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HIV and secondary causes of immune deficiency Flashcards

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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
What are the possible mechanisms of long term non progressors (LTNP) with HIV?
Host genetic factors Host immune response factors Virological factors (e.g. infection with attenuated strains of HIV)
26
Which host genetic factors may impact LTNP?
``` 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 ```
27
Which host immune response factors may impact LTNP?
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
28
How do we detect HIV?
ELISA (anti HIV Abs) + Western blot (confirmatory) | PCR (viral load)
29
What are the 4 steps of PCR?
1. Reagent Preparation (Pre-PCR) 2. Specimen Preparation (Pre-PCR) 3. Amplification (Post-PCR) 4. Detection (Post-PCR)
30
How do we do a CD4 count?
Flow Cytometry
31
Which markers are use in flow cytometry?
Cell surface markers (anti human CD3, CD4, CD8, CD19 and CD56) Activation markers (Anti human CD57 and CD158b)
32
How do we establish drug resistance?
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
What is HAART?
Highly active antiretroviral therapy (HAART)
34
Why is HAART good?
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
How do you prescribe HAART?
Two drug backbone (NRTI) + One binding agent (NNRTI/ PI/ INI/ AI/ FI)
36
Give an example of a drug regimen for HAART
Abacavir + Lamivudine + Dolutegravir Bictegravir + Tenofovir alafenamide +Ritonavir
37
When do you initiate HAART?
``` 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
What are the disadvantages of HAART?
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
What is the most common cause of secondary immune deficiency?
Malnutrition
40
What else causes secondary immune deficiencies?
Drugs Age Surgery/ trauma Environment
41
What are the features of immune deficiencies?
Susceptible to infections (severe) AI conitions/ allergy Persistent inflammation Cancer (viral associated EBV/ HHV-8)
42
Common secondary ID
``` Malnutrition Measles - mortality/ morbidity Mycobacterium TB - inflammatory immune re constitution syndrome HIV SARS CoV 2 ```
43
Which drugs can cause ImmuneD?
Small molecules (Steroids, cytotoxic agents (methotrexate, azathrioprine etc.), calcineurin inhibitors, antiepileptic drugs, DMARDs (sulphasalazine) JAK inhibitors (Tofacitinib etc.)
44
How do mabs affect ID?
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
How does cancer affect ImmuneD?
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
What do you ask for in the history?
Clinical Hx of infection, unusual complication of childhood inf., reaction to vx Hx of other illness FHx MED Vx history (childhood, flu etc.)
47
How do you FISH for an immune deficiency?
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
What are front line investigation for immunodeficiency?
``` Renal/ liver profile calcium/ bone profile total protein/ albumin Urine protein/ Cr ratio Serum protein electrophoresis ``` Serum free light chains
49
What may you have if you have an Isolated reduction in IgG?
Protein losing enteropathy | Pred >10mg/day
50
What may you have if you have a reduced IgG and IgM?
Monitor for B cell neoplasia | History of Rituximab ues
51
what may you have if you have a reduced IgA and IgG?
? Primary antibody deficiency?
52
What can SPE miss?
Serum protein electrophoress can miss free light chain disease (e.g. in 20% myeloma)
53
What are second line investigation for immunodeficiency?
Measure conc of Vx Abs (Tetanus toxoid- protein ag, pneumovax vaccine-carbohydrate ag)
54
How may the test for PADS be used?
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
What are the third line investigations for immune deficiencies?
Analysis of T cell and B cell subsets Assessment of IgG subclasses Determination of anti cytokine and complement Abs Genetics/ genome sequencing
56
Management of Secondary immune deficiency?
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
How do you decide on giving IgG replacement therapy?
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
What is the epidemiology of HIV?
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
How does HIV get into cells?
``` 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
What is the origin of HIV?
4 distinct lines (MNOP) From Chimpanzees
61
What is the natural history of HIV?
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
How does latent infection happen?
Integration of HIV virus in memory CD4 T cells within 72 hours = latent infection which don't respond to current ART
63
How do cells change in HIV?
Look at picture notes
64
What are the key features of the immunology of HIV-1 infection?
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
What happens in acute phase?
Significant increase in HIV 1 viral load Flu like symptoms Significant viral transmission
66
Diagnosis
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
What is the non pharmacological management of HIV?
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
What baseline tests should you do in clinic?
``` FBC REnal liver bone Sexual health TB - IGRA Baseline CXR Toxoplasma serology ```
69
Which HIV-1 specific tests do you do?
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
What is Viral load set point linked to?
Viral load set point linked to outcomes
71
At what CD4 levels do you get PCP?
200 x 10^9
72
At what CD4 level do you get Toxoplasmosis?
100 x 10^9
73
What do you get at a CD4 level of 75 x 10^9?
MAC disease
74
How can you use ART?
Test and Treat Treat to prevent Prophylaxis
75
What drugs are used in ART?
Reverse transcriptase inhibitors Boosted protease inhibitors (Ritonavir + PI) Integrase inhibitors (DTG, RTG and EVG) CCR5 antagonists (Maraviroc) Fusion inhibitors
76
What does ART do?
Prevent new cells not old Cannot eliminate if DNA integrated already Cannot reverse chronic immune inflammation - bad for morbidity
77
How do you monitor people on ART?
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
What are the challenges for HIV?
HIV prevention: Education, protection Vx: new strategies and use of new research still needed Cure: Allogenic stem cell transplant, shock and kill strategy

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