Immunology 4 - HIV infection

Question 1

Using which enzyme does HIV replicate inside cells?

Answer 1

Reverse Transcriptase - so it replicates via a DNA intermediate even though HIV itself is a double stranded RNA virus

Question 2

How many genes are inside the HIV genome?

Answer 2

9

Question 3

What is the role of reverse transcriptase in HIV?

Answer 3

Converts RNA into DNA which can be incorporated into host cells’ genes

Question 4

What are the two key glycoproteins encoded by the HIV virus?

Answer 4

gp120

gp41

Question 5

Which cell of the immune system is particularly affected by HIV?

Answer 5

CD4+ T cells

Question 6

Recall the receptor and co-receptors for HIV on CD4+ T cells

Answer 6

CD4 receptors

CCR5 CXCR4 coreceptors

Question 7

In people who have natural immunity to HIV, what antibodies may be present in serum?

Answer 7

Anti-gp120 and anti-gp41 (Nt) antibodies

Question 8

How does HIV infection affect CD8+ T cells?

Answer 8

Interferes with activation, as CD4+ T cell and antigen-presenting cell help are not present due to the virus

Question 9

How does HIV infection affect monocytes and dendritic cells?

Answer 9

Not activated by CD4+ T cells and so cannot prime naive CD8+ T cells

Question 10

How does HIV affect immunological memory?

Answer 10

CD4+ T cell memory is lost

CD8 memory cell not activated by antigen-presenting cell

Question 11

Why is there so much variation/mutation in HIV infection?

Answer 11

HIV lacks same checking mechanisms in DNA transcription

Question 12

Why is HIV mutation within the host problematic?

Answer 12

Escape from neutralising antibodies.

Escape from HIV-1-specific T cells.

Resistance and escape from antiretroviral drugs.

Question 13

Recall the 7 steps of the HIV life cycle

Answer 13

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

Question 14

Which drugs are capable of inhibiting the action of reverse transcriptase in HIV infection?

Answer 14

1. Nucleoside analogues

2. Non-nucleotide reverse transcriptases

Question 15

Which class of HIV drugs can prevent integration of viral DNA?

Answer 15

Integrase inhibitors

Question 16

Which HIV drugs can prevent modification of translated viral proteins?

Answer 16

Protease inhibitors

Question 17

What is the median time of infection with HIV to AIDS development?

Answer 17

8-10 years

Question 18

What does it mean if someone is an HIV exposed seronegative individual?

Answer 18

Partner of individual with HIV who remains uninfected

Question 19

What are the 3 major markers used to monitor HIV?

Answer 19

CD8
CD4
Plasma viral load

Question 20

What is long-term nonprogression of HIV?

Answer 20

Individual who is asymptomatic 10 years after infection

Question 21

How can HIV be detected?

Answer 21

anti-HIV antibodies (ELISA)

Viral load (PCR) - more sensitive

ELISA = screening

Western Blot = Confirmatory test

Question 22

How are CD4+ T cell levels measured in HIV infection?

Answer 22

Flow cytometry

Question 23

What are the two methods of testing for ARV resistance?

Answer 23

Phenotypic

Genotypic (involves directly sequencing the amplified genome)

Question 24

Which drugs make up a HAART regimen?

Answer 24

Three or more drugs + one or more binding agents

Question 25

When should HAART treatment be initiated?

Answer 25

Immediately

Question 26

Give 2 examples of NRTI HIV drugs

Answer 26

Zidovudine

Lamivudine

Question 27

Recall 2 examples of protease inhibitor HIV drugs

Answer 27

Tenofovir

Truvada

Question 28

What class of drug is raltegravir?

Answer 28

Integrase inhibitor

Question 29

Which drugs make up the HAART regimen initially?

Answer 29

2 NRTIs + PI

Question 30

What CD4 count defines AIDS?

Answer 30

<200 cells/ nanolitre

Question 31

Which drugs make up the atripla pill?

Answer 31

Emtricitabine + tenofavir + efavirenz

Question 32

Which ARV is best to use in pregnancy?

Answer 32

Zidovudine

Question 33

How can CD8+ T cells provide HIV entry into cells?

Answer 33

Producing chemokines MIP-1A, MIP-1b and RANTES

Question 34

What is the most common cause of secondary immune deficiency?

Answer 34

Malnutrition

Secondary immune deficiencies are far more common than primary immune defects

Question 35

What are the clinical features of immune deficiencies?

Answer 35

Infections (severe, persistent, recurrent, unusual)

Autoimmune conditions (cytopaenias) and allergic disease

Persistent inflammation

Cancer (viral associated - EBV, HHV-8)

Question 36

Which infections can cause immune deficiency?

