HIV and AIDS Global: 40M HIV positive 25M AIDS deaths from ‘80 (60% sub-Saharan Africa) 80+% male...

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