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The Immune System Flashcards

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1
Q

what is the immune system?

A
  • integrated system of cells and molecules that defend against disease
  • recognises, reacts against and destroys infectious pathogens
  • can be manipulated by vaccination to protect against disease
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2
Q

how can the immune system malfunction?

A
  • immunodeficiency: rare inherited defect or caused by a disease like HIV
  • allergy: overactivity of immune system e.g. recognising grass pollen
  • autoimmune disease: immune system cannot recognise its own tissues and attacks them
  • graft rejection: tissue transplantation can be rejected as tissue is seen as foreign
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3
Q

what are immunological techniques?

A
  • research

- diagnostics and therapeutics - antibodies e.g. pregnancy tests, treatment of cancer via monoclonal antibodies

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4
Q

what are the 2 branches of the immune system?

A
  1. innate immune system: what we are born with and present in all organisms
  2. adaptive immune system: adapts during lifetime to the different pathogens we encounter
    - evolved 500 million years ago)
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5
Q

what is the overview of the innate system?

A
  • broad specificity
  • no memory: not improved by repeat infection
  • rapid response: hours
  • always ready to act
  • phagocytes and natural killer cells
  • soluble factors: lysozymes (can digest cell wall of gram -ve bacteria), complement proteins and interferons
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6
Q

what is the overview of the adaptive system?

A
  • highly specific
  • memory: improved by repeat infection
  • slower response: days
  • contains B lymphocytes and T lymphocytes
  • antibodies are its soluble factors
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7
Q

what are the cells of the immune response?

A

White blood cells: leukocytes

  • derived from haematopoietic pluripotent stem cells in bone marrow
  • they give rise to 2 main linneages: myeloid cells and lymphoid cells
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8
Q

what are myeloid cells?

A
  • part of innate immune system
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9
Q

what are lymphoid cells?

A
  • part of adaptive immune system, except NK cells which are innate
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10
Q

how does the innate immune system affect the adaptive immune system?

A
  • the innate system helps to initiate and mediate adaptive immune responses
  • adaptive immune system uses elements of the innate immune system to control infection
  • there is interaction between the two systems
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11
Q

what are the external barriers to infection?

A
  1. keratinised skin: keratin protein forms effective, tough barrier
  2. secretions by sebaceous glands: sebum, fatty acids, lactic acid and lysozyme deter growth of pathogens
  3. mucous surfaces:
    - cilia in the respiratory tract waft mucus containing pathogens out the body
    - moist surfaces interact with oxygen
    - mucus traps microbes from reaching tissues
  4. low pH in stomach (pH 2.5) kills microbes
  5. commensals: surface of body is covered by beneficial bacteria/fungi which deter pathogens
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12
Q

what are the 2 types of phagocyte?

A
  1. neutrophils

2. mononuclear phagocytes

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13
Q

what are neutrophils?

A
  • most numerous of the phagocytes
  • contains granules in cytoplasm which contain lysozymes
  • short-lived and fast-moving
  • lysozymes release lysosomes and hydrogen peroxide to kill pathogens
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14
Q

what are mononuclear phagocytes?

A
  • monocyte: found in blood and circulate for 3 days
  • migrate into tissues and develop into macrophage
  • macrophage so is found in tissues, and can engulf 100 bacteria
  • long-lived (months)
  • help initiate adaptive immune responses
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15
Q

what are natural killer cells?

A
  • kill virally infected cells non-specifically
  • only kill host cells, not the pathogens themselves
  • important in self/non-self recognition
  • kill cancer cells
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16
Q

how do phagocytes recognise pathogens?

A
  • they have general pathogen-recognition receptors (PRRs) that recognise microbe-associated molecular patterns (MAMPs)
  • MAMPs are shared by many microbes e.g. peptidoglycan
  • MAMPs are essential for the microbes’ survival and are distinct from our own tissues
  • e.g. Toll-like receptor 4 (TLR4) recognises lipopolysaccharide found in bacteria
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17
Q

how do NK cells recognise pathogens?

A
  • they kill targets unless they recognise self MHC proteins that are present on all nucleated cells
  • when pathogens infect cells, the pathogen interferes with expression of MHC proteins, so NK cells also kill the infected cells too
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18
Q

what are the soluble factors of the innate immune system?

A
  1. complement system
  2. defensins
  3. interferons
  4. cytokines and inflammatory mediators
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19
Q

what is the complement system?

