HIV therapy

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

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

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

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

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.

Saquinavir inhibits nelfinavir to inhibit its protease activity 

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. 

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

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

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

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?

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

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

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 

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