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4 - Y5 a Path lectures 2021/22 > Immuno 2: HIV Infection (& secondary causes of immunodeficiency) > Flashcards

Immuno 2: HIV Infection (& secondary causes of immunodeficiency) Flashcards

1
Q

What are the strains of HIV that can cause infection?

A
  • HIV-1
  • HIV-2
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2
Q

What is the difference in virulence between HIV-1 and HIV-2?

A

HIV-2 is less virulent and harder to transmit

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3
Q

Name some retroviruses

A
  • HIV-1
  • HIV-2
  • HTLV-1 to 4
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4
Q

Explain how HIV replicates

A
  • Genes = RNA molecules
  • Replicates inside a cell using Reverse Transcriptase (RT) to convert RNA to DNA to be integrated into the host genome
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5
Q

Describe the structure of HIV

A
  • HIV has an icosahedral (20-faced) structure
  • Genome is diploid
  • Contains 9 genes (i.e. env, gag, pol) that encode 15 structural, regulatory and auxiliary proteins
    • I.E. gp120, gp41 and RT
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6
Q

Which cells does HIV target?

A
  • CD4+ T-helper cells, (esp in the gut)
  • CD4+ monocytes / MO,
  • CD4+ dendritic cells / DC
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7
Q

Describe how HIV targets cells

A
  • HIV uses host CD4+ cells to replicate and move from cell to cell –> changes the function of these cells
    • These are critical to mount a full immune response, hence the critical failure & AIDS
    • You will also lose immune memory as the memory T-cells are depleted
  • This leads to a selective loss of CD4+ T helper cells
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8
Q

Which cells are necessary for protection from HIV?

A
  • Antibodies (B cells) to prevent infection and neutralise the virus
  • Sufficient CD8+ T cells to eliminate latently infected cells
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9
Q

Describe the HIV-1 receptor and co-receptor

A
  • HIV-1 receptor and co-receptor:
    • Receptor = CD4 molecule/antigen
    • Co-receptor (most strains require) = CCR5 or CXCR4
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10
Q

How is HIV transmitted?

A
  • Sexually – through mucosa (esp. damaged sites / MSM), infects CD4+ cells (inc. CD4+ DC) which carry virus to LN
  • Infected blood – transfusion, needle sharing, blood products
  • Vertical (mother to child) – ante-/intra-partum, breastmilk
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11
Q

How long does natural immunity to HIV take to be mobilised?

A

mobilised within hours of infection

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12
Q

What does natural immnity to HIV involve?

A
  • Inflammation
  • Non-specific activation of macrophages, NK cells and complement
  • Release of cytokines and chemokines (i.e. those made by NK cells can reduce infection of CD4+ T-cells by HIV)
  • Stimulation of plasmacytoid dendritic cells (pDC) by toll-like receptors (TLRs)
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13
Q

Which cells are involved in acquired immunity?

A

Antibody and B cells

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14
Q

Describee acquired immunity to HIV

A
  • Anti-gp120 and anti-gp41 (Nt) antibodies are important in protective immunity
  • Non-neutralising anti-p24 gag IgG are also produced
  • HIV remains infectious even when coated with antibodies
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15
Q

What is the role of CD4+ T cells / AKA Th-cells in the immune response to HIV?

A
  • Usually recognise processed antigens (especially Gag p24 peptides) in the context of MHC class II molecules
  • Important in the coordination of the immune response (i.e. long-term maintenance of CD8+ t-cell response)
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16
Q

What is the role of CD8+ T cells in the immune response to HIV?

A
  • Able to suppress viral replication – can kill HIV-infected cells or other cells that have become malignant
  • Secrete soluble molecules (i.e. cytokines/chemokines) to prevent infection by blocking entry to CD4+ T cells
  • Recognise processed antigens in the context of MHC Class I
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17
Q

Summarise the effects of HIV on body cells

A
  • Activated infected CD4+ helper T cells die and are lost
  • Infected CD4+ T cells are also disabled (ANERGISED) by the virus:
    • MO/DC are not activated by the CD4+ T cells and cannot prime naïve CD8+ CTL
    • CD8+ T cell and B cell responses are diminished without help
    • CD4+ T cell memory is lost
  • Infected MO/DC are killed by virus or CTL:
    • Defect in antigen presentation
    • Failure to activate memory CTL
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18
Q

During the replication of HIV, in which 2 steps can errors occur?

A
  • Reverse Transcriptase (RNA to DNA) – lacks proof-reading mechanisms from cellular DNA polymerases
  • Transcription of DNA into RNA copies
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19
Q

What is the clinical significance of errors in HIV replication?

