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Module 2 > T cell responses to OIs in HIV > Flashcards

T cell responses to OIs in HIV Flashcards

1
Q

What is an opportunistic infection?

A

infections that are more frequent or more severe because of immunosuppresssion in HIV-infected persons

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2
Q

What is the general function of lymphocytes in hte lymph nodes?

A

response to tissue associated antigen

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3
Q

What is the general function of lymphocytes in the spleen?

A

response to blood antigen

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4
Q

What is the general function of lymphocytes in MALT?

A

response to antigen at mucosal surfaces

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5
Q

What is the function of NKTs?

A

recognise glycolipids via CD1 molecule

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6
Q

What receptors for NKTs express?

A

TCR and NK1.1

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7
Q

What are anchors in MHC?

A

invariant residues that bind to allele-specific pockets of Mhc

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8
Q

What happens when T cells meet antigen and are activated?

A

shift into proliferative state- clonal expansion; cytokine production and differentiation into effectors- T cell subset

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9
Q

What does the uncoating of the viral capsid release?

A

the pre-integration complex

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10
Q

What is the pre-integration complex routed to nucleopores via?

A

microtubular network

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11
Q

When integrated into the genome what does the 5’LTR act as?

A

any eukaryotic promoter

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12
Q

When integrated into the genome what does the 3’LTR act like?

A

the polyadenylation and termination site

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13
Q

Where do viral structural and enzymatic proteins localise to in the plasma membrane?

A

lipid rafts

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14
Q

What protein facilitates the viral assembly?

A

negative effector- Nef

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15
Q

What does gag stand for?

A

group-specifc antigen

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16
Q

What does gag recruit to allow virions to be released?

A

components of multivesicular bodies

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17
Q

what is the main risk factor for OI?

A

CD4 count

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18
Q

Why does HAART protect against OI?

A

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

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19
Q

Why is there a reduction in HIV-specific CD4 and CD8 effector T cells with HAART?

A

decrease in HIV-RNA load

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20
Q

what type of immunity is required for PCP?

A

cell mediated

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21
Q

What is the lung injury in PCP associated with?

A

inflammatory response not just pathogen burden

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22
Q

Why do HIV patients not have an increase in all infections?

A

get infections that rely upon cell-mediated immunity

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23
Q

What cell type are essential for clearance of PCP?

A

Cd4 - SCID mice injected with CD4 have lowest pathogen burden and highest inflammation, Cd8 cells cannot lcear PCP

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24
Q

Which cells contribute to the respiratory compromise seen with PCP?

A

Cd8 cells and neutrophils- mice without had no lung impairment, and when CD4 were knocked out, there was the decrease in lung function

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25
Q

What happens when there is Cd4 and Cd8 depletion in mice with PCP?

A

infection but normal lung compliance and respiratory rate

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26
Q

What happens with CD4 deficiency in PCP?

A

PCP is not lceared, CD8 dominates with inflammation

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27
Q

What does immune reconstitution of CD4 cells allow with PCP?

A

cd4 infiltrate with intense inflammation but eventual pathogen clearance

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28
Q

What is the rationale of PCP treatment?

A

reduce pathogen burden with anti-PCP antibiotics- co-trimoxazole; control inflammatory response with steroids; treat HIV

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29
Q

What type of virus is CMV?

A

beta human herpes virus type 5

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30
Q

What is the seroprevalence in US of CMV in the over 80s?

A

90%

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31
Q

How does the priamry injfection with CMV in healthy individuals initate?

A

replication in the mucosal epithelium

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32
Q

Which cells does CMV disseminate into?

A

monocytic cells of myeloid lineage

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33
Q

What happens when latently infected monocytes differentate into macrophages?

A

initiation of productive infection

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34
Q

What is released by activated cells infected with CMV?

A

virus particles of virus-associated dense bodies

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35
Q

How big is the CMV-specific T cells response in health individuals?

A

10% of peripheral CD4 and Cd8 cells are CMV-specific

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36
Q

What happens to pateitns with very low CD4 coutns infected wi th CMV?

