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Immunology > Exam 3 > Flashcards

Exam 3 Flashcards

1
Q

secondary immune response

A

memory cells respond faster and more strongly upon reencountering the same specific antigen.

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2
Q

Characteristics of memory

A
  1. long lived antibody secreting plasma cells
  2. Memory B cells
  3. Memory T cells
    more memory cells are produced when infection is being resolved.
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3
Q

stromal cells

A

in bone marrow, help support plasma cell survival; give pro survival signals with direct interaction and release of IL-6

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4
Q

B cells in unimmunized primary response

A

IgM, IgG, IgA, IgE— low affinity and low somatic hypermutation

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5
Q

B cells in immunized secondary response

A

IgG, IgA, IgE– high affinity and high somatic hypermutation

downregulated FcR on memory cells

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6
Q

negative activation signal

A

B cell receptor and FcR engagement

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7
Q

hemolytic anemia

A

Frist pregnancy where child is RH pos
- primary response, mostly IgM, low affinity, cannot cross placenta, no disease
Second pregnancy where child is RH pos
-secondary response, IgG, high affinity, crosses placenta, hemolytic anemia in child in RBCs

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8
Q

anti-Rhesus D IgG

A

prevents hemolytic anemia in the newborn by suppression of B cell response
-anti-RhD IgG binds to erythrocytes

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9
Q

orignal antigenic sin

A
  • the response to first infection contrains the response to infection with strain variants
  • highly mutable pathogens such as influenza
  • memory response effectiveness diminishes with each infection
  • fifth exposure elicits a full blown infection and new primary response
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10
Q

Central memory t cells

A
  • L selectin positive
  • CCR7 positve
  • circulate in lymphoid organs
  • stem cell like; can be activated by antigen
  • low activation threshold and high potential for IL-2 production, proliferation and rapid differentiation
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11
Q

effector memory cells

A
  • L selectin negative
  • CCR7 negative
  • circulate in non lymphoid tissues
  • already differentiated; have high levels of effector molecules
  • Express chemokine receptors that enable entry into tissues
  • respond immediately with effector response upon Ag re-encounter but limited proliferation.
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12
Q

Primary response

A
  • small number of pathogen specific cells
  • delay before pathogen-specific antibodies
  • non isotype switched antibody having a mixture of affinities for pathogen is produced at the start
  • high threshold of activation
  • delay before effector t cells are generated and able to enter infected tissues
  • innate immunity works alone until an adaptive responses is generated.
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13
Q

Secondary response

A
  • large number of pathogen-specific cells respond immediately
  • pathogen specific antibodies already present
  • antibodies are isotype switched and have high affinity for the pathogen
  • lower threshold of activation
  • effector t cells are present and can enter infected tisues
  • close cooperation between innate and adaptive immunity from the start
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14
Q

Vaccines and vacination

A
  • exploit secondary/memory immune response
  • started by noticing patterns in reinfection resistance
  • Edward Jenner innoculated with cowpox to induce resistance to small pox
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15
Q

Variolation

A

introduction of a small lesion material to prevent small pox

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16
Q

Basis for vaccination against smallpox

A
  • cowpox and smallpox share some of the same surface antigens
  • immunization with cowpox induces antibodies against cowpox surface antigens
  • cowpox antibodies bind to and neutralize the small pox viruses
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17
Q

Success of smallpox vaccination

A
  • virus evolves slowly
  • vaccination involves a live virus (local infection and viral proliferation provides strong stimulus of immunity)
  • humans are the only host of small pox, no animal reservoirs
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18
Q

Two major types of vaccines

A
  1. Killed/inactivated virus vaccines

2. live-attenuated vaccines

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19
Q

Kill/ inactivated virus vaccines

A
  • virus inactivated by chemical, heat of irradiation
  • large amounts of pathogen necessary to produces
  • not as effective as live vaccines because there is no infection
  • do not cause any ill effects
  • Ex; rabies and influenza
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20
Q

Live-attenuated vaccines

A
  • some limited infection and viral replication stimulates an immune response
  • possibility for some level of virulence
  • Ex: measles, mumps, and some flu (mist)
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21
Q