A
  • means that HIV can accumulate a lot of mutations with numerous variants or quasispecies
  • can lead to HIV gaining advantageous features
    • Escape from neutralising antibodies
    • Escape from HIV-1 specific T cells
    • Resistance and escape from antiretroviral drugs
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20
Q

Describe the life cycle of HIV

A
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21
Q

Name some therapy targets within the life cycle of HIV

A
  • Attachment (Attachment Inhibitors / AI)
  • Fusion (FI)
  • Reverse transcription (RTI)
  • Integration of viral DNA into host (INI)
  • Transcription of DNA to viral RNA
  • Translation of viral RNA to produce viral proteins
  • Viral protein cleavage by proteases (PI)
  • Assembly and budding of new HIV
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22
Q

Name the suffixes of HIV therapies, and what they inhibit

A
  • -gravir = Integrase Inhibitor
  • -avir = protease inhibitor
  • -ines = NRTI (nucleotide reverse transcriptase inhibitor)
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23
Q

Describe the clinical course of HIV disease

A
  • Median time from HIV infection to development of AIDS = 8-10 years
  • Viral burden predicts disease progression
    • Rapid progressors (10%) will take 2-3 years (these are mainly seen in Africa)
    • Long-term non-progressors (LTNP < 5%) will have stable CD4+ counts and no symptoms after 10 years
    • Exposed-seronegatives (ESN) are people who are repeatedly exposed to HIV but do not seroconvert
    • Elite Controllers (EC) can suppress the viral replication
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24
Q

Which therapy can greatly improve the prognosis of HIV infection

A

HAART (Highly Active Antiretroviral Therapy)

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25
Q

Describe how the numbers of these cells change over the course of HIV infection:

  • CD8+ lymphocytes
  • CD4+ lymphocyte
  • plasma viral load (amount of HIV cells)
A
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26
Q

Summarise the % of HIV infection that are typical, rapid and long-term non-progressors, and their respective times taken to progress into AIDS

A
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27
Q

Summarise the host genetic factors that allow long-term-non-progressor infections to occur

A
  • HLA profile (slow progressor)
  • Heterozygosity for 32-bp deletion in chemokine-r CCR5
  • MBL alleles
  • TNF c2 microsatellite alleles
  • Gc vitamin D-binding factor alleles
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28
Q

Summarise the host immune response factors that allow long-term-non-progressor infections to occur

A
  • Effective CTL, HTL and humoral responses
  • Secretion of:
    • CD8 antiviral factor
    • IL-16
    • Secretion of chemokines that block HIV entry co-receptors CCR5 and CXCR4
      • CCR5  chemokines = MIP-1a, MIP-1b, and RANTES
      • CXCR4  chemokines = SDF-1
  • Maintenance of functional lymphoid tissue architecture
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29
Q

Summarise the virologic factors that allow long-term-non-progressor infections to occur

A
  • Infection with attenuated strains of HIV
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30
Q

Which techniques are used to detect HIV?

A
  • Anti-HIV antibodies (ELISA) – screening test
  • Anti-HIV antibodies (Western Blot) – confirmation test
  • Viral load (viral RNA detection using PCR) – very sensitive; steps:
    • Regent preparation
    • Specimen preparation
    • Amplification
    • Detection
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31
Q

Which factor is a good predictor of the time taken for the disease to appear?

A

Initial baseline plasma viral load

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32
Q

How are CD4+ T Cell Counts derived/measured?

A

flow cytometry

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33
Q

Which cell count change correlates with the onset of AIDS

A
  • The onset of AIDS correlates with a decrease in the number of CD4+ T cells
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34
Q

Name the antigens on T cells

A
  • Antigens on T cells:
    • CD3, CD4
    • CD8
    • CD19
    • CD56
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35
Q

Can HIV-1 be resistant to ART?

A

yes, it can be

36
Q

Which assays are used in HIV-1 ART resistance testing?

A
  • (1) Phenotypic –> viral replication is measured in cell cultures under selective pressure of increasing concentrations of antiretroviral drugs (compared to wildtype)
  • (2) Genotypic –> mutations detected by sequencing amplified HIV genome (limited to sequencing RT and P)
  • Both assays are available commercially (but are EXPENSIVE)
37
Q

What are the aims/outcomes of HAART?

A
  • Substantial control of viral replication
  • Increase in CD4+ T cell counts
    • Initial rise = redistribution of memory T cells
    • Later rise = thymic naïve T cell creation
  • Improvement in host defences (decline in opportunistic infections (AIDS) and mortality)
38
Q

Can HAART eliminate HIV from the body? Explain your answer

A
  • NOTE: HAART does NOT eliminate HIV from the body because there is a reservoir in CD4+ T cells
39
Q

What is HAART? Give some examples

A
  • HAART = combination of ≥3 ART drugs:
    e. g.
  • 2 backbone drugs
  • x2 NRTIs
  • ≥1 binding agent
  • x1 NNRTI or INI (2nd line: boosted PI (protease inhibitor))
40
Q

Are boosted PIs (protease inhibitors) easy for HIV to gain resistance to? What is the clinical significance of your answer?

