17 - HIV Flashcards
What 3 things do I need to know
- How a virus causes illness
- How does immune deficiency and chronic inflammation cause illness
- How does a viral infection impact on people’s lives
How may an HIV patient present
- non-specific symptoms i.e. fever and adenopathy (enlarged lymph nodes)
- fever, sweats, malaise, sore throat, anorexia, enlarged tonsils, lymphadenopathy but no hepatosplenomegaly
How did HIV first present
In the early 1980s young homosexual men were being diagnosed with strange illnesses like pneumonia, thrush and mucosal infections in otherwise healthy young people
This indicated that their immune systems were failing
HIV virus
- single stranded RNA virus in a protein capsid in a host envelope
- host envelope is from Th cells so is studded with CD4 T cell
- the envelope also has VIRAL glycoprotein 120
glycoprotein 120
enables the virus particle to interact with the CD4 molecule on helper T cells with the help of CCR5
Where is CD4 found
Surface molecule of some WBCs mostly Th cells
What is CCR5
Co-receptor on Th cells associated with CD4
Chemokine Coreceptor 5
Why is CCR5 important
- drugs can block CCR5 and prevents HIV binding so is an effective treatment for some HIV patients
- Some people also lack CCR5 which limits HIV attachment and slows HIV infection
HIV infection
- HIV GP120 attaches to CD4 (and CCR5)
- a conformational change occurs allowing the virus envelope to fuse with the T cell
- protein capsid and RNA enter the host cell
- capsid is dissolved by host enzymes so genetic info is released
- viral proteins are translated
- reverse transcriptase a viral enzymes makes a DNA copy of the virus RNA (humans make DNA > RNA via polymerases)
- a resulting DNA/RNA hybrid
- DNA is removed by RNAseH and enters the nucleus
- integrase in the nucleus locates a section of DNA that is downstream from transcription activating factors; when these factors are activated the cell will transcribe the viral DNA and proteins
- once activated and transcribed the virus particle assembles with virus RNA and a single long protein and buds off the T cell
- virus particle is still not mature; protease cuts this into appropriate pieces and ensures the proteins fold properly (protease is only active once the virus is released)
Why is reverse transcriptase a good drug target
Humans don’t have these enz so minimal side effects
RNAseH?
Removes the DNA portion of the hybrid piece of genetic information so it can enter the host cell nucleus
What does integrase do
Once in the nucleus the DNA is integrated into the host chrom into a section of DNA downstream from transcription activating factors - when these are activated the cell will transcribe viral DNA and proteins
Special feature about integrase
Integrase is a multifunctional enzyme and often makes mistakes and puts the viral DNA in the wrong/ineffective place so not ALL infected cells will proliferate with the virus
Important HIV proteins for drug targets
protease
integrase
reverse transcriptase
How does HIV deplete T cells
Infects, damages directly and adaptive IS recognises and destroys them
What is a consequence of low Th cells
- a very low number of Th cells occurs about 6 years post infection
- results in a deficient IS and getting mysterious illnesses
- this is advanced HIV infection i.e. there is too few Th cells for them to do their job and so very vulnerable to infection
Difference between HIV and influenza
Influenza has a very short incubation period and turns up the IS to a maximum causing max symptoms almost immediately (INF a)
HIV does not - takes a while for IS to deplete and end up with a CHRONIC illness everyday which can lead to collateral damage to the rest of your body
What are the 2 outcomes of HIV infection and replication?
- Depletion of Th cells
- Immune system activation
> IS activation leads to bone loss, cardiovascular disease, neurological defects
How does virus and Th levels change
- virus levels peak in first 6-8 weeks (SEROCOVERSION ILLNESS)
- immune response occurs and virus level settles (50000 copies per mL of blood)
- during the immune reaction Th cells deplete slightly but mostly recover. May or may not get mild fever like symptoms at this point (asymptomatic HIV)
- over time CD4 cells become more deplete > very low levels lead to changes in the body that are not fixable i.e. changes to the IS and can acquire diseases that cannot be fixed (late stage HIV)
Risks associated with various levels of CD4 cells
At less than 500 there is a risk of illness
Less than 200 increases risk and at this point the viral count is also increasing
At least than 50 the patients are usually very sick and chances of living more than 2 years is very slim q
What happens when CD4 levels drop
Aren’t able to co-ordinate, work with and importantly regulate the IS. Causes viral count to increase even more.
When are mothers screened for HIV
In there first trimester
2 ways we try manage HIV
- Maintain Health
- exercise, sleep, eat well
- reduce alcohol
- stop smoking (eases inflam)
- get on with life/optimism
- stop HIV replication - Prevent transmission
- safe sex, condoms
What is the current treatment for HIV
- 3 drugs with at least 2 different targets
- early treatment in 2017 >90% chance of receiving treatment that works, is safe and durable
- viral load drops to - 0
- CD4 starts to recover and IS recovers
- lifestyle is very important
Why did using a single drug not work previously
Virus would mutate and quickly increase again
Targets
- Fusion
- Reverse transcriptase
- Integrase
- Protease
Why does HIV have a high diagnosis trend
Identifying older cases as well as new
Will a mother with HIV who is being treated pass it on
No 0% if she is being treated hence screening
ARt
antiretroviral treatment
Reduces risk of transmission to 90 > 1%
What are 5 immune system components
- Inflammation and phagocytosis by neutrophils
- Antibody production
- Antigen-specific cytotoxicity (CD8 + antibody dep K cells)
- Non-antigen specific cytotoxicity (NK cells)
- Cytokine mediated immune regulation (Th cells - cytokines released to control and regulate IS)
B clonal activation
B cells specifically recognise antigen, present specific receptors for helper signals (CD4), proliferate and differentiate to plasma and memory cells
CD8 clonal activation
Presented antigen on Class 1 MHC (all nucleated) > helper > diff and prolif
CD4
presented antigen on APC cells with MHC ll > helper > proliferate into cells that secrete cytokines to control all other immune processes
What are the central role of cytokines released from Th cells
- regulate the differentiation of B cells and T cells
- regulate phagocytes in order to carry out phagocytosis and inflammation responses
- regulates OTHER symptoms
Th depletion…
compromises the central method of regulating and controlling immune responses to produce and activate appropriate and effective responses to foreign material and so patients are susceptible to infection and invasion
How are CD4 cells killed
- directly
2. infected cell presents viral protein on MHC l (HLA - A/B/C) recognised by TCR and MHC recognised by CD8
End point of HIV
such a low CD4 cell count that the immune system cant control processes it would usually take care of = Acquired Immunodeficiency Disorder
