Immunology 4 - HIV infection Flashcards
Using which enzyme does HIV replicate inside cells?
Reverse Transcriptase - so it replicates via a DNA intermediate even though HIV itself is a double stranded RNA virus
How many genes are inside the HIV genome?
9
What is the role of reverse transcriptase in HIV?
Converts RNA into DNA which can be incorporated into host cells’ genes
What are the two key glycoproteins encoded by the HIV virus?
gp120
gp41
Which cell of the immune system is particularly affected by HIV?
CD4+ T cells
Recall the receptor and co-receptors for HIV on CD4+ T cells
CD4 receptors
CCR5 CXCR4 coreceptors
In people who have natural immunity to HIV, what antibodies may be present in serum?
Anti-gp120 and anti-gp41 (Nt) antibodies
How does HIV infection affect CD8+ T cells?
Interferes with activation, as CD4+ T cell and antigen-presenting cell help are not present due to the virus
How does HIV infection affect monocytes and dendritic cells?
Not activated by CD4+ T cells and so cannot prime naive CD8+ T cells
How does HIV affect immunological memory?
CD4+ T cell memory is lost
CD8 memory cell not activated by antigen-presenting cell
Why is there so much variation/mutation in HIV infection?
HIV lacks same checking mechanisms in DNA transcription
Why is HIV mutation within the host problematic?
Escape from neutralising antibodies.
Escape from HIV-1-specific T cells.
Resistance and escape from antiretroviral drugs.
Recall the 7 steps of the HIV life cycle
- Attachment/Entry
- Reverse Transcription and DNA Synthesis
- Integration
- Viral Transcription
- Viral Protein Synthesis
- Assembly of Virus and Release of Virus
- Maturation
Which drugs are capable of inhibiting the action of reverse transcriptase in HIV infection?
- Nucleoside analogues
2. Non-nucleotide reverse transcriptases
Which class of HIV drugs can prevent integration of viral DNA?
Integrase inhibitors
Which HIV drugs can prevent modification of translated viral proteins?
Protease inhibitors
What is the median time of infection with HIV to AIDS development?
8-10 years
What does it mean if someone is an HIV exposed seronegative individual?
Partner of individual with HIV who remains uninfected
What are the 3 major markers used to monitor HIV?
CD8
CD4
Plasma viral load
What is long-term nonprogression of HIV?
Individual who is asymptomatic 10 years after infection
How can HIV be detected?
anti-HIV antibodies (ELISA)
Viral load (PCR) - more sensitive
ELISA = screening
Western Blot = Confirmatory test
How are CD4+ T cell levels measured in HIV infection?
Flow cytometry
What are the two methods of testing for ARV resistance?
Phenotypic
Genotypic (involves directly sequencing the amplified genome)
Which drugs make up a HAART regimen?
Three or more drugs + one or more binding agents
When should HAART treatment be initiated?
Immediately
Give 2 examples of NRTI HIV drugs
Zidovudine
Lamivudine
Recall 2 examples of protease inhibitor HIV drugs
Tenofovir
Truvada
What class of drug is raltegravir?
Integrase inhibitor
Which drugs make up the HAART regimen initially?
2 NRTIs + PI
What CD4 count defines AIDS?
<200 cells/ nanolitre
Which drugs make up the atripla pill?
Emtricitabine + tenofavir + efavirenz
Which ARV is best to use in pregnancy?
Zidovudine
How can CD8+ T cells provide HIV entry into cells?
Producing chemokines MIP-1A, MIP-1b and RANTES
What is the most common cause of secondary immune deficiency?
Malnutrition
Secondary immune deficiencies are far more common than primary immune defects
What are the clinical features of immune deficiencies?
Infections (severe, persistent, recurrent, unusual)
Autoimmune conditions (cytopaenias) and allergic disease
Persistent inflammation
Cancer (viral associated - EBV, HHV-8)
Which infections can cause immune deficiency?
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)
Which drugs can cause immune deficiency?
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)
What is Good’s syndrome?
Thymoma and antibody deficiency - combined T and B cell absence
Susceptible to PJP, candida etc.
Also susceptible to autoimmune conditions including myasthenia gravis
What is the method of looking for an immunodeficiency?
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
What are the second line tests to investigate immune deficiencies?
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
What are the important third line tests to investigate immune deficiencies?
Looking for anti-cytokine and anti-complement antibodies
How do you manage secondary immune deficiencies?
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
What is the natural history of HIV infection?
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
What are the characteristic immune features of HIV infection?
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
How is HIV diagnosed?
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
How is HIV managed?
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
What are some important baseline investigations for an HIV patient?
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
What is the HLA-B*5701 test for?
To decide whether to avoid prescribing Abacavir - an NRTI (can cause toxic epidermolysis necrolitis if they have this gene)
What are the limitations to HAART?
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