Answer 36

Measles

Mycobacterium TB (inflammatory immune re-constitution syndrome)

HIV (despite successful treatment, residual immune dysfunction persists)

COVID (virus itself, co-morbidities caused by the virus, drugs used to control inflammation)

Question 37

Which drugs can cause immune deficiency?

Answer 37

Small molecules (steroids, cytotoxic agents like methotrexate, calcineurin inhibitors like cyclosporine, antiepileptic drugs like phenytoin, DMARDs like sulphasalazine)

JAK inhibitors (tofacitinib)

Biological agents (anti-CD20, anti-TNF-alpha monoclonals)

Cellular therapy (anti-CD19/BCMA chimeric antigen receptor T cell therapy)

Question 38

What is Good’s syndrome?

Answer 38

Thymoma and antibody deficiency - combined T and B cell absence

Susceptible to PJP, candida etc.

Also susceptible to autoimmune conditions including myasthenia gravis

Question 39

What is the method of looking for an immunodeficiency?

Answer 39

FISH

FBC (Hb lower than 10g/L, neutrophil count, lymphocyte count, platelet count)

Immunoglobulins (IgG, IgA, IgM, IgE) - remember there are age-related reference intervals

• Isolated reduction in IgG -> protein losing enteropathy, prednisolone over 10mg/day*
• Reduction in IgG and IgM -> monitor for B cell neoplasm, history of rituximab treatment*
• Reduction in IgG and IgA -> primary antibody deficiency*

Serum complement (C3, C4)

HIV test (18-80 years)

Strategy will pick up to 85% of all immune defects

Question 40

What are the second line tests to investigate immune deficiencies?

Answer 40

Measure concentration of vaccine antibodies

Tetanus toxoid - protein antigen
Pneumovax vaccine - carbohydrate antigen

Failure to respond to vaccination is a diagnostic criteria for many primary immune deficiencies

Question 41

What are the important third line tests to investigate immune deficiencies?

Answer 41

Looking for anti-cytokine and anti-complement antibodies

Question 42

How do you manage secondary immune deficiencies?

Answer 42

Treat underlying cause

Advise on measures to reduce infection exposure

Immunisations and offer vaccines to household contacts (e.g. flu vaccine)

Education to treat bacterial infections prompts -> may require higher and longer therapy courses

Prophylactic antibiotics for confirmed recurrent bacterial infection (give them rescue antibiotics to keep at home)

IF INDICATED: IgG replacement therapy

Question 43

What is the natural history of HIV infection?

Answer 43

Acute phase (high plasma viraemia = high risk of transmission, but low viral diversity)
*Dramatic decline in mucosal CD4 count which doesn't recover, whereas blood CD4 count initially drops and then recovers*

Asymptomatic but progressive (low plasma viraemia but increasing viral diversity)
CD4 count in blood is stable

AIDS (high plasma viraemia and high viral diversity)
CD4 count in blood falls steeply

Question 44

What are the characteristic immune features of HIV infection?

Answer 44

CD4 cell depletion

Chronic immune activation

Impairment of CD4 and CD8 cell function (present but not doing anything, exhausted)

Disruption of lymph node architecture and impaired ability to generate protective T and B cell immune responses

Loss of antigen-specific humeral immune responses

Question 45

How is HIV diagnosed?

Answer 45

4th generation combined HIV antigen/antibody tests will detect infection 1 month post-acquisition of infection

Rapid point of care HIV tests: result available within 20 minutes but this is less sensitive than 4th generation tests

HIV RNA tests (viral load tests) used when serological tests are negative but there is high clinical suspicion

Question 46

How is HIV managed?

Answer 46

Confirm understanding

Check for relevant co-morbidities like TB, HepB and HepC, anxiety and depression) - influences choice of ART and needs to be managed

Sexual history and vaccine history

Discuss partner notification but emphasise importance of undetectable = untransmissible

Screen for factors which may impair adherence to HAART e.g. psych issues, alcohol and drug dependency

Question 47

What are some important baseline investigations for an HIV patient?

Answer 47

IGRA to screen for latent TB

Toxoplasma serology screen

CD4 T cell count - to stratify the risk of certain infections and therefore who needs prophylactic antibiotics e.g. septrin, co-trimoxazole (HAART is given regardless)

Viral load - viral load set point at 3-6 months correlates with outcomes

Question 48

What is the HLA-B*5701 test for?

Answer 48

To decide whether to avoid prescribing Abacavir - an NRTI (can cause toxic epidermolysis necrolitis if they have this gene)

Question 49

What are the limitations to HAART?

Answer 49

Doesn’t eliminate infection once HIV is integrated into DNA

Doesn’t usually reverse chronic immune inflammation issues -> therefore there is a risk of CVS, liver, bone, CNS disease