A
  • consists of 20 proteins in the blood which are activated on infection
  • they cause bacterial cell lysis
  • complement antibodies kill pathogens in adaptive immunity, but do not need antibodies to be activated (innate)
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20
Q

what are defensins?

A
  • positively charged peptides made by neutrophils

- insert into membrane of bacterial cells and cause lysis by disrupting the membrane

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21
Q

what are interferons?

A
  • proteins that interfere with viral replication
  • produced by virally-infected cells to protect uninfected cells
  • activate macrophages and NK cells
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22
Q

what are cytokines and inflammatory mediators?

A

soluble factors that are involved in cell-cell communication
- they cause changes in cell behaviour/gene expression

cytokines:

  • hormones e.g. interleukins act between leukocytes
  • produced by cells of innate and adaptive immune systems

inflammatory mediators: e.g. histamine and prostaglandins

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23
Q

what is inflammation?

A

a localised response to infection/damage

  • main 4 symptoms: heat, redness, swelling and pain caused by stimulation of nerve endings
  • infection/damage induces release of inflammatory mediators and production of cytokines
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24
Q

why is the inflammatory response beneficial if it is localised?

A
  • dilation of blood vessels cause redness: increased blood supply so more immunity proteins can reach area of infection
  • swelling caused by increased capillary permeability: fluid can leak from blood to tissues so antibodies or complement can help stop infection
  • phagocytes can migrate into tissues and engulf pathogens that are present
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25
Q

what is the temperature response (fever)?

A
  • on infection, macrophages may release cytokines e.g. interleukin 1 which acts on hypothalamus and causes increase in body temperature
  • some bacteria are very sensitive to temperature so a slight increase by 1C can kill them
  • increased temperature stimulates phagocytosis and lymphocytes
  • reduces iron levels in blood as increased temperature causes iron to bind with iron-chelating proteins (ferritin) so it is less available to bacteria
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26
Q

what drugs inhibit prostaglandins and histamine?

A

aspirin inhibits prostaglandins

antihistamines inhibit histamine

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27
Q

how can pathogen variation cause problems for the immune system?

A
  • pathogens vary in size and rate of reproduction
  • they can evolve quickly, so the immune system must be able to keep up via adaptive immunity
  • some are extracellular, some are intracellular
  • some use tricks to evade the immune system e.g. HIV interferes with T cell immunity
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28
Q

how does adaptive immunity work?

A
  • adaptive responses are slower to develop but show specificity and memory
  • antigen foreign material is recognised by specific receptors on T and B lymphocytes
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29
Q

where do B cells mature and what receptors do they possess?

A
  • B cells mature in the bone marrow and acquire receptors in the bone marrow to interact with antigens
  • these receptors are antibody receptors, and are formed in antigen-independent differentiation
  • once they have differentiated further, they leave the bone marrow and encounter antigen
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30
Q

where do T cells mature and what receptors do they possess?

A
  • T cells mature in the thymus
  • they acquire T cell receptors in antigen-independent differentiation
  • they leave the thymus to encounter antigen
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31
Q

what is antigen-dependent differentiation?

A
  • occurs in lymph nodes, lymph tissue, spleen etc
  • lymphocytes recognise antigen with antibody receptors/T cell receptors
  • B cell secrete soluble antibody in response
  • T cells either kill infected host cells or make cytokines to control the immune response
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32
Q

what is the difference between B cells and T cells?

A

B cells:

  • humoral immunity
  • used against extracellular pathogens

T cells:

  • cell-mediated immunity
  • used against intracellular pathogens such as viruses, bacteria and parasites
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33
Q

how are lymphocyte receptors specific and diverse?

A
  • body produces billions of lymphocytes
  • each lymphocyte has a specific type of receptor, unlike innate cells which have receptors for MAMPs, commonly found on pathogens
  • body is capable of producing millions of different receptors using unique genetic mechanism to keep up with fast-evolving microbes
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34
Q

can B cells and T cells work together?

A

yes: both humoral and cell-mediated immunity work together
- but they are both important in particular types of infection
- memory is developed for both B and T cells, which is the basis for vaccination

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35
Q

what are antibodies and antigens?

A
  • antibodies (anti-foreign bodies) are produced in response to an antigen (antibody generating material)
  • antibodies are made by B cells
  • there are millions of different B cells each with different receptors to recognise different antigen
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36
Q

what is the clonal selection hypothesis (B cells)?

