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PathY5 > HIV and secondary causes of immune deficiency > Flashcards

HIV and secondary causes of immune deficiency Flashcards

1
Q

What type of Virus is HIV?

A

A retrovirus which infects immune system cells (can cause AIDS)

It is also a lentivirus- slow evolution of disease

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2
Q

What is a retrovirus?

A

A virus with (ds)RNA that uses reverse transcriptase to convert RNA to DNA to integrate into host cell genes.

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3
Q

What is the organisation of HIV?

A

Icosahedral (20 sided)
Diploid genome (Plus ssRNA)
9 genes
15 structural/ regulatory/ auxiliary proteins

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4
Q

What are the important proteins in HIV?

A 
gp120
gp41
p17
p24
p9
p7
RT
IN
PR
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5
Q

What is the structure of HIV?

A

RNA + p7 + p9 + Reverse transcriptase

Surrounded by p24 capsid

Surrounded by p17 matrix

Surrounded by host derived lipid bi layer

With surface protein gp 120, transmembrane protein gp41 and myristic acid in the lipid bilayer

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6
Q

Which cells does HIV target?

A

CD4+ T helper cells

Also monocytes

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7
Q

Can the body protect against HIV?

A

Yes- immunity required antibodies (B Cells) to prevent and neutralise the virus and CD8 (CTL) cells to kill infected cells

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8
Q

Why may the immune system fail to control HIV?

A

One reason that the immune system fails to control HIV-1 infection is that the CD4+ T helper cells are the target of the virus.

Progressive decline in CD4 T-cell function & numbers: HIV-specific, Recall, Allo, and Mitogen (and even IL-2).

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9
Q

How does HIV-1 enter target cells?

A

Using CD4R and CCR5/ CXCR4

Other chemokine receptors may be necessary for entry also

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10
Q

How id HIV transmitted?

A

Sexual contact (Mucosal entry via damage to blood and LN)

Infected blood (penetration)

Vertical transmission (Mother to child)

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11
Q

How does natural immunity play a part in defence against HIV?

A

Within hours: inflammation, non specific activation of macrophages, NK cells and complement

Release of cytokines and chemokines

stimulate pDCs via TLRs

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12
Q

How does acquired immunity (B cells) defend against HIV?

A

Specific Abs
Anti gp120 and Anti gp41
Non neutralising anti p24 gag IgG

BUT HIV infectious even when coated with Abs

This response (antibody mediated cellular cytotoxicity) peaks at 6 months

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13
Q

How does acquired immunity (CD4 T cells) defend against HIV?

A

White blood cells that orchestrate the immune response, signalling other cells in the immune system to perform their special functions.

Recognise processed antigen - especially Gag p24 (peptides) - in the context of class II HLA molecules.

Also known as T helper (Th) cells, these cells are infected, killed or disabled during HIV-1 infection.

Selective loss of CD4+ T cells.

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14
Q

How does acquired immunity (CD8 T cells) defend against HIV?

A

White blood cells that kill cells infected with HIV or other viruses, or transformed by cancer (CTL). Also able to suppress viral replication.

Secrete soluble molecules (cytokines and chemokines such as MIP-1a, MIP-1b, and RANTES) which are able to prevent infection by blocking entry of virus into CD4+ T cells.

Recognise processed antigen - (peptides) - in the context of class I HLA molecules.

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15
Q

How does HIV interfere with CD8 activation?

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 can not 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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16
Q

How does HIV become mutated?

A

Reverse transcriptase lacks proof reading - retrovirus genome is copied into DNA with low fidelity

Transcription is low fidelity

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17
Q

What escape tactics do HIV have?

A

Escape from neutralising antibodies.

Escape from HIV-1-specific T cells.

Resistance and escape from antiretroviral drugs.

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18
Q

How can we target mutation for Vaccines?

A

Vaccine strategies that focus on highly conserved and functionally important regions of the virus could result in ether an inability of the virus to escape or the emergence of an escape variant that replicates poorly.

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19
Q

What is the life cycle of HIV?