A

CMV retinitis–blindness

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37
Q

What are CD4 T cell responses predominantly against in CMV?

A

viral protein pp65

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38
Q

What are CD8 cell repsonses predominantly against in CMV?

A

viral protein IE-1

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39
Q

What is protective immunity to CMV associated with?

A

CMV-specific T cells that express IFN-g and IL-2 and have a CD8 early maturational phenotype

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40
Q

What T cells are important for CMV control?

A

Cd8

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41
Q

What protein causes gradual down-regulation of MHC-II in TB infected macrophages?

A

19kDA protein

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42
Q

What is the function of CD4 T cells in TB infection?

A

produce IFN-y and IL-2, maintain CD8 CTL repsonses; inhibit growth in macropahges

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43
Q

What demonstrates that IFN-y is the main macropahge and monocyte activator?

A

IFN-y receptor polymorphisms

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44
Q

What is the function of CD8 cells in TB infection?

A

restrict MTC growth, produce IFNy and TNFa; lyse MTB infected cells

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45
Q

What is the function of IL-2 produced by Th cells?

A

stimulates Th cells and CD8 cells

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46
Q

What is the effect of HIV on TB?

A

increases reactivation of latent TB infection; increases MTB infection and re-infection

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47
Q

What happens to the percentage of T cells specigic to MTB during reconstitution using ARt?

A

decreases (more overall T cells) but a bigger response to TB as actual numbers increase

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48
Q

What is the prognosis of PCP correlated with?

A

markers of inflammation rather than organism numbers

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49
Q

Why was P.carinii cahnged to P.jirovecci?

A

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

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50
Q

What suggest that PCP results from new infection rather than reactivation of latent infection?

A

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

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51
Q

Before the AIDS epidemic, which pateitns got PCP?

A

oncological

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52
Q

What initially suggested that PCP clinical manifestations are the restul of host immune repsonse?

A

PCP occured after cessation of steroids; onset of clinically reocnisable PCP followed engraftment with bone marrow receipients

53
Q

What is thought to be the cause of mortality being much higher in non-AIDs patietns vs AIDs with PCP?

A

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)

54
Q

What suggests that it is not pathogen burden which results in higher mortality in non-AIDs patietns with PCP vs AIDs?

A

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

55
Q

What experiment in mice helped show the importance of the immune response in PCP?

A

SCID mice with PCP demonstrated rapid deterioration and death when infused with functional lymphocytes

56
Q

Which type of Th effector response is capable of protecting afainst PCP?

A

both Th1 nad Th2 - although the consequence of polarisation for the severity of lung injury isn’t known

57
Q

depletion of what type of cell is necessary to make mice susceptible to the developmetn of PCP?

A

Cd4 cells

58
Q

What happens to mice deplted in Cd4 t cells with PCP?

A

develop intense inflammation; hypoxia and decreased dynamic lung compliance- associated iwth TNFa and chemokines; infiltration of Cd8 and neutrophils

59
Q

What happens to mice depleted of both Cd4 and CD8 cells with PCP compared with Cd4 depletion only?

A

dramatically reduced lung inflammation and relatively normal lung function despite having a similar P.carinii burden

60
Q

What is the role of Cd8 cells in PCP?

A

contribute to pulmonary injury but do not have a significant role in clearance of PCP in absence of Cd4s; beneficially suppress the CD4 response

61
Q

What is immune restoration disease?

A

after immune reconstituation, the immune response restored is immunopathoglogical and causes disease

62
Q

What are CD25 postiive T cells?

A

Tregs

63
Q

What are the 3 key cytokines involved in the protection against PCP?

A

IL-1; TNF-a and IFNy

64
Q

What happens when PCP infected SCID mice are depleted of IL-1 or TNFa?

A

when they are reconstituated they are unable to clear PCP

65
Q

What is the function of IFNy in PCP?

A

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

66
Q

What happens in TNFa knock out mice?

A

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

67
Q

Therefore what is the overall role of pro-inflamamtory cytokines?