Making live/attenuated vaccines

A
  • pathogenic virus is isolated from a patient and grown in culture
  • virus used to infect monkey cell
  • acquires variety of mutations that allow it to be specific to monkeys
  • no longer grows well in humans and can be used in vaccines
  • loses it’s virulence in humans
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22
Q

Vaccination against polio

A
  • inactivated vaccine given by injection
  • oral vaccine was more effective; stimulation of mucosal immune response at site of natural infection
  • both have three strain variants.
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23
Q

Complications of polio vaccine; disease and social

A
  • reversion to virulent polio
  • vaccination programs disrupted by extremists
  • civil war in Syria caused a local resurgence of polio
  • the virus flourishes in areas of human conflict
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24
Q

Vaccines against bacteria and their products

A
  • not very many live-attenuated bacterial vaccines in use
  • BCG- vaccine against TB derived from cattle strain. not very effective
  • vaccines against toxins secreted by bacteria. work by stimulating neutralizing Ab. (diptheria toxin, tetanus toxin)
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25
Q

Conjugate vaccines

A
  • elicit TFH responses to promote potent B cell responses
  • Carbohydrate Ag is linked to a protein Ag
  • through linked recognition, t cells provide help for b cell response
  • meningitidis vaccines used to use pure carb and was not effective.
  • new vaccine is more effective because of carb conjugation to a protein Ag
  • TFH response now incorporated
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26
Q

adjuvants boost the effectiveness of vaccines

A
  • act by stimulation innate immune response
  • mixed in with the protein Ag to boost immunogenicity
  • provide danger signals triggering upregulation of CD80/CD86 (costim) on DC and other cells that promote t cell activation
  • many adjuvants in development are TLR ligands
  • risk of inflammation damage
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27
Q

Microbial substances act as adjuvants

A
  • induce costim activity in macs and DC
  • nonbacterial antigen: do not deliver costim, induce anergy
  • bacteria: stimulate macs to deliver costim to t cells for proliferation
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28
Q

forward vaccinology

A
  • isolate organism
  • inactivate but preserve immunogenicity
  • inject into experimental animals and test for protection
    • most vaccines today uses this approach
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29
Q

reverse vaccinology

A
  • genomic sequencing of pathogen
  • identify candidate antigens using bioinformatics
  • produce purified antigen and use as an immunogen
  • -does not require any preexisting knowledge of the pathogen
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30
Q

Neisseria menigngitidis

A

-bacterial lipoprotein binds factor H and inactivates C3b deposit on the bacterial surface

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31
Q

Neisseria meningitidis vaccine

A

-specific anti fHbp cannot bind fHbp complement is fixed and the bacteria can be killed

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32
Q

fHbp

A
  • factor H binding protein
  • neisseria protein identifed by DNA sequencing
  • binds specifically to human factor H. used to inactivate C3b component on bacteria
  • vaccine interferes with this so bacteria can be killed by complement
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33
Q

case of influenza virus

A
  • replication is error prone, very high rate of mutation resulting in many different strains
  • consquently vaccines quickly become ineffective
  • antibody response mainly to hemagglutinin (H) and neuraminidase (N)
  • 16Hs and 9N
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34
Q

pandemic

A

affecting the entire country of world

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35
Q

epidemic

A

localized disease outbreak

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36
Q

herd immunity

A

if majority of population are vaccinated, the few that are not vaccinated are protected because of lack of susceptible host to maintain reservoir of infection

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37
Q

no effective vaccines against pathogens that cause chronic disease

A
  • vaccines work against pathogens that can normally be confused by IS
  • pathogens that cause chronic do not elicit effective immunity
  • many have mechanisms to suppress immunity
  • antigenic variation can interfere with immunity and vaccination
  • parasitic diseases difficult to vaccinate against due to complexity and the fact that they are closely related to us
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38
Q

Two lineages with characteristics and innate and adaptive

A

natural killer cells and delta gamma

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39
Q

Three theories of evolution of innate and adaptive immunity

A
  • with emergence of adaptive immunity, innate immunity stopped evolving
  • independent evolution of both
  • coevolution of both
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40
Q

NK cells: antibody-dependent cellular cytotoxicity (ADCC)

