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HIV and AIDS
Global: 40M HIV positive
25M AIDS deaths from ‘80 (60% sub-Saharan Africa)
80+% male
Canada: 63K HIV positive
16K AIDS deaths since 1980 (83% male)
BC: 13K HIV positive
3K AIDS deaths since 1980
AIDS and HIV Cases in Canada over the past 30 years
THE HIV VIRUS
Disease discovered in 1981; virus discovered 1983
RETROVIRUS – Normally DNA is used to form RNA in the host cellIn HIV, RNA forms DNA in the host cellIt is a cell parasite, can only live in a cell, uses host material to reproduce
It is a piece of RNA packaged in a protein with a fatty envelope.It attacks our T4 cells, preventing defense against other viruses, bacteria
Symptoms: fever, cough, headache, sweatsIn 6-12 weeks blood tests +ve for HIV
Disease (AIDS) can switch on at any time: swollen lymph nodes, tiredness, loss of weight,
abdominal discomfort, diarrhea, fevers, itching, attack by opportunistic infections(pneumonia is most common in Canada)
TREATMENT
Three main types1) REVERSE TRANSCRIPTASE INHIBITORS2) PROTEASE INHIBITORS3) ENTRY INHIBITORS
coming now: Integration inhibitors and Maturation inhibitors
Sugar
Base
O PO
OOH
na nucleotide
Sugar Phosphate Sugar Phosphate
Base Base
RNA: sugar is riboseDNA: sugar is deoxyribose
THE BASES:
HN
N
O
O
S
N
N
NH2
O
S
N
N
N
N
S
NH2
N
N
N
N
S
OH
NH2
S = attachment point of sugar
T = Thymine C = Cytidine A = Adenine G = Guanine
OPhosphate-O
OH
BaseOPhosphate-O
OH
Base
OH
THE SUGARS
2-deoxyribose (DNA) Ribose (RNA)
1) REVERSE TRANSCRIPTASE INHIBITORS
RNA/DNA
Made of
Nucleotides:
These provide the templates for making proteins (we will see this in detail under proteins):
each set of 3-bases provides a template or code for a single amino-acid in a protein
so if the virus can be tricked by feeding useless mimics of these nucleotides, it might produce a useless protein or not even produce one
prevents the virus from building new DNA from its RNA, and they are thus called REVERSE TRANSCRIPTASE INHIBITORS
AZT DDI DDCmimics: thymidine guanosine cytidine
HN
N
O
O
OHO
N3
N
N
NH2
O
OHO
N
N
N
N
OH
OHO
Azidothymidine Dideoxyinosine Dideoxycytidine[zidovudine, Retrovir] [didanosine, Videx] [zalcitabine, Hivid]
5 x 100mg 2 x 200mg 3 x 0.7 mg /day
cocktails work better: eg. 0.75 mg DDC + 200 mg AZT every 8 h
AZT was first made in 60's as an anti-cancer drug (same mechanism) but it did not work
BUT it does work for the HIV virus
Approved in 1987: Burroughs-Welcome stock rose $3B overnight!
DOSE then was 1.2 g/day ($8000/yr), now about 500 mg/day (at the same cost!)
AZT SIDE EFFECTS: supressed bone marrow production, low white cell counts, anaemia, nausea, headaches, muscle wasting
DDI is less active BUT less toxic, so less side effects: peripheral nerve damage - feet tingle(About 40% cannot tolerate AZT)
In Canada: didanosine (DDI), lamivudine (3TC); stavudine (d4T), zalcitabine (DDC)
zidovudine (AZT)
3TC = Heptovir = 3-thia( )-dideoxycytidined4T = Zerit = 3-deoxy-thymidine-ene ( )
ACYCLOVIR [ZOVIRAX]
N
N
N
NH
CH2OCH2CH2OH
O
NH2
HERPES VIRUS INHIBITOR
for HIV, AZT + ZOVIRAX works better than AZT alone
For herpes (lips or genitals): cream (50 mg/g) or oral: 200 mg/4 h (5x per day) for 10 days
Herpes: famciclovir, valacyclovir, valganciclovir, ribavirin
2) PROTEASE INHIBITORS: Inhibit the enzyme that cleaves
the viral large proteins in to new ones used for assembly
HON
O
NHO
H
H
S O N
Viracept - nelfinavir
O
O N
O
HO
NSOO
NH2
Agenerase - amprenavir
N
N
N
O N
N
HOO
OH
Crixivan - indinavir
NN
O
N
O
OH
N
NO
H
HO
NH2
Invirase - saquinivir
S
N
N
O
NN
O OH
N O
O
S
N
Norvir - ritonivir
atazanivirfosamprenavirlopinavirdarunavir
Use about 800mg every 8 h; $10-15,000/y
Most cocktails knock down the virus levels rapidly in 1st two weeks, more slowly after that
Cannot stop drugs, even for one day!
Cocktails have advantage of reducing resistance.
Relenza (zanamivir), and Tamiflu (oseltamavir) for FLU are also protease inhibitors (not effective against H5N1):
3) ENTRY (FUSION) INHIBITORS
Glycoproteins on virus (GP41 and GP120) bind to surface protein receptors (CD4 and CCR5) on T-cell facilitating cell fusion and virus entry
Enfurvitide: 36-peptide chain that binds to GP41
and prevents it binding to CCR5
Approved drugs in this class
Maraviroc (Selzentry) by Pfizer:
binds directly to CCR5 and blocks fusion
appears quite safe for longterm use
Maturation Inhibitor: disrupts protein protecting virus core
Virus budding inhibitors –yet to come
Integration Inhibitor: stops integration of viral dna into host cell’s dna to replicate virus – not in other cellsraltegravir (Isentress) from Merck approved FDA Oct 07
Other strategies being explored