A
  • Boosted PIs are difficult to breed resistance to
  • so they are used as a 2nd line medication before INI
41
Q

Name the two main types of ART drugs

A
  • Backbone drugs
  • binding agents
42
Q

Name some types of backbone drugs (ART)

A
  • Nucleoside Reverse Transcriptase Inhibitors (NRTI) – e.g. Zidovudine / AZT
  • Nucleotide RTI – e.g. Tenofovir
  • Non-NRTI (NNRTI) – e.g. Efavirenz
  • Protease inhibitor (PI) – e.g. Indinavir
43
Q

Name some types of binding agents (ART)

A
  • Integrase inhibitors (INI) – e.g. Raltegravir
  • Attachment inhibitors (AI) – e.g. Maraviroc
  • Fusion inhibitors (FI) – e.g. Enfuvirtide
44
Q

What are the indications for HAART?

A
  • All symptomatic patients
  • All CD4+ count < 200 cells/uL
  • CD4 count 200-350 cells/uL
  • All offered IMMEDIATE treatment – more for _public health_ than an individual’s health
45
Q

Name some drugs that interact with HAART

A
  • Boosted PI – block cytochrome P450
  • Efavirenz – P450 inducer
  • INI – interacts with indigestion remedies (Gaviscon, aluminium salts, calcium salts) and is sequestered which can be very bad as some INI is absorbed but very little and so resistance is bred very quickly
  • I.E. if treating >55yo HTN with amlodipine, the amlodipine will seem to not work if the patient is also on Efavirenz (they might not tell you this) as the amlodipine will be broken down too quickly
46
Q

What are the limitations and complications of HAART?

A

limitations:

  • Does NOT eradicate latent HIV-1
  • Fails to restore HIV-specific T cell responses
  • High pill burden
  • Adherence
  • Quality of life
  • Cost (>40% with no access)

complications:

  • Threat of drug resistance
  • Significant toxicities
47
Q

Name some practices/factors that limit the spread of HIV

A
  • Male circumcision (APCs in foreskin at a high density)
  • Condoms
  • PrEP (Truvada)
  • TasP (Treatment as Prevention – if on treatment, cannot transmit infection; i.e. U=U)
48
Q

Are primary or secondary causes of immodeficiences more common?

A

Secondary immune deficiencies are far more common than primary immune defects

49
Q

How are immune deficiencies classified?

A
50
Q

Name some common causes of secondary immunodeficiencies

A
  • Malnutrition: commonest cause worldwide,
  • Measles: immune defect lasts months to years, implicated in increased morbidity and mortality
  • Mycobacterium Tuberculosis: inflammatory immune re-constitution syndrome
  • Human Immunodeficiency Virus (HIV) infection: residual immune dysfunction persists despite successful ART
  • SARS-CoV-2 infection: multi-factorial causes, virus, drugs co-morbidities ( renal disease and DM)
51
Q

Name some drugs that can cause secondary immunodeficiency

A
  1. Small molecules
  • Glucocorticoids and mineralocorticoids
  • Cytotoxic agents: methotrexate, mycophenolate, cyclophosphamide and azathioprine
  • Calcineurin inhibitors: cyclosporine and tacrolimus
  • Antiepileptic drugs (phenytoin, carbamazepine, levetiracetam
  • DMARD (sulphasalazine, leflunomide )
  1. JAK inhibitors
    * Tofacitinib, upadacitinib, ruxolitinib
52
Q

Name some biologics and cellular therapies that can cause of immune deficiency

A
  • Biologics agents:
    • anti-CD20/CD38/BCMA monoclonals
    • anti-TNF-α protein and receptor antagonists
  • Cellular therapy: anti-CD19/BCMA CAR-T cell therapy
  • Antibody deficiency and bacterial/viral infections are observed with rituximab and other anti-CD20 agents.
  • Risk of infection increased with repeated courses and in patient with a history of B cell malignancy and vasculitis.
  • Anti-TNF agents are linked to reactivation of TB infection
53
Q

Name some haemotological cancers that can present with immune deficiency

A

B and plasma cell cancers (antibody deficiency syndromes are most common)

54
Q

Name some B cell lymphoproliferative disorders associated with immune deficiency

A
  • Multiple myeloma
  • Chronic lymphocytic leukaemia
  • Non Hodgkin’s lymphoma
  • Monoclonal gammopathy of uncertain significance
55
Q

What is Goods’ syndrome?