A
  • anti CD20 Ab binds to CD20 on surface of B cell lymphoma
  • Fc receptors on NK recognize bound anti CD20 Ab
  • cross-linked Fc receptors signal NK cells to kill the B cell lymphoma cell
  • B cell lymphoma cell dies by apoptosis
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41
Q

Natural Killer cell function

A
  • kill virally infected cells and secreted IFN-gamma
  • virus triggers interferon response
  • type 1 interferon drives proliferation of NK cells
  • NK differentiate into cytoxic effector cells
  • induce apoptosis in apoptosis
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42
Q

Differences between CD8 and NK cells

A
  • NK cells do not undergo gene arrangement
  • CD8 are only activated by a specific Ag and NK express a variety of activating and inhibiting receptors
  • NK cells leave the bone marrow ready to function
  • NK cells are a primitive lineage of lymphocyte like cells.
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43
Q

Similarities between CD8 and NK cells

A
  • use perforin/granzymes to kill

- secrete IFN-gamma

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44
Q

Activating and inhibitory receptors of NK cells

A
  • NK cells express many molecules expressed by T cells (not TCR, CD3, CD4, CD8)
  • killing activity similar to CD8
  • no gene arrangement to make Ag specific receptors
  • they express a large panel of activating and inhibiting receptors
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45
Q

NK mixed receptors

A
  • 30 different activating and inhibitory
  • each individual NK cell expresses a subset of these
  • all express inhibitory receptor for self MHC1
  • all express CD56
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46
Q

First way to activate NK cell

A
  • signals from two or more activating receptors required
  • CD48 binds to 2B4, MIC binds with NKG2D
  • during an innate response, this helps ensure that inappropriate activation does not occur
  • ligands on target cells often induced in response to stress
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47
Q

Second way to activate NK cell

A
  • In presence of IgG, the Fc receptor can activate without another receptor
  • FcR acts as a bridge between adaptive and innate
  • during adaptive immune response, antigen-specific Ab provides specificity to the NK cell response
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48
Q

Co evolution of innate and adaptive immunity

A
  • NK cells have acquired Fc receptor to work with B cell response
  • NK cells have acquired receptors for MHC class I
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49
Q

NK cell recognition of MHC class I

A

-HLA-E and HLA-G

50
Q

oligomorphic

A

-a small number of different alleles

51
Q

NK cells express receptors for MHC 1 and MHC 1-like molecules

A

-inhibitory recognize MHC1
-activating recognize MHC1-like
-

52
Q

CD94: NKG2A

A

dimer that delivers an inhibitory signal to the NK cell

  • ligand is HLA-E which has preferential specificity for bound peptides from HLA-A, B, C
  • amount of HLA-E is a measure of amount of MHC1 being synthesized
  • healthy cells express high MHC 1, unhealthy cells produce less
53
Q

NK cell activation requires release from inhibitory and activating signal

A
  • interaction of HLA-E with CD94:NKG2A prevents NK cell from attacking healthy cell
  • unhealthy cell lacks HLA-E and expresses MIC, this engages NKG2D in combo with 2B4 and activates
54
Q

MIC

A

glycoproteins resemble MHC class I heavy chain molecules (do not bind peptides)

  • classified as stress proteins that are only expressed in sick or infected cells
  • engagement by NKG2D in combination with another activating receptor activates Vav if there is no inhibitory signal
55
Q

Killer cell immunoglobulin like receptors (KIRs)

A
  • another way to monitor MHC1
  • CD94:NKG2A is used as a measure of totatl MHC1 on the cell surface
  • KIR recognize haplotype specific MHC
  • enables monitorying of decreases in expression of specific MHC loci or allotypes which can happen in infected cells and tumors
  • function through combined activity of activating and inhibitory receptors
56
Q

Education of NK cells

A
  • education towards self reactivity occurs in bone marrow
  • CD9;NKG2A is expressed first
  • KIR expressed from bi-direction promotors in which forward txn=gen expressine and reverse=permanent gene splicing
  • this is a random process and generates an NK population having diverse but stable KIR expression profiles
57
Q

Expression of CD94;NKG2D and KIR’s is controlled during development

A
  • immature first express CD94:NKG2A and then express KIR
  • no expressed KIR reacts with self MHC class I CD94NKG2A is retained
  • an expressed KIR reacts with self MHC1; CD94: NKG2A is not retained
58
Q

