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HIV - Coggle Diagram
HIV
Epidemiology
Pandemic
- Global outbreak of an infectious disease
- Took over the world in the 80s, but has since declined. Much better in 1st world countries, but 3rd world countries are still struggling
- Deaths are declining globally, thanks to ART
- But deaths are rising in Eastern Europe + Central Asia bc of drug use being criminalised/stigmatised
- Most people who get diagnosed late are from high prevalence countries
Cause: MSM
- Asia/Pacific
- Latin America, Caribbean
- Western/Central Europe, North America
- AU non-Indigenous (71%), AU Indigenous (45%).
Cause: Sex Clients, Drugs
- Eastern Europe, Central Asia
- Middle East, North Africa
Cause: Other/Everyone
- Western/Central Africa
- Eastern/Southern Africa
Stats
- 36.7 mil people living with HIV globally
- Risk of serious illness/death reduced by 53% in immediate vs deferred ART
- 10% strains are drug resistant
- ART reduces infectiousness by 96%
Australia
- Once testing was available, cases peaked. Then eventually cases started decreasing because of prevention, but not much has decreased since 1999, until 2018
- 1000 new infections each year
- Higher rates in Indigenous (6x)
- MSM is biggest cause, but PreP has resulted in decline
- Cohort of Australians with HIV is aging bc life expectancy is increasing thanks to ART
Virology
HIV Entry
- GP120 in envelope binds to CD4 receptor
- GP120 x CD4 complex binds to CCRT/CXCR4 in host cell
- Virus fuses with membrane, then enters
Main receptors: CCR5, CXCR4
- CCR5 is most common, nearly all infections are R5. Cause less TC destruction
- CXCR4 is rare, but emerge late in infection. 50% AIDS patients are X4 bc slow detection
- Natural resistance to CCR5 caused by lack of CCR5 expression —> no binding with HIV
CD4+ Cells
- Activated: causes death
- Resting: remains latent
Monocyte/Macrophages
- Long lived, slow release of virus
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Immunology
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Evading Immune Response
- Frequent mutation —> lots of sequence variation, sometimes antagonism
- Altered Ag presentation caused by Tat, Vpu, Nef down-regulating MHC I molecules
- Less effector cells bc clonal exhaustion, loss of CD4 cell help
- Latency. In resting TCs, macrophages, privileged sites (brain, GIT, testes)
- Certain HLA types can tackle HIV epitopes more effectively, but some are more susceptible
Primary Infection: normal CD4 count
Early: CD4 > 500
Intermediate: 500 > CD4 > 200
Advanced: CDR < 200. AIDS, basically
CD4 Cell Effects
Increased destruction
- Affects GIT more than heart
- Incomplete rev transcription
Indirect effects
- Syncitium (cluster of gated cells, binds to other cells
- Apoptosis
- Immune activation
- Lymph node fibrosis
Impaired production
- Thymus
- CD34+ progenitor cells
There’s more CD4 loss indirectly than directly
Immune Activation
- HIV elevates markers that activate more immune cells
- Overwhelms the immune system, allows more virus targets to open up
- Tends to persist even during treatment
Caused by
- Mucosal depletion of CD4s
- Innate immune response activation (pDCs)
- CMV specific TCs are activated, expand. Characteristic sign of ageing (dysregulated immune response)
- Loss of Tregs (anti-inflamm cells)
Effects on Other Cells
- CD8+ abnormally high when acute, but declines later
- NK impaired
- Mono/Macrophages have defects
- BCs produce more IgA and IgG but less Abs. Affected indirectly
General
Lentiviridae, a retrovirus.