A
  1. Attachment/Entry
  2. Reverse Transcription & DNA Synthesis
  3. Integration
  4. Viral Transcription
  5. Viral Protein Synthesis
  6. Assembly of Virus & Release of Virus
  7. Maturation
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20
Q

How do we target attachment for treatment?

A

Attachment inhibitors

Fusion inhibitors

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21
Q

How do we target Reverse transcriptase for treatment?

A

Reverse transcriptase inhibitors

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22
Q

How do we target Integration & Transcription for treatment?

A

Integrase inhibitors

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23
Q

How do we target viral protein synthesis for treatment?

A

Protease inhibitors

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24
Q

What is the clinical course of the disease?

A

Median time from infection with HIV to development of AIDS is 8 - 10 years.

Viral burden (set point) predicts disease progression.

Rapid progressors (10%) in 2 - 3 years.

LTNP (<5%) stable CD4 counts and no symptoms after 10 years. >8 years, > 500 cells/ul, <50 copies/ml, no symptoms & no history of ART (group is however heterogeneous).

ESN
Effect of HAART.

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25
Q

What are the possible mechanisms of long term non progressors (LTNP) with HIV?

A

Host genetic factors
Host immune response factors
Virological factors (e.g. infection with attenuated strains of HIV)

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26
Q

Which host genetic factors may impact LTNP?

A 
Slow progressor HLA profile
Heterozygosity for 32-bp deletion in CCR5
Mannose binding lectin alleles
TNF c2 microsatellite alleles
Gc vitamin D-binding factor alleles
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27
Q

Which host immune response factors may impact LTNP?

A

Effective CTL & HTL responses
Secretion of CD8 antiviral factor
Secretion of chemokines that block HIV entry co-receptors CCR5 (e.g., MIP-1a, MIP-1b, and RANTES) and CXCR4 (e.g., SDF-1)
Secretion of IL-16
Effective humoral immune response
Maintenance of functional lymphoid tissue architecture

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28
Q

How do we detect HIV?

A

ELISA (anti HIV Abs) + Western blot (confirmatory)

PCR (viral load)

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29
Q

What are the 4 steps of PCR?

A
  1. Reagent Preparation (Pre-PCR)
  2. Specimen Preparation (Pre-PCR)
  3. Amplification (Post-PCR)
  4. Detection (Post-PCR)
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30
Q

How do we do a CD4 count?

A

Flow Cytometry

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31
Q

Which markers are use in flow cytometry?

A

Cell surface markers (anti human CD3, CD4, CD8, CD19 and CD56)

Activation markers (Anti human CD57 and CD158b)

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32
Q

How do we establish drug resistance?

A

Phenotypic: Viral replication is measured in cell cultures under selective pressure of increasing concentrations of antiretroviral drugs – compared to wild-type

Genotypic: Mutations determined by direct sequencing of the amplified HIV genome (so far limited to sequencing of RT and P)

33
Q

What is HAART?

A

Highly active antiretroviral therapy (HAART)

34
Q

Why is HAART good?

A

Substantial control of viral replication
Increase in CD4 T cell counts
Improvement in their host defences (dramatic decline in opportunistic infections (AIDS-related disease) & deaths (mortality))

Causes:
Suppression of VL
Initial CD4 rise – memory T-cells redistributed
Later CD4 rise is thymic naïve T-cells

35
Q

How do you prescribe HAART?

A

Two drug backbone (NRTI) + One binding agent (NNRTI/ PI/ INI/ AI/ FI)

36
Q

Give an example of a drug regimen for HAART

A

Abacavir + Lamivudine

+ Dolutegravir

Bictegravir + Tenofovir alafenamide

+Ritonavir

37
Q

When do you initiate HAART?

A 
All symptomatic patients
All CD4 <200 cells/ml
START: CD4 200-350 cells/ml 
(All offered immediate treatment)
Choices: 2NRTIs + NNRTI or boosted PI
38
Q

What are the disadvantages of HAART?