Balance of receptors set in bone marrow

A
  • immature in bone cells express inhibitory KIR that recognizes self HLA-C
  • signaling from activating receptors
  • educated NK cell leaves the bone marrow and enters the circulation
  • NK cell encounters a healthy cell and inhibitory receptor is engaged
  • encounters an unhealthy cell and activating receptors are engaged
59
Q

Evidence for pathogen driven NK cell responses

A
  • CMV is common infection in humans
  • humans have coevolved with CMV
  • CMV suppresses CD8 T cell responses by preventing presentation of viral peptides
  • MHC class I downregulated on infected cells-susceptibleto NK killing
  • expansion of NK cells with CD94: NKG2C- activating receptor recognizing HLA-E
  • evolutionary adaptation to deal with reoccuring CMV infections in individuals and over generations
60
Q

Inhibitory and activating signals

A
  • If inhibitory binds with MHC– cell lives
  • if inhibtory binds MHC and activating binds stress ligand– cell lives
  • if activating binds with stress ligands– cell dies
61
Q

gamma delta t cells

A
  • development similar to alpha beta
  • nature of antigen recognized very different
  • do not use CD4 and CD8 in the same way
  • their function is unclear
  • found in high numbers in peripheral tissues like the intestine
62
Q

Main differences of gamma delta

A
  • small
  • most dont have CD4/8.. some have CD8aa
  • self proteins resemble MHC, non peptide presented by MHClike
  • present in tissues in a form that’s quick to respond
  • involved in tissue homeostasis, surveillance, protection, and repair
63
Q

Gamma delta before birth

A

-produced in waves to go to skin, uterus, lungs, lymph nodes, and intestines

64
Q

development of gamma delta

A
  • precedes alpha beta
  • restricted patterns of v genes; evolved to recognize specific ag
  • specific set of cytokines produced by each tissue subset
  • after birth, produced in greater diversity
65
Q

Vy9Vd2

A
  • recognize phosphoantigens based on diversity generated by VDJ recombination
  • isopentenyl pyrophosphate is a phosphoantigen that is made in large amounts by bacterial pathogens and stressed cells
  • hydroxymethyl-but-2-enyl pyrophosphate is expressed by bacteria and some parasites
66
Q

phosphoantigens presented by BTN3A1 to gamma delta

A

-infecting bacteria produce HMBPP, binds to 3A1 on a tissue cell and is presented to Vy9Vd2 receptor to activate

67
Q

BTN3A1

A
  • similar to B7 costim, expressed by many types of cells

- no need for costim to activate gamma delta

68
Q

CD1

A

-MHC 1 like
-expressed with beta 2 microglobulin
-binds self and bacterial glycolipids
-

69
Q

CD1d

A
  • presents glycolipid ag to VyVd1 T cells
  • Vy can be any y chain
  • lipid recognized and bound by Vd1
70
Q

VyVd1 location

A
  • found in lamina propria and intraepithelial region of intestine
  • may be inloved in intestinal homeostasis and tissue repair
  • CD1d can be endocytosed and self lipid can be exchanged for internalized bacterial lipid
71
Q

intertwining of innate and adaptive properties

A
  • gamma delta are closely related to conventional T cells
  • however, vast receptor diversity is not generated during development
  • limited rearrangement to generate specific, predetermined specificities
  • receptors are like pattern recognition of innate
  • yet they are generated by mechanisms of adaptive immunity
72
Q

aB t cells restricted by nonconventional MHC like molecules

A
  1. some aB recognize lipid ag presented by CD1a/b/c
  2. NKT cells limited TCR specificity, recognize lipids/CD1d and express surface molecules usually associated with NK and T
  3. MAIT have limited TCR specificity and recognize small organic molecules presented by MHC1 like MR1
73
Q

MAIT

A

mucosa-associated invariant t cells

74
Q

CD1a/b/c restricted aB t cells

A
  • important in response to mycobacterial lipids
  • CD1 restricted T cells can be either CD4/8
  • diverse TCR
  • CD1a-c expressed by professional APC which are targets of mycobacterial infection
  • selected in the thymus by DP thymocytes
75
Q