A

Thymoma and antibody deficiency

  • Combined T and B cell (absent) defect
  • CMV PJP and muco-cutaneous candida
  • Autoimmune disease (Pure red cell aplasia, Myasthenia gravis, Lichen planu
56
Q

How is secondary immune deficiency evaluated?

A
  • Clinical history infection, unusual complication of childhood illnesses, reaction to vaccines, loss of schooling etc
  • History of other illnesses: autoimmune cytopaenia, bronchiectasis, investigation of therapy for lymphoma/cancer, TB, Hepatitis B and C
  • Family history of infection, autoimmune disease, cancer
  • Medication history
  • Vaccine history (childhood , pneumococcal vaccine, influenza )
57
Q

What are the investigations for ?immunodeficiency?

A

FISH

  • Full Blood count
    • Hb < 10g/L
    • neutrophil count
    • lymphocyte count
    • platelet count
  • Immunoglobulins (IgG, IgA, IgM, IgE )
  • Serum complement (C3, C4)
  • HIV test (18-80 years)

Strategy will pick up to 85% of all immune defects

  • Renal and liver profile
  • Calcium and bone profile
  • Total protein and Albumin
  • Urine protein/Cr ratio
  • Serum protein electrophoresis
  • Serum free light chains
58
Q

What is the clinical significance of reduced Ig?

A
59
Q

What is monoclonal proteins in Serum protein electrophoresis (SPE) associated with?

A
  • multiple myeloma,
  • WMG,
  • NHL
  • MGUS
60
Q

Name one limitation of Serum protein electrophoresis (SPE). How is this worked around?

A
  • SPE can miss free light chain disease which is seen 20% multiple myeloma cases):
  • hence measurement of free light chains is essential for work up of B cell Lymphoproliferative disease
61
Q

Name some second line tests for ?immune deficiency

A

Analysis of lymphocyte subsets using flow cytometry

  • Quantify lymphocyte subsets
  • CD3+CD4+ T cells
  • CD3+CD8+ T cells
  • CD3-CD56+CD16+ NK cells
  • CD19+ B cells
62
Q

What should be done if antibody levels for vaccines are low? What is implied by this?

A
  • If vaccine antibody levels are low offer test immunisation with Pneumovax II and tetanus to investigate immune function
  • Failure to respond to vaccination is part of diagnostic criteria for a number of primary antibody deficiency syndromes and is a criteria fro receipt of IgG replacement therapy for secondary antibody deficiency syndromes.
63
Q

Name some 3rd line tests for ?immune deficiencies

A
64
Q

What is the management of immune deficiencies?

A
65
Q

Describe IgG replacement therapy for
secondary antibody deficiency syndromes

A
66
Q

Which are more common, primary or secondary immune deficiencies?

A

secondary

67
Q

Is there one clinical syndrome exhibited in immune deficiencies?

A

NO

can range from:

  • infections (severe, persistent, recurrent, unusual)
  • autoimmune conditions (cytopenias), and allergic disease
  • persistent inflammation
  • cancer (viral associated EBV, HHV-8)
68
Q

What are the commonest causes of secondary immune deficiencies world wide?

A
69
Q

Name some drugs that are important causes of immune deficiency

A
70
Q

What else can be an iatrogenic cause of immune deficiencies?

A
71
Q

Which haematological cancers can present as immune deficiency?

A

B cell and plasma cell cancers (antibody deficiency syndromes are the most common)

72
Q

Name some B cell lymphoproliferative disorders associated with immune deficiency

A
73
Q

What is Good’s syndrome?

A

Thymoma and antibody deficiency

74
Q

How do you evaluate ?secondary immune deficiency?

A
75
Q

What is the acronym for assessment of immunodeficiency?

A

FISH

76
Q

Which biochemical tests should be ordered for ?immune deficiency?

A
77
Q

How do you interpret serum immunoglobulins for ?immune deficiency?

A
78
Q

What is serum protein electrophoresis? Which conditions have monoclonal protein?

A
78
Q

What is serum protein electrophoresis? Which conditions have monoclonal protein?

A
79
Q

What are some second line tests to investigate ?immune deficiency?

A
  • measure concentration of vaccine antibodies
  • analysis of lymphocyte subsets using electrophoresis
80
Q

What is the point of measuring concentration of vaccine antibodies?

A
81
Q

What is the point of analysing lymphocyte subsets using electrophoresis?

A
82
Q

What are some third line investigations for ?immune deficiency?

A
83
Q

What is the Mx of secondary immune deficiency?

A
84
Q

What is IgG replacement therapy?

A

4 - Y5 a Path lectures 2021/22 (37 decks)

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