Immunology 4 - HIV infection Flashcards
Using which enzyme does HIV replicate inside cells?
Reverse Transcriptase
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
**both of these are envelope proteins
They are used to enter cells
**they bind to the CD4 receptor on helper T cells**
Which cell of the immune system are affected by HIV?
- CD4+ T cells
- Other cells of monocytic lineage that express CD4
- monocytes
- macrophages
- Also dendritic cells - especially follicular dendritic 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 does HIV have high mutation rate?
- reverse transcriptase conversion of RNA –> DNA - enzyme lacks proofreading mechanisms
- High error rate in transcription of integrated viral DNA –> RNA
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
- 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 - initially they rise in response to infection then fall as CD4 cell count falls
CD4 - eventually falls
Plasma viral load
What is long-term nonprogression of HIV?
Individual who is asymptomatic 10 years after infection
How can HIV be detected?
1) screening
anti-HIV antibodies (ELISA) - need to do 3 assays to avoid false positives
2) confirmatory test of infection
Western Blot = Confirmatory test
3) most sensitive test
Viral PCR (detects HIV RNA)
4) monitoring course of HIV
- flow cytometry- detects CD4 cell count
How are CD4+ T cell levels measured in HIV infection?
Flow cytometry
What are the two methods of testing for ARV resistance?
- *Phenotypic** - viral replication is measured in cell cultures exposed to HAART and compared to wild type
- *Genotypic** (involves directly sequencing the amplified genome)
Which drugs make up a HAART regimen?
Three or more drugs from 2 different classes + one or more binding agents
Two possibilities:
1) 2 NRTIs + 1 NNRTI
2) 2 NRTIs + 1 protease inhibitor
When should HAART treatment be initiated?
Immediately
Give 2 examples of NRTI HIV drugs
Zidovudine
Lamivudine
Recall 2 examples of nucleotide RTI
TENOFOVIR
bone and renal toxiicty!
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
Which infectious disease causes the most deaths?
HIV
What type of virus is HIV?
Retrovirus
It has an RNA genome
That is converted to DNA using reverse transcriptase enzyme once inside the human cell
How is the HIV genome organised?
- contains 2 RNA molecules
- each of the 2 RNA moelcules contains HIV genome and reverse transcirptase enzyme
- each of the RNA moelcules is encapuslated by capsid gag p24
- p17 matrix closely attached to the envelope in virus membrane
- virus membrane is derived from the host cell and contains protease enzyme
How does HIV enter T cells? What happens to the T cells when infected by HIV?
- gp120 on HIV binds to CXCR4 on T cells
- This then exposes GP41 on HIV membrane
- binding of gp41 to T cell stabilises the binding
Once HIV enters T cells, it injects its RNA which integrates into host DNA–> kills off the T cell
How does HIV infect macrophages and what happens to macrophages afted they’re infected?
HIV binds to macrophages via CCR5 receptor
Macrophages don’t die, but contain a reservoir of HIV
macrophages can then infect the CNS as they are able to cross the blood brain barrier
What is the innae immune response to HIV?
- non specific activation of macrophages
- activation of NK cells
- non specific activation of complement
- release of cytokines and chemokines
- stimulation of plasmacytoid dendritic cells via TLR
Is our antibody response to HIV effective and why?
- takes a while to produce these neurtaolising antibodies (3-6 months)
- by then it’s too late to neutralise the virus
- also just because the antibodies coat the virus doesn’t affect the virus as it can still infect cells via Fc receptor
How long from HIV–> AIDS?
8-10 years (usually)
2 examples of integrase inhibitors
Raltegravir
Elvitagravir
2 examples of entry inhibitors
Maraviroc
Example of fusion inhibitor
Enfuvirtide
Mechanisms of action of HAART
Why is it problematic?
- reduces viral replication
- causes 2 rises in CD4 count because a) redistributes memory T cells from lymphoid tissues to blood and b) preserves thymus so it’s able to pump out naive T cells
–> improvement in immune defenses
Problematic because:
1) does not elminate the virus
2) fails to restore HIV specific T cell responses
Life expectancy of people with HIV if not treated?
only 20 years
which protein provides structural support for HIV?
Gag protein
summarise the immune response to HIV infection
How does HIV damage the immune response?
what is the median time from infection with HIV to development of AIDS?
typical: 8-10 years
rapid: 2-3 years
**some don’t progress, have stable CD4 counts and no sx after 10 years
examples of protease inhibitors
What is a protective antibody in HIV?
anti gp 120
protective mutation in
hiv
ccr5