NKT cells

A
  • can be CD4/8
  • recognize lipids bound to CD1d
  • restricted TCR composed of V and J genes
  • the restricted TCR makes them reminiscent of an innate immune receptor
  • Activation is rapid
  • NKT cells can produce IFN-y and IL-4
76
Q

MAIT info

A
  • present in mucosal tissues esp lung and liver
  • TCR restricted V and J chains
  • MAIT cells recognize small heterocyclic organic molecules made by bacteria and fungi during riboflavin synthesis
  • presented by the MHC1 like molecule MR1
  • positively selected in the thymus by MR1-expressing DP thymocytes
  • kill bacteria through unknown mechanism
77
Q

MAIT cell differnatiation

A
  • depends on exposure to microbiota
  • accompanied by proliferation
  • rare at birth but accumulate with age and express T memory phenotype
  • DC cells present metabolite pterin on MR1 to the MAIT T cell receptors
78
Q

Genetic Immunodeficiency diseases

A
  • Extend of primary immunodeficiency diseases was not appreciated until advent of antibiotics
  • before, high rate of infant mortality due to obscured underlying inherited defects
  • approx 200 known
  • can be dominant, recessive, x linked
  • most caused by recessive mutations– dominant tend to be less serious
79
Q

Mannose binding lectin deficiency

A

Results in susceptibility to Neisseria menigitidis

80
Q

Ommen syndrome

A
  • no functional RAG1 or RAG2
  • inability to recombine antibody and T cell receptor gene segments
  • T and B cell development halted
  • Susceptible to many infections
81
Q

Lack of function AIRE

A
  • widespread autoimmune disease
  • transcription factor in thymine medulla epithelial cells– usually induces low amount of tissue specific ag to test T cell autoreactivity
  • without; can result in polyendocrinopathy candidiasis ectodermal dystrophy (APECED)
82
Q

Lack of FoxP3

A
  • autoimmunity and inflammation
  • FoxP3 is transcription factor in making Treg cells
  • IPEX syndrome: immunodysregulation, polyendocrinopathy, enteropathy xlinked syndrome
  • deficiencies can be polysymptomatic because factors like foxp3 are used for more than one function
83
Q

X lined affammaglobulinemia (XLA)

A
  • x linked defect in Bruton’s tyrosine kinase which is required in B cell development
  • -Bruton’s’ tyrosine kinase transmits signals from the pre B cell receptor
  • susceptibility to encapsulated bacteria that are normally controlled by opsonizing Ab
84
Q

Evolutionary arms race; red queen hypothesis

A
  • IS has evolutionary pressure to recognize essential components of invaders
  • infectious organisms have evolutionary pressure to escape recognition under the constraint of function
85
Q

Inducing strain specific antibodies

A
  • way to defeat immune response
  • Strepptococccus pneumoniae
  • 90 distinct strains or serotypes
  • differ in the structure of their antigenic polysaccharide capsule
86
Q

Influenza virus– antigenic drift

A
  • protective immunity conferred ab response to hemagglutinin and neuraminidase on the viral envelope
  • RNA virus with eight RNA molecules compromising the genome
  • replication is prone to error making mutation and emergence of new strains a commone phenomenon– antigenic drift
  • when it goes to epidemic, relatively mild symptoms and rapidly subsides
87
Q

Antigenic drift causes flu outbreaks every year

A
  • neutralizing ab binding to H prevents virus V from infecting cells of person P
  • while infection person Q virus V mutates give virus V with altered H
  • Virus V infects infects person P because Ab made against V does not neutralize V
88
Q

Flu pandemics

A
  • occur when widely disparate flu strains re as sort genetic material in common host to generate new strain
  • reassortment in pigs
  • this is called antigenic shift
89
Q

African trypanosomes

A
  • use antigenic variation to escape immune response
  • African sleeping sickness
  • after blood phase, enters CNS and disrupts sleep cycle
  • transmitted in tsetse fly
90
Q

T. Brucei

A
  • covered in a surface coat of VSG (variant surface glycoproteins) that triggers a strong ab response and periodically changes to escape immune response
  • other pathogens use this strategy
  • -malaria, salmonella typhimurium, Neisseria gonorrhoeae
91
Q