A
  1. when a pathogen has a particular antigen on its surface, a B cell binds to that antigen: clonal selection
  2. B cells begin dividing, and all the daughter cells recognise the same antigen as the parent B cell
  3. B cells differentiate to plasma cells to secrete antibody which bind to the same antigen
  4. the antibody marks the pathogen for destruction
  5. B cells differentiate to memory B cells also which are long living and respond to second infections by dividing to plasma cell and secreting antibody
  6. any B cells that recognise ‘self’ are deleted early in development
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37
Q

how do T cells also undergo clonal selection?

A

same as B cells

  1. clonal expansion
  2. differentiation into killer T cells/cytokine-producing T cells, memory cells

T cells can only recognise antigens bound to our own host cells that have been infected (APCs)

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38
Q

what occurs in primary lymphoid tissue?

A
  • lymphocytes reach maturity and acquire their specific receptors
  • bone marrow (B) and thymus (T)
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39
Q

what occurs in secondary lymphoid tissue?

A
  • mature lymphocytes are stimulated by antigen

- e.g. lymph nodes, spleen, appendix, lymphatic vessels, tonsils

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40
Q

what are antibodies?

A
  • antibodies can be either antibody receptors or soluble antibody proteins
  • antibodies are important in the defence against extracellular bacteria and secondary viral infections
  • they act as labels for infectious material, and labelled material is eliminated
  • they are widely used in research and medicine
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41
Q

what is the basic structure of the antibody?

A
  • they are a class of soluble glycoproteins called immunoglobulins
  • Fab region: antigen recognition site that is variable in sequence and binds to different antigens specifically
  • Fc region: antigen elimination site which is constant in sequence and binds to complementary Fc receptors on phagocytes and NK cells
  • hinge allows Fab arms to move and bind to antigens at varying distances
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42
Q

what is the detailed structure of an antibody?

A
  • 4 polypeptide chains: 2 identical light chains and 2 identical heavy chains
  • chains are linked by disulphide bridges
  • light chains = 25kDa molecular weight
  • heavy chains = 50kDa molecular weight
  • antibodies have molecular weight of 150kDa
  • light chains have 2 domains, heavy chains have 4
  • papain cleaves the hinge region to form a fragment antigen binding (Fab) and a fragment crystallisable (Fc)
  • fragments were produced in ratio 2:1, so antibodies can grab onto 2 antigens at once
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43
Q

what are the constant and variable regions of an antibody?

A

Constant (C) regions: same for antibodies and given a H chain type or an L chain type
- Fc

Variable (V) regions: bind antigen

  • N terminal of light chain and heavy chain
  • differ between antibodies with different specificities
  • Fab

V and C regions are encoded by separate exons

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44
Q

why can variable regions change in sequence?

A
  • multiple variable region exons in the genome can recombine and mutate during B cell differentiation to give different antibody specificities
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45
Q

what are the immunoglobulin classes?

A
  • 5 classes which differ in amino acid sequence of the constant regions of their heavy chains
  1. IgG (gamma)
  2. IgM (mu)
  3. IgA (alpha)
  4. IgD (delta)
  5. IgE (epsilon)
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46
Q

what are IgG (gamma) immunoglobulins?

A
  • main class in serum and tissues
  • important in secondary/memory responses
  • only class of antibody that can cross the placenta
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47
Q

what are IgM (mu) immunoglobulins?

A
  • important in primary responses
  • first kind of antibody that we make
  • pentametric structure when in serum, so can bind to up to 10 antigens
  • high valency
48
Q

what are IgA (alpha) immunoglobulins?

A
  • found in serum and secretions
  • protects mucosal surfaces
  • monomer when in blood
  • dimer when secreted
49
Q

what are IgD (delta) immunoglobulins?

A
  • unknown function
  • may be important in protecting against respiratory infections
  • make up 1% of antibodies in serum
50
Q

what are IgE (epsilon) immunoglobulins?

A
  • present at very low levels
  • protective against extracellular parasites
  • involved in allergy by binding to mast cells
51
Q

what are the two light chain immunoglobulin types?

A
  1. Kappa
  2. Lambda

these are not class restricted e.g. can have IgG (kappa) or IgG (lambda) antibodies

52
Q

what antibodies are involved in the primary immune response?