A

Effective HAART does not eradicate latent HIV-1 in the host
Fails to restore HIV-specific T-cell responses
Is dogged by the threat of drug resistance
Significant Toxicities
High pill burden
Adherence problems
Quality of life issues
Cost (>40%)

39
Q

What is the most common cause of secondary immune deficiency?

A

Malnutrition

40
Q

What else causes secondary immune deficiencies?

A

Drugs
Age
Surgery/ trauma
Environment

41
Q

What are the features of immune deficiencies?

A

Susceptible to infections (severe)

AI conitions/ allergy

Persistent inflammation
Cancer (viral associated EBV/ HHV-8)

42
Q

Common secondary ID

A 
Malnutrition
Measles - mortality/ morbidity
Mycobacterium TB - inflammatory immune re constitution syndrome
HIV 
SARS CoV 2
43
Q

Which drugs can cause ImmuneD?

A

Small molecules (Steroids, cytotoxic agents (methotrexate, azathrioprine etc.), calcineurin inhibitors, antiepileptic drugs, DMARDs (sulphasalazine)

JAK inhibitors (Tofacitinib etc.)

44
Q

How do mabs affect ID?

A

Biologic agents (Anti- CD20 etc.)

Cellular therapy (Anti CD19/ CAR-T cell therapy)

Antibody deficiency in rituximab

Risk of infection increased

Anti TNF linked to TB infection reactivation

45
Q

How does cancer affect ImmuneD?

A

B/ Plasma cell cancers (Multiple myeloma, CLL, NHL, MGUS)

Chemo + drugs

Goods’ syndrome [thymoma + antibody deficiency] (T/ B cell absent, CMV/PJP/ muco cutaneous candida, AI disease)

46
Q

What do you ask for in the history?

A

Clinical Hx of infection, unusual complication of childhood inf., reaction to vx

Hx of other illness

FHx

MED

Vx history (childhood, flu etc.)

47
Q

How do you FISH for an immune deficiency?

A

F- FBC- Hb<10, differential white cell count

I- Immunoglobulins (IgG, igA, IgM, IgE)

S- Serum complement (C3,4)

H - HIV test (18-80yrs)

48
Q

What are front line investigation for immunodeficiency?

A 
Renal/ liver profile
calcium/ bone profile
total protein/ albumin
Urine protein/ Cr ratio
Serum protein electrophoresis

Serum free light chains

49
Q

What may you have if you have an Isolated reduction in IgG?

A

Protein losing enteropathy

Pred >10mg/day

50
Q

What may you have if you have a reduced IgG and IgM?

A

Monitor for B cell neoplasia

History of Rituximab ues

51
Q

what may you have if you have a reduced IgA and IgG?

A

? Primary antibody deficiency?

52
Q

What can SPE miss?

A

Serum protein electrophoress can miss free light chain disease (e.g. in 20% myeloma)

53
Q

What are second line investigation for immunodeficiency?

A

Measure conc of Vx Abs (Tetanus toxoid- protein ag, pneumovax vaccine-carbohydrate ag)

54
Q

How may the test for PADS be used?

A

If Abs low- offer test immunisation with pneumovax II + tetanus

Dynamics test for primary antibody deficiency syndromes

Criteria for receipt of certain therapy for secondary Antibody Deficiency Syndromes

55
Q

What are the third line investigations for immune deficiencies?

A

Analysis of T cell and B cell subsets

Assessment of IgG subclasses

Determination of anti cytokine and complement Abs

Genetics/ genome sequencing

56
Q

Management of Secondary immune deficiency?

A

Treat underlying cause

Advise in measures to reduce exposure to infection

Immunisation against respiratory viruses/ bacteria + offer household contacts

Education to treat bacterial infections promptly (may require higher and longer therapies) (co amox 625 mg TDS for 10-14 days rather than 375 mg for 5-7 days)

Prophylactic antibiotics for confirmed recurrent bacterial infection

57
Q

How do you decide on giving IgG replacement therapy?

A

If irreversible IgG drop OR lack of B cells through cancers etc.