VSG expression

A
  • controlled by gene conversion
  • only one VSG expressed at a time
  • genes are copied into active site randomly at about 1/10e5
  • only one can be in expression site at a time
  • this is called gene conversion
92
Q

Consequences of VSG antigenic variation on the host ab response

A
  • ab controls the parasite
  • ab also form immune complexes and inflammation contributing to neurological damage, coma, death
  • ab control is only effective until a switch is made
93
Q

Herpesvirus persist in the host by hiding from the immune response

A
  • neurons are a good place to hide, have low levels of MHC 1
  • reactivation cause by stress, hormonal changes, sun
  • during reactivation, virus leaves neuron and reinfects epithelial cells
  • can occur over and over
  • herpes varicella zoster (chicken pox) does similar things– shingles
  • if you’re a pathogen the brain is a good place to go because it is an immunopriviledged site (immune cells are generally blocked fro entering)
94
Q

When host defense fails

A
  1. Inherited diseases of the immune system
  2. how pathogens escape or subvert the immune system
  3. acquired immunodeficiency (HIV/AIDS)
95
Q

Sabotage and subversion

A
  • many viruses target the MHC class I presentation pathway to subvert the CD8 T cell response
  • viral evasins U56 and ICP 47 block antigen presentation by preventing peptide movement though the TAP peptide transporter
  • adenovirus protein E19 competes with tapasin and inhibits peptide loading onto nascent MHC class I proteins
  • Cytomegalovirus protein US11 in conjuction with derlin causes dilocation of nascent MHC1 molecules back into the cytosol for degradation
96
Q

Evasin

A

protein that interferes with MHC class I presentation

97
Q

US6

A

cytomegalovirus

98
Q

ICP47

A

herpes simplex virus

99
Q

derlin

A

ubiquitous ER membrane protein. involved in recognition of misfolded protein in ER and translocation into cytosol for degradation

100
Q

Mycobacterium tb sabotage

A

enters macrophages by phagocytosis and blocks the phagosomal-lysosomal fusion pathway

101
Q

Listeria monocytogenes and mycoplama marinum sabotage

A

enters through a macrophage phagosome but escapes into the cytoplasm

102
Q

Bacterial superantigens

A
  • Staphylococcal enterotoxins (SEA, SEB, SEC) secreted by staph aureus
  • cause of many foodborne illness
  • superantigens bind to VB chain of aB t cell receptor and cause widespread T cell activation and cytokine overproduction
  • activate large families of CD4 cells based upon common VB gene
103
Q

In vivo effects of superantigen

A
  • jamming the immune system in overdrive followed by burn out
  • high IL2 has systemic effects/toxic shock
  • followed by activation induced apoptosis and immunosuppression
104
Q

strategies for dealing with the immune system

A
  • be a moving target: antigenic drift/shift/variation
  • location
  • subvert specific immune functions: MHC class I presentation
  • confuse host defense by turning everything on at once
105
Q

Acquired immune deficiency syndrome (AIDS)

A
  • first described in 1980s
  • major reduction of CD4 t cells
  • severe infection by normally innocuous pathogens
  • kaposi’s sarcoma
  • b cell lymphoma
  • Caused by HIV 1 and 2
106
Q

HIV 1

A
  • most prevalent type

- from chimpanzees

107
Q

HIV 2

A
  • less virulent, causes slower progression to AIDS. Endemic in West Africa and Asia
  • from sooty mangabeys
108
Q

Nature of HIV

A
  • a retrovirus which is an RNA virus that integrates its nucleic acid into host cell genome
  • RNA is reverse transcribed into DNA
  • Incorporates into genome as a provirus
  • HIVE is a type of retrovirus that causes slow progression (lentivirus)
  • cannot be eliminated by host immune response
  • lethal once AIDS
  • exogenous retrovirus
109
Q

endogenous retroviruses

A

-there are some that have permanently integrated into our genome (about 8% of genome)

110
Q

LTR

A

long terminal repeats that HIV uses to integrate into the genome

111
Q

HIV receptors, co receptors and relation to disease pathogenesis

A
  • Viral gp120 binds to CD4
  • HIV infects CD4 t cells, macrophages and DCs because in humans they all express CD4
  • Viral gp41 mediates evelope and host membrane fusion
  • co receptor is also required for entry– chemokine receptors (CCR5 and CXCR4) form part of the complex along with CD4 that binds to gp120
  • variant strains differ in use of co receptors
112
Q