A

IgM as they can bind to multiple antigens at once

53
Q

what antibodies are important in secondary immune responses?

A

IgG,

- also, but less so IgA and IgE

54
Q

what are the functions of the Fab regions in protecting against infection?

A

Specific binding/multivalency:

  • neutralise e.g. toxins (IgG, IgA)
  • immobilise motile microbes (IgM)
  • preventing pathogens binding to and infecting host cells
  • form complexes: IgM and IgA have high valency
55
Q

what are the functions of the Fc regions in protecting against infection?

A

Effector functions:

  • activate complement: IgG, IgM
  • bind Fc receptors: Phagocytes = IgG, IgA, mast cells = IgE, NK cells = IgG
  • antibodies label pathogen then recruit parts of the innate immune system to eliminate pathogens
56
Q

what is complement?

A
  • immune defence against bacteria and viruses
  • inducer of inflammation
  • 20 serum proteins are activated via an enzyme cascade
  • contents are usually inert but are activated to form enzymes
  • activated specifically by antigen/antibody complexes
  • uses classical pathway or non-classical pathway e.g. certain bacteria (MB-lectin or alternative pathway activated by lipopolysaccharide)
57
Q

what is the order of the major proteins of the classical complement pathway?

A

C1, 4, 2, 3, 5, 6, 7, 8, 9

58
Q

what are the proteins roles in the classical complement pathway?

A
  • many components have protease activity
  • they generate fragments with biological activity:

C3 convertase hydrolyses C3 to C3a and C3b peptides
- a is small peptide, b is big peptide

59
Q

which is the most abundant complement component?

A

C3

60
Q

where are complement components made?

A

liver

61
Q

what is the process of initiation of the classical complement pathway?

A

requires 1 antigen, 2 antibodies, C1, C4 and C2:

  1. activation of complement needs 2 adjacent IgG molecules so that C1 can interact with 2 Fc regions
    - IgM is a more potent activator of complement as it is a pentamer so has 5 Fc regions close together
  2. activation of C1, C4 and C2 leads to generation of C3 convertase
  3. C3b joins the C3 convertase to make C5 convertase
62
Q

what are the 3 major biological activities of complement?

A
  1. activation
  2. opsonisation
  3. cell lysis
63
Q

what happens during activation by complement?

A

Phagocyte recruitment and induction of inflammation:

  1. peptides are cleaved to form C5a and C3a which travel into bloodstream and act as chemoattractants
  2. chemoattractants induce movement of cells along concentration gradient to the site of infection
  3. anaphylatoxins induce inflammation by binding to mast cells and activating them to release inflammatory mediators e.g. histamine
64
Q

what happens during opsonisation of complement?

A
  1. C3b coats bacteria to make them attractive to phagocytes
    - C3b binds to pathogens which are then recognised by phagocytes which have C3b receptors
  2. increased binding and phagocytosis of pathogens
65
Q

what happens during cell lysis of complement?

A

membrane attack complex:

  1. C5-9 are hollow cylinders and form pores in bacterial membranes
    - effective against gram negative bacteria as they lack peptidoglycan layer
    - less effective against gram positive bacteria as their peptidoglycan layer is too thick to penetrate
66
Q

what are effector cells?

A
  • any white blood cell which destroys pathogens
67
Q

how do antibodies activate phagocytes?

A
  • IgG and IgA can act as opsonins

- these antibodies enhance the recognition of microbes by binding to Fc receptors on the phagocyte surface

68
Q

what is the process of phagocytosis?

A
  1. antibodies bound to pathogen form a zipper around the pathogen
  2. phagocyte forms pseudopods which fuse around the pathogen and encapsulate it
  3. vesicle with bacterium inside fuse with lysosomes to form a phagolysosome
  4. phagolysosome contains lysozymes which digest peptidoglycan, lactoferrin which steals iron from bacteria to prevent growth, and reactive oxygen species e.g. H2O2
69
Q

what is the function of NK cells?

A
  • mediate antibody-dependent cell-mediated cytotoxicity (ADCC)
  • virus-infected cells express viral proteins on surface
  • NK cells recognise these foreign receptors and destroy the host cell by apoptosis
  • only IgG antibodies mediate this
70
Q

how do NK cells induce apoptosis?

A
  1. NK cells release perforin which forms pores in membrane of target cell
  2. NK cell secretes enzymes which enter the target cell through the pores
  3. enzymes activate apoptotic pathway of the target cell
71
Q

what are mast cells?