A

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)

68
Q

What happens when IL-6 is depleted in PCP infected mice after reconstitution?

A

exacerbated inflammatory response

69
Q

What is thought to be the reason that depletion of IL-6 results in increased inflammation?

A

IL-6 downregulates TNF-a which enhances inflammatory responses

70
Q

What is surfactant?

A

am macromolecular complex of lipids and proteins that is responsible for maintaining reduced surface tension in the alveoli

71
Q

Which surfactant proteins are part of the collectin family thorugh their lectin-binding activity?

A

SpA and SpD

72
Q

What happens to mice deficient in Spa or SpD with PCP?

A

enhanced inflammatory repsonse and lung injury as well as increased pathogen coutns

73
Q

What is the alveolar epithelium composed of?

A

type I and type II pneumocytes

74
Q

What is the function of type II pneumocytes?

A

secretory cell in the alveolus and are required for surfactnat, protein and phospholipid production; express PRRs

75
Q

What is hte first event after exposure to PCP?

A

direct activation of type II pneumocytes that results in NFkB activation and release of inflammatory signals

76
Q

What is the course of infection in CD4 depleted patietns with PCP?

A

PCP continues to proliferate and a CD8 dominated response is seen–severe surfactant dysfunction and respiratory failure

77
Q

What suggests that HIV affects innate immune response to P.carinii?

A

reduces the ability of macrophages to respond to P.carinii with NFkB activation and IL-8 secretion

78
Q

When does the clinical disease recognised as PCP manifest after infection?

A

when organism numbers reach a sufficient level to trigger a T-cell driven inflammatory response

79
Q

What happens when CD8 cells are deficient but have CD4 T ells in PCP e.g during IRD?

A

an effective but exaggerated inflammatory response is seen

80
Q

What is the clinical hallmark of PCP?

A

hypoxia nad reduced lung compliance

81
Q

Why would you consider delaying instituion of HAARt in AIDS patient who present with PCP and poor viral control?

A

immune reconstituion can result in IRD and considerable bystander injury to the lung

82
Q

What is thought t be the cause of poor lung function in inflammatory responses?

A

disruption of surfacant activity

83
Q

What are the histological findings in PCP?

A

inflammation; oedema; septal thickening; fibrosis; erosion of type I penuocytes; proliferation of type II pneumocytes (surfactant composition abnormalities)

84
Q

What type of genome does HCMV have?

A

DNA

85
Q

What is the most abundant protein in the matrix of CMV?

A

lower matrix phosphorptein 65 pp65

86
Q

Waht are the 2 functions of the matrix proteins?

A

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

87
Q

What surface receptor does CMV use to access a cell?

A

platelet-derived growth factor a

88
Q

What happens in response to viral DNA release in the nucleus?

A

expression of IE-1/IE-2 genes

89
Q

How can HCMV be transmitted?

A

saliva; sexual contact; placental transfer; breastfeeding; blood transuffsion; solid-organ transplantation or stem cell transplatation

90
Q

What cytokine is thought to be a key mediator in the reactivation of CMV?

A

TNFa by the activation of protein kinase C and NFkB

91
Q

What is the normal course of primary CMV infection in the immunocompetent host?

A

usually asymptomatic, but can resutl in a mononucleosis syndrome indistinguishable from EBV

92
Q

What is the leading cause of infectious deafness ?

A

congenital CMV

93
Q

When is the risk and severity of CMV disease in the baby greatest?

A

if primary infection in a seronegative mother occurs during the ifrst trimester

94
Q

Why does reactivation of CMV during pregnancy have a lower risk of congenital infection?

A

preexisting maternal CMV antibodies ahve a protective role against intrauterine transmission

95
Q

How many HIV patients suffered from CMV disease before HAARt?

A

40%

96
Q

What is the CD4 threshold for CMV in HIV?

A

<100

97
Q

Why does CMV infection remain a problem in HIV?

A

can directly or indirectly accelerate progression to AIDs and death

98
Q

What is CMV retinitis characterised by?