Variant 1 HIV

A
  • CD4 and CCR5
  • macrophage tropic
  • infect macrophages, DC and nonactivated CD4 t cells (CCR5)
  • first cells to be infected in mucosal tissue
  • responsible for disease spread
113
Q

Variant 2 HIV

A
  • CD4 and CXCR4
  • lymphocyte tropic
  • infect activated CD4 t cells (CXCR4)
  • rapid decline in CD4 t cells and progression to full blown AIDS
114
Q

Life cycle of HIV

A
  • virion binds to CD4 and coreceptor on T cell
  • viral envelope fuses with cell membrane and viral genome enters cell
  • reverse transcriptase copies viral RNA genome into ds cDNA
  • viral cDNA enters nucleus and integrates into host DNA
  • t cell activation induces some transcription of provirus
  • RNA transcripts are spliced to allow synthesis of the early proteins Tatand Rev
  • Tat amplifies transcription of viral RNA rev increases transport of RNA to cytoplasm
  • Gag, pol, and env are made and assemeled with viral RNA into virions which bud from the cell
  • t cell activation causes emergence of virus from genome due to transcription factor NFKB
115
Q

Changes in CD4 T cell numbers during HIV infection

A
  • onset of protective immune response (ab, CD8, CTL)
  • CD4 t cells rebound temporarily
  • viremia (virus particles in blood) declines to low or undetectable levels
116
Q

Tragic collision of the US hemophilia population and HIV population

A

At the beginning of AIDS epidemic the blood supply became contaminated with HIV
•A huge number of hemophiliacs (50%), whose blood does not clot and who must receive regular
blood transfusion, were inadvertently infected with HIV. Thousands died.
•The data here show that if you have HIV you inevitably progress to AIDS (without appropriate
intervenKon)

117
Q

Genetic determinant of susceptibility to AIDS

A
  • there is a naturally occurring CCR5 deletion mutant in the Causcaian population
  • CCR5 d32- 10% population is heterozygous 1% is homozygous
  • homozygotes are resistant to HIV
  • high frequency of deletion mutant suggest it has served some important function in the past
  • evidence based on DNA mutations surrounding deletion that it occurred relatively recently
  • timing frame puts emergence at a time when the plague and smallpox were high in Europe– high selective pressure
118
Q

HIV leads to loss of CD4 T cells and susceptibility to infection

A
  • initially production of CD4 maintains stability but eventually CD4 T cell numbers collapse
  • leads to immune deficiency and susceptibility to infection
119
Q

opportunistic pathogens that kill AIDS patients

A
  • many of these are commensal microbes that healthy individuals spend their lives with little to no ill effect
  • before AIDS, many of these infections were rare and not well known
  • ultimately the pathology caused by multiple infections, HIV itself, and various medical interventions is a lethal combination
120
Q

Treatment of HIV infection

A
  • drugs to treat HIV target virus reverse transcriptase and the protease that cleaves viral polyproteins
  • in a patient treated with a single drug, the antiviral effect is limited because the drug selects for drug resistant variants present in the population
  • better success with combination of drugs this is called highly active anti retroviral therapy (HAART)
  • idea is to hit the virus hard at multiple sites so that even variants are targeted.
121
Q

HAART mechanism of action

A
  • HAART drugs prevent new infection. They do not treat infection in cells themselves (in which virus has integrated into host cell)
  • because activated CD4 cells are short lived, virus must constantly reinfect new cells
  • antiviral drugs work fast
  • long lived infected cells (macs, DCs, Memory T) persist
  • HAART must be maintained for the life of the infected individual
122
Q

Broadly neutralizing antibodies as a wat to treat HIV

A
  • gp120 is a promising target (binds to host receptor)
  • some people over time generate a broadly neutralizing antibody response effecting against multiple variants of HIV
  • broadly neutralizing antibody have gone through multiple rounds of somatic mutation
  • some of these are polyreactive. They are composed of different antibody fine specificities that bind to different antigenic determinants, favoring efficiency in cross linking

Immunology (4 decks)

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