A
  • white blood cells found under mucosal surfaces
  • they recognise infection an mediate allergy defence against large parasites
  • they have receptors that have high affinity for Fc receptors of IgE antibodies
72
Q

how do mast cells function?

A
  1. people with allergies have B cells which bind tightly to Fc receptors on mast cells, so is sensitised to a specific antigen
  2. nothing happens until in contact with the allergen it is sensitised to, which causes cross-linking of receptors
  3. this activates degranulation in which inflammatory mediators are released e.g. histamine to cause local inflammation
73
Q

how are antibodies used in research and medicine?

A
  • antibodies are produced by immunisation of animals to get high levels of IgG against specific pathogens
  • blood is collected from animal, clots, and the serum fluid formed contains antibodies
  • this serum fluid is called antisera

conventional antisera = polyclonal antisera

74
Q

what are polyclonal B cells response to antigen?

A
  • different B cells with different antibody specificities recognise different antigen epitopes

epitope = shape of an antigen that an antibody binds to

limitations:

  • lacks fine specificity as it is polyclonal
  • difficult to standardise
75
Q

what are monoclonal antibodies?

A
  • single specificity
  • derived from single B lymphocytes
  • specific and standardised
76
Q

how are monoclonal antibodies produced?

A
  1. animal is immunised with antigen A
  2. B cells produce antibodies specific to antigen A
  3. B cells are isolated from animal and fused with tumour cell line which can grow indefinitely in tissue culture
  4. production of hybridomas which can make anti-A antibody and divide indefinitely in tissue culture
77
Q

what is the process of using antibodies in diagnostics and therapy?

A
  1. identify and label molecules in complex mixtures
  2. identify pathogens
  3. characterise cell surface proteins and identify cell types
  4. humanised antibodies can now be used in therapy
78
Q

summarised role of different immunoglobulins in humoral immunity:

A
  1. IgM and IgG can activate complement by the classical pathway, leading to opsonisation, inflammation and direct bacterial killing
  2. IgG and IgA: enhance phagocytosis by binding to Fc receptors
  3. IgG promotes antibody directed cellular cytotoxicity (ADCC) by NK cells
  4. IgE is important in mast cell inflammation response and defense against parasites
79
Q

what are T lymphocytes?

A
  • mature in thymus
  • bind to antigen via T cell receptors
  • a single T cell will have a single receptor that recognises a single antigen
80
Q

what are the 2 major subdivisions of T cells?

A
  1. T helper cells: CD4+ -> release cytokines
    - help B cells make antibody
    - activate macrophages and NK cells
    - help development of cytotoxic T cells
  2. Cytotoxic T cells: CD8 +
    - recognise and kill infected host cells
    - specific
81
Q

what is the structure of the T Cell Receptor (TCR)?

A
  • structure is very similar to Fab arm of an antibody
  • 2 chains: alpha and beta
  • each chain is made of 2 immunoglobulin domains
  • one domain is variable in sequence, the other is constant
  • this receptor is always expressed on the T cell, it is never secreted
82
Q

how do T cells recognise antigen?

A
  • they recognise cell-associated, processed antigens on infected body cells (APCs)
  • they recognised Major Histocompatibility Proteins MHCs
83
Q

what are MHC proteins?

A
  • encoded by the Major Histocompatibility gene Complex (MHC) chromosome 6
  • important in graft rejection
  • the most polymorphic proteins in humans: many different alleles at each gene locus
  • major role in initiating T cell responses
84
Q

what are MHC I proteins?

A
  • expressed by all nucleated cells

- display antigen to CD8 + cytotoxic T cells

85
Q

what are MHC II proteins?

A
  • expressed by macrophages, dendritic cells and B cells

- display antigen to CD4 + T helper cells

86
Q

how do cytotoxic T cells recognise peptide bound to MHC I?

A
  1. virus-infected cell contains viral proteins broken down in the cytosol by proteosomes into short peptides
  2. peptides are transported to ER, where they bind to MHC I
  3. MHC I heads to cell surface with the viral peptides
  4. cytotoxic T cells recognise foreign peptide on cell surface
  5. activated cytotoxic T cells kill the infected cell with porins to induce apoptosis
87
Q

how do T helper cells recognise peptide bound to MHC II?

