in several studies
Why is there thought to be increased CD4 counts at diagnosis of OIs?
there are increased numbers of patients on HAART who live for longer with higher CD4 counts
What was the asbolute risk of an OI for patients wtih the same level of immunodefiecency with and wthout HAARt?
risk was lower for patients receiving HAART
Why has there been an increase in the proportion of HIV patients with non-hodgkins lymphoma?
recovery in immune status might not be as effective against non-hodgkins as in other OIs, risk factor for it is chronic stimulation of B cells by HIV-1 related antigens- HAART may reduce antigens in blood but its effect in lymphoid tissue (major HIV reservoir and optimum environemnt for B cell activation) is less clear
How many individuals are thought to be latently infected with M.tb worldwide?
a third
What is the primary role of Th17 cells in M.tb infection?
production of IL-17 which attracts and activates neutrophils; monoyctes and Th1 lymphocytes to the site of granuloma formation
What happens in m.tb with unrestricted Th17 stimulation?
exaggeration inflammation mediated by neutrophils and inflammatory monocytes that are attracted to site of disease causing tissue damage
How are Cd8 cells activated in TB?
intracellular pathogen or Mtb protein diversification from the phagosome to the cytosol; apoptotic vesicles taken up by DCs which are cross-presented onto the MHC-I pathway
How are CD4 cells activated in TB?
mycobacterial Ags from the phaogosomal compartment are processed onto MHCII
How are memory T cells maintained?
retention of Ag; stimulation.boosters; homeostatic proliferation
What are CCR7+ memory cells named?
central memory cells
What is the function of Tcm cells?
home to secondary lymphoid tissues; produce high amounts of IL-2 but low levels of other cytokines
What are CCR7- cells named?
effector memory cells
what is the function of Tem cells?
produce high levels of cytokines; exert rapid effector functiosn and home to peripheral tissues
What cluster of differentation is expressed by all memory cells?
CD95
What is the function of polyfunctional T cells?
proliferate and secrete multiple cytokines, play a protective role in antivrial immunity in chronic infections when Ag load is low
Give an example of a functional defect in CD4 T cells in TB-HIV coinfection?
impaired IFNy production by CD4 cells in repsonse to Mtb Ags
What could contribute to the development of active TB in latent infection?
impairment of mycobacterial specific T cells