AND

Recurrent bacteria
IgG<4g
did not respond to other vaccine challenges

58
Q

What is the epidemiology of HIV?

A

75 mil over 40 yrs

21/37 mil on ART

101,200 people in UK with HIV

Incidence of new HIV dropped by 70% in 4-5 yrs

59
Q

How does HIV get into cells?

A 
Binds to CD4 then coreceptors
replicates via DNA intermediate
Integrates into host genome
HIV DNA to translation to viral mRNA
Viral RNA transcribed to viral proteins
Makes viral enzymes
60
Q

What is the origin of HIV?

A

4 distinct lines (MNOP)

From Chimpanzees

61
Q

What is the natural history of HIV?

A

Acute phase - 2 weeks - 6 months ish [High risk of transmission]

Asymptomatic phase (steady state) - up to 10 years [Lower risk of transmission and increasing diversity]

Symptomatic phase [Highest viral diversity and high risk of transmission]

62
Q

How does latent infection happen?

A

Integration of HIV virus in memory CD4 T cells within 72 hours = latent infection which don’t respond to current ART

63
Q

How do cells change in HIV?

A

Look at picture notes

64
Q

What are the key features of the immunology of HIV-1 infection?

A

CD4 T cell depletion

Chronic immune activation

Impairment of CD4 and CD8 function (exhaustion)

Disrupt LN architecture and impaired ability to generate protective T and B cell immune responses

Loss of antigen-specific humoral immune responses

65
Q

What happens in acute phase?

A

Significant increase in HIV 1 viral load

Flu like symptoms

Significant viral transmission

66
Q

Diagnosis

A

4th generation combine HIV-1

Assay: p24, gp41 (HIV1O), gp160 (HIV1M), gp36 (HIV2)

rapid POC testing (less sensitive)

HIV-1 RNA tests in cases where HIV-1 serological tests are negative but high clinical suspicion of acute HIV-1 infection

HIV RNA/ DNA test are used to diagnose infection in children <18months

67
Q

What is the non pharmacological management of HIV?

A

Education

Co morbidities

Sexual health history and Vx

Discuss partner notification to prevent transmission

Screen for factors which may adherence to ART (Psych etc.)

68
Q

What baseline tests should you do in clinic?

A 
FBC
REnal liver bone
Sexual health 
TB - IGRA
Baseline CXR
Toxoplasma serology
69
Q

Which HIV-1 specific tests do you do?

A

HIV 1 viral load

HIV-1 genotype for ART resistance

HIV-1 tropism test

HLA-B*5701 to avoid Abacavir (sensitivity)

Analysis of T cell counts (CD4 cell count and %, CD4:CD8 T cell ration)

70
Q

What is Viral load set point linked to?

A

Viral load set point linked to outcomes

71
Q

At what CD4 levels do you get PCP?

A

200 x 10^9

72
Q

At what CD4 level do you get Toxoplasmosis?

A

100 x 10^9

73
Q

What do you get at a CD4 level of 75 x 10^9?

A

MAC disease

74
Q

How can you use ART?

A

Test and Treat

Treat to prevent

Prophylaxis

75
Q

What drugs are used in ART?

A

Reverse transcriptase inhibitors

Boosted protease inhibitors (Ritonavir + PI)

Integrase inhibitors (DTG, RTG and EVG)

CCR5 antagonists (Maraviroc)

Fusion inhibitors

76
Q

What does ART do?

A

Prevent new cells not old

Cannot eliminate if DNA integrated already

Cannot reverse chronic immune inflammation - bad for morbidity

77
Q

How do you monitor people on ART?

A

Check for compliance

Regular HIV viral load

Monitor liver renal bone and lipids

CD4 T cell monitoring not needed if count >350 cells/ ul

Assess cardiovascular and osteoporosis risk

78
Q

What are the challenges for HIV?

A

HIV prevention: Education, protection

Vx: new strategies and use of new research still needed

Cure: Allogenic stem cell transplant, shock and kill strategy

PathY5 (98 decks)

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