A
  1. macrophage/dendritic cell/B cell internalises and breaks down foreign material
  2. peptides bind to MHC II in endosomes which go to cell surface
  3. activated T helper cells recognise the foreign peptide on the surface, help B cells make antibody and produce cytokines to activate other leukocytes
88
Q

what is thymic selection?

A
  • T cells acquire their receptors and are educated in the thymus in development
  • only T cells that recognise self-MHC but not self-peptides survive
  • only 5% of T cells that enter the thymus for selection are able to leave as immunity cells in peripheral lymphoid tissue
89
Q

what are cytokines?

A
  • small (5-20kDa) secreted proteins involved in communication between immunity cells
  • T cells and other cells can make cytokines
  • usually produced and act locally
  • they are broken down quickly if they aren’t used soon
  • act by binding to specific cytokine receptors on target cells
90
Q

what are the main groups of cytokines?

A
  1. interleukins (IL-1 - IL-38): made my T cells
  2. interferons (IFNs):
    - viral infection IFN alpha, IFN beta made from any cell type
    - cell activation by IFN gamma made by T cells and macrophages
  3. chemokines: cell movement or chemotaxis e.g. IL-8
  4. Colony-stimulating factors (CSFs): leukocyte production e.g. GM-CSF induces formation of neutrophils and macrophages
91
Q

what are cytokine receptors?

A
  • binding of a cytokine to its receptor causes cell activation and changes in gene expression
  • many are dimeric enzyme-coupled receptors
  • chemokine receptors are G-protein coupled receptors
92
Q

what is the overall response of the adaptive immune system?

A
  1. infection by bacterium first recognised by macrophages and dendritic cells in the skin
  2. lymphatic vessels in skin drain lymph to nearest lymph node
  3. bacteria enters lymph node
  4. lymph node contains naive T cells and B cells which can recognise the antigen of bacteria and divide in clonal selection
  5. T cells differentiate into cytotoxic/helper T cells, B cells differentiate to plasma cells to secrete antibody
  6. they leave to enter lymphoid tissues
93
Q

how do the arms of the immune response interact to produce coordinated responses?

A
  • innate system is needed to stimulate adaptive immune system
  • T helper cells produce cytokines which help activation of B cells and phagocytes
  • both responses co-evolved
94
Q

what are the types of vaccine?

A
  • attenuated strains
  • killed pathogen
  • subunit e.g. toxoid (derived from toxin)
  • engineered virus, RNA, DNA
95
Q

what diseases have no effective vaccine produced against them?

A
  • malaria
  • schistosomiasis
  • TB
  • HIV/AIDS
96
Q

what is HIV and AIDS?

A
  • AIDS first recognised in 1981
  • HIV first recognised in 1983
  • HIV is a retrovirus (tumour virus): has association with cancer shown by Peyton Rous
  • HIV attaches to host cells via receptors and injects its genetic material into the host cytoplasm
  • genetic material is 2 copies of ssRNA
97
Q

what is the flow of genetic information in HIV?

A
  • HIV is a lentivirus: slow virus

- retroviruses use reverse transcriptase which transcribes RNA to DNA which integrates into the host chromosome

98
Q

what is the structure of the HIV virion?

A
  • Gp120 viral receptor
  • contains reverse transcriptase enzyme
  • envelope: obtained from the host cell that it infects
  • RNA
99
Q

what is the process of HIV infection?

A
  1. HIV binds to surface proteins on host cell with Gp120
  2. virus envelope fuses with plasma membrane
  3. nucleocapsid containing viral RNA enters cytoplasm
  4. viral RNA is reverse transcribed into dsDNA by reverse transcriptase
  5. viral DNA is transported to nucleus and integrates into host genome via enzyme integrase
    - provirus
  6. viral DNA is transcribed to RNA and mRNA using host machinery
  7. new viral genomic RNA and mRNA go to cytoplasm to be translated to viral proteins
  8. new nucleocapsids form, enclose the viral RNA and virus buds from cell, acquiring the lipid envelope
100
Q

what are the 3 types of retroviral infection?

A
  1. latent: can remain in host cell chromosome as viral DNA
  2. permissive: can produce a few viral particles and shed them
  3. lytic: lots of virus particles are produce, causing host cell to lyse (die)
101
Q

which cells are mostly susceptible to HIV infection?