- Has an envelope
- Icosahedral capsid
Genome
- Highly variable proteins: gag, env
- Regulatory proteins: tat, rev, vpr, vpu (allows virus to exit), vif (inhibits host’s enzyme to edit RNA), nef
- Main structural protein: gag
- Viral enzymes: pol
- Envelope glycoproteins: env
- Also, Integrase (integrates HIV RNA into host DNA)
- m7G cap
- AAAA at the end
Structure
- Lipid bilayer membrane, gp 120 embedded in it
Env —> Gag —> Pol
- Has different clades in different regions
Primary retroviruses;
- SIV
- EIAV (Equine)
- BIV (Bovine)
- FIV (Feline)
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Replication
- Highly prone to error
- Rapid (each cell produces 100,000s of virions, 10 bil particles produced per day)
Treatment
Cure
Barriers
HIV rebounds rapidly when ART is stopped
Latent Infection
Latent cells are
- DNA +ve
- RNA -ve
- HIV protein (Ag) -ve
- rare, hard to find
- hidden from immune system
- Clonally expanded infected cells can account for almost 50% of infected cells
Residual Viral Replication
- Normal cells can’t be infected, but they can survive + dribble out low levels of virus on standby for attack after ART is stopped
Anatomical Tissue Reservoirs
- Brain
- Testes
- GIT
- BC follicles in lymph node are closed off to CTLs and ART, so HIV can persist there
Only two patients who are fully recovered. Needed bone marrow transplant , which normally never happens under ART/HIV bc of high toxicity/rejection risk. The donor had a CCR5 defect, making them resistant to most types of HIV
Cured vs remission
- Stop ART, see if the viral load increases again. Only recommended during trials, not clincal
environments
- Rare remission cases happen during (v) early treatment, and heavy treatment (chronic/sc transplant)
Remission off ART
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Gene Therapy
- Eliminate CCR5: Extract CD4 use ZFN modification on CCR5, reinfuse
- Can get 5-15% of cells treated, but doesn’t seem to be enough to work
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Latency Reversal: Shock and Kill
- Use latency reversing agent, expose infectious cell
- Use immune-mediated killing/pro-apoptotic drugs
- Kill cell
Multiple latency reversal agents exist btw, most potent are TLR agonists. Need more work though
Permanent Silencing: Block and Lock
- Make a cell so latent that it’ll never activate, like brain death
- Use RNA-silencing inhibitors
- Not clinical yet
Antiviral Treatments
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- Must treat with multiple drugs, otherwise HIV will develop resistance quickly
- Rapidly declines HIV RNA count, CD4 recovers too
- Life expectancy greatly increased now
- Don’t delay treatment
- Hoping to streamline treatment to make dosages less frequent
- Want to have fast track targets so that most who are aware, are on HIV treatment, and are virally suppressed. Also less infections
Current Challenges
- Life expectancy still hampered if treatment is delayed
- ART doesn’t adhere, HIV resurges when it stops
- Side effects
- Drug resistance is rare if medication is taken properly, but it still happens
- Persistent TC activation, immune activation (multiple causes + effects), even when on ART
- Even with ART, risk of ageing diseases increases (2x)
Prevention
Prevention as Treatment: PreP.
- Treatment can reduce the virus to an undetectable and untransmittable level, reducing infection.
- U = U
Prevention of Maternal Transmission
- Even with weak ART, risk of transmission is significantly reduced
PreP
- Less effective in women, but highly efficacious in MSM
- Take daily, intermittently, but must adhere
- V few cases where PreP didn’t work; involved drug resistance, inadequate dosing, etc
- Global uptake is still limited. Need to widen access, but it’s costly
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Treatment as Prevention
- ART reduces infectiousness significantly
Vaccines
- Must cater to different clades
- Aim 1: Develop better CTLs
- Aim 2: Develop Abs to bind + neutralise HIV. More focus here
Recombinant Proteins
- Good Ab, bad TC
- No protection
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Prime + Boost Strategies
DNA + protein
- Thai trial, N = 16,000
- Reduced HIV acquisition by 30%, only successful study
- Need 60% success rate to be enough though
DNA + live vector
- STEP trial, 2008
- Used Ad5 boost; Ad5 induces TC activation —> could open up more targets
- Possibly increased infection risk
Ad26 + gp140 (Vector + protein)
- Phase 2/3 of clinical trial
- Gave monkeys 67% protection
bnAbs
- Atm administration is only passive
- Only made by some individuals (they can’t clear the virus themselves bc they develop slowly. Detected after 1-2 yrs)
- Directed against highly conserved, normally hidden regions in envelope
- Can help in all aspects: prevention, treatment, cure
- Good, but ART is still more effective
- Robust protection with multiple bNAbs
- Good, but ART is still more effective. Need serum-level concentration to be effective
- Try to combine bNabs (mono/di/trispecific) to enhance efficacy/reduce resistance
- Modify Fc to improve performance
- Aim to generate bNabs in vivo through vaccination (instead of injecting passively)
CMV (Cytomegalovirus) Vectors
- Persistent Ag presentation
- Look promising in macaque reseearch
Adenovirus Vectors
- Ad26 has minimal prior immunity, so will not be rejected by body
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Dapivarine
- Non-nucleoside RVT inhibitor
- Two studies done, poor effectivity due to low compliancy
Circumcision
- Removes Langerhan cells in foreskin, which contain targets for HIV
- Needs more funding to stay consistently successful
Diagnosis
- Late diagnosis identified when CD4 < 350 upon diagnosis