A

haemorrhagic retinal necrosis

99
Q

What is the major target for neutralising antibodies to HCMV?

A

gB (glycoprotein involvedi n cell attachment and penetration)

100
Q

What is the role of natibodies in CMV infection?

A

in guinea pigs, passive immmunisation increased survival but did not prevent infection; reduces transmission to fetuses

101
Q

What is the predominant mechanism by which CMV replication is controlled?

A

cell mediated immunity

102
Q

What is the CTL response directed against during the early CMV infection?

A

antigenic peptides derived from IE-I transcription factor

103
Q

How does CMV evade the immune response against IE-1 protein?

A

matrix protein pp65 can phosphorylate the IE-1 protein preventing its prcoessing and presentation on MHC-I

104
Q

If CMV downregulated MHC-I, how does it evade NK cells?

A

expresses virus-encoded MHCI homologues, upregualtes HLA-E expression

105
Q

What suggested that passively restoring CMV cellular immunity could be successful?

A

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

106
Q

What are some of the strategies for adoptic immunotherapy of CMV?

A

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

107
Q

What was the success of MHC-peptide tetrameric complexes to select CMV-specific T cells from peripheral blood and transfer?

A

resultedi n massive expansion of virus-specific T cells invivo and induced clearacne of active viral replication in 8/9 stem cell transplant patients

108
Q

What mayu be a problem with immunodominance by CMV in elderly population?

A

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

109
Q

Which type of T cell are most important in controlling CMV?

A

Cd8 T cells

110
Q

How many CD8 t cells in the peripheral blood are CMV specific in the lederly?

A

upto 40%

111
Q

What happens to mice depleted of CD4 with CMV?

A

increased incidence of recurrent CMV infection

112
Q

What suggests that there may be a changein the natural history of HIV wit hthe introduction of effective treatmetn?

A

increased CD4 counts at diagnosis of OIs have been noted in several studies

113
Q

Why is there thought to be increased CD4 counts at diagnosis of OIs?

A

there are increased numbers of patients on HAART who live for longer with higher CD4 counts

114
Q

What was the asbolute risk of an OI for patients wtih the same level of immunodefiecency with and wthout HAARt?

A

risk was lower for patients receiving HAART

115
Q

Why has there been an increase in the proportion of HIV patients with non-hodgkins lymphoma?

A

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

116
Q

How many individuals are thought to be latently infected with M.tb worldwide?

A

a third

117
Q

What is the primary role of Th17 cells in M.tb infection?

A

production of IL-17 which attracts and activates neutrophils; monoyctes and Th1 lymphocytes to the site of granuloma formation

118
Q

What happens in m.tb with unrestricted Th17 stimulation?

A

exaggeration inflammation mediated by neutrophils and inflammatory monocytes that are attracted to site of disease causing tissue damage

119
Q

How are Cd8 cells activated in TB?

A

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

120
Q

How are CD4 cells activated in TB?

A

mycobacterial Ags from the phaogosomal compartment are processed onto MHCII

121
Q

How are memory T cells maintained?

A

retention of Ag; stimulation.boosters; homeostatic proliferation

122
Q

What are CCR7+ memory cells named?

A

central memory cells

123
Q

What is the function of Tcm cells?

A

home to secondary lymphoid tissues; produce high amounts of IL-2 but low levels of other cytokines

124
Q

What are CCR7- cells named?

A

effector memory cells

125
Q

what is the function of Tem cells?

A

produce high levels of cytokines; exert rapid effector functiosn and home to peripheral tissues

126
Q

What cluster of differentation is expressed by all memory cells?

A

CD95

127
Q

What is the function of polyfunctional T cells?

A

proliferate and secrete multiple cytokines, play a protective role in antivrial immunity in chronic infections when Ag load is low

128
Q

Give an example of a functional defect in CD4 T cells in TB-HIV coinfection?

A

impaired IFNy production by CD4 cells in repsonse to Mtb Ags

129
Q

What could contribute to the development of active TB in latent infection?

A

impairment of mycobacterial specific T cells

Module 2 (38 decks)

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