A

CD4+ T helper cells:

  • Gp120 interacts with CD4 receptors
  • virus is initially cleared, but a pool of infected T helper cells gradually increases
  • t cell stimulation activates HIV provirus transcription
  • leads to lysis of T cells and release of more viruses
  • number of T cells infected increases with each round of viral replication
102
Q

what other cells are susceptible to HIV infection?

A

Monocytes, macrophages and dendritic cells all express CD4:

  • dendritic cells present antigen to T cells in lyphoid tissue
  • infection of dendritic cells is permissive as they act as a reservoir for the virus
  • monocytes may traverse the blood-brain barrier and affect the CNS
103
Q

is CD4 expression sufficient for HIV infection?

A

no:

  • co-receptors: chemokine receptors e.g. CCR5 is required for HIV fusion with host cell
  • may influence susceptibility to infection progression
104
Q

what is the immune response to HIV?

A
  1. initially high levels of virus are cleared via cytotoxic T cells
  2. antibodies to HIV proteins may not be detected for 3 months: seroconversion
    - antibody secretion requires activation by T helper cells, but this is delayed due to T helper cells being infected
  3. immune system mounts a strong response: cytotoxic T cells very important
  4. virus mutates to avoid immune detection by cytotoxic T cells
105
Q

what causes AIDS?

A

T helper cell depletion:

  • direct T cell lysis by virus
  • syncytium formation
  • killed by cytotoxic T cells or NK cells
  • apoptosis

Blood count CD4+ T cells < 200/mm3 = AIDS

infected T cells exist in lymphoid tissue, not blood

106
Q

what are the symptoms associated with AIDS?

A
  • susceptible to pathogens which healthy people would be able to fight off
  • opportunistic infections: TB, parasites, pneumonia, thrush, chicken pox
  • memory T cells are lost
  • all adaptive immune responses are compromised
  • reactivation of latent viruses e.g. chicken pox and herpes
  • rare cancers
  • CNS effected: dementia
107
Q

what is the epidemiology of HIV?

A

HIV-1: Central Africa

  • Group M: pandemic form
  • source: related virus affecting chimpanzees
  • cross-species transmission from 1910-1930
  • proved in 1990 when virus from chimp was almost identical as HIV sequence

HIV-2: West Africa

  • predates HIV-1?
  • source: related virus affecting sooty mangabeys
  • less virulent and less easily transmitted
108
Q

what is the adult prevalence of HIV?

A
  • 38 million infected worldwide at end of 2019
  • > 70 million infected since pandemic began
  • 33 million have died
109
Q

how is HIV transmitted?

A
  • unprotected sex: 70%
  • blood/blood products, mainly drug use: 28%
  • breast-feeding
  • mother to foetus

virus requires direct contact with mucous membranes: not easily transmitted

individuals are most infectious in early stage of disease

110
Q

how can changes in behaviour prevent and treat HIV?

A
  • blood tests
  • use of condoms
  • decrease in drug use and needle sharing
  • treat HIV+ pregnant women
111
Q

how can vaccines prevent HIV infection?

A
  • several vaccine clinical trials to date
  • some failures: recombinant Gp120
  • most recent success: RV144 = pox virus + HIV virus gives 28% protection
112
Q

what are the problems with vaccination for HIV?

A
  • high mutation rate of HIV: 60x greater than flu virus
  • humoral immunity may not be protective
  • needs to induce cytotoxic T cells
113
Q

how can drug therapy help to treat HIV?

A
  • combination therapy: cocktail of drugs directed at different viral targets
  • e.g. AZT, inhibitors of reverse transcriptase, HIV protease inhibitors to prevent capsid formation, fusion inhibitors
  • > 25 licensed drugs block HIV replication
114
Q

what are the problems with drug therapy in treating HIV?

A
  • high mutation rate of virus: multiple drugs needed
  • toxicity: side effects can kill own cells
  • viral latency: hard to target latent viruses in host cells
  • cost
115
Q

how successful have antiretroviral drugs been?

A

By the end of 2019, 67% of HIV+ people were receiving antiretroviral therapy and 59% had suppression of HIV virus

116
Q

what are the future treatments of HIV?

A
  • Stem cell therapy (bone marrow cells lacking CCR5)
  • Immunisation of infected patients and then teat with antiretroviral drugs to kill latent viruses– ‘kick and kill’
  • Passive immunisation using human monoclonal antibodies or engineered T cells
  • Gene editing with CRISPR/Cas9?

Microbiology (8 decks)

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