HIV therapy

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Current therapies

3 classes of drugs licenced for standard therapy:
1. Nucleoside analogue reverse transcriptase inhibitors (NRTI's)
2. Non nucleoside analogue reverse transciptase inhibitors (NNRTI's)
3. Protease inhibitors 

Highly activate anti-retroviral therapy (HAART)
- Triple therapy, usually 2 NRTI's and NNRTI's or PI
- 99% reduction in viraemia in 8 weeks

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NRTI's

e.g AZT
- Selective inhibitor of HIV RT
- Phosphorylated by cellular kinase 
- Binds to RT better than TTP
- 100 fold greater affinity for RT than cellular polymerase 
Stops nucleotide being added to growing DNA chain by competing 

Problems:

Toxicity- Causes issues in non viral genome replication 
Resistance- Mutates so RT no longer recognises AZT

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AZT

1st synthesised 1964- Anti tumour agent 
Shown to inhibit murine leukaemia virus in 1974
Feb 1985- Shown to be active against HIV in vitro
March 1987- FDA licensed for the treatment of HIV 
- Used in combination therapy to avoid resistance occuring 

Others include: 

ddI, ddC

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NNRTI's

Efavirenz
Nevirapines
Etravirine
Dont get reistant to all at the same time as they are chemically very different

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HIV maturation

Budding 
Release of the virus 
--> Cleavage of the Gag and Gag-pol to individual polypeptides causes maturation. 

Maturation

Before= Gag, Gag-Pol are imbedded into membrane, they cannot infect new cells
Then= Protease cleaves them into:
MA- Matrix antigens that remain imbedded
CA- Capsid antigens 
NC
P6
Pro
RT
IN
To form mature structure of virus.

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HIV inhibitor

Saquinavir inhibits nelfinavir to inhibit its protease activity 

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Pros and Cons of HAART

Pros 

  • Manipulate treatment to avoid cross resistance due to so many different drugs. The patient virus is sequenced,often to determine if it is becoming resistant. If so can start new drugs 
  • Treatment interuption- If patient becomes resistant it is because the drugs provide those resistant virus' with a selective advantage. If you take a break, there is no selective advantage
  • Highly effective at reducing viral load and disease progression

Cons 

  • Cost
  • Compliance- effect on the lifestyle- less so now 
  • Side effects- Some people cannot tkae all types
  • Drug- drug interaction- Cant use all together 
  • Post therapy reversion- Drugs for life. 
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Salvage therapy

Entry inhibitors for HIV therapy
e,g Maraviroc: CCR5 antagonist (competes with virus budding) Only useful in early stages of life cycle 
Approved by FDA August 2007 for salvage therapy for patients infected with R5 virus

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T20

Peptide based entry inhibitor 
Blocks conformationa change involved in fusion of viral and cellular membranes by gp41 fusion domain.
16 HIV infected people- parental administration of 3 100mg twice daily for 14 days 
100 fold reduction in viral load at higher dose 
Non toxic 
Subsequent studies in combination with other anti-HIV agents:
- 1000 fold reduction in viral load maintained for 20 weeks
- Limited evidence for genetic resistance
- No anti T20 antibodies detected- No immune response 

It is now licenced for clinical use:
- ENF, synthetic 36 AA peptide
- Licensed by FDA in 2003 for salvage therapy in combination with HAART
- Given 2x daily- injection 
- Expensive ($25,000 per annum) only small quantities are available 
- Resistance can develop but virus shows reduced replication 
- TRI1144 in development

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Intergrase

Catalyses a series of independent events that result in the cleavage of host DNA and splicing of provirus into the cleavage site
Inhibitors
- Raltegravir- Approved Oct 2007 by FDA
- Elvitegravir- Approved Aug 2012
- Doltegravir- Approved Aug 2013

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AIDS vaccine

Problems:
Dont know what nature of protective immunity to induce
HIV genetic variability 
- Especially in the env gene, 10 genetic subtype
- Uneven geographical distribution 

Animal models- Cant use chimps 
Clinical trials
- Phase I/II- safety and immunogenicity ( does it induce immunological response) and does it cause adverse effects 
- Phase III- efficacy- ethical issues
Moral/ethical issues- Who would you give it to?

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Candidate AIDS vaccines

60 phase I+II trials of 30 candidate vaccines so far worldwide
Most envelope glycoprotein based
Safe and immunogenic, induced neutralising AB's in 100% of recipients
Rarely induced CD8 and CTL responses
Combination vaccine: Prime boost
-Prime: Recombinant canary pox-expres envelope glycoprotein gp120
-Boost: Recombinat gp120

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AIDS VAX

VaxGen Inc
Phase III trial 
Bivalent vaccine- recombinant gp120 from lab and primary isolate
Only stimulate Ab- Humoral immunity 
3 Year study- USA/Netherlands/Puerto Rico and Thailand- 8000 volunteers at 40 sites

Failure: 5009 participants
- 3300 vaccines- 5.7 % became infected
- 1679 placebo-  5.8 % became infected

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RV144

Prime boost protocol 
- Prime with recombinant Canarypic virus expressing gp120
-Boost with AIDSVAX recombinant gp120 protein

6 year trial with 16,000 participants in thailand
The cost was $105 million
Results:
- Placebo= 74/ 8198 infected
- Vaccine= 51/ 8198 infected 

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Future

July 2005- NIH established centre for HIV/AIDS vaccine immunology (CHAVI) 
- $300 million

International AIDS vaccine initiative (IAVI) 
-Coordinatiing effort between companies (30) academics institution and government agencies
-Support from world bank, Bill Gates etc

WHO- UNAIDS also has an AIDS vaccine initiative 

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