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Wednesday, August 17, 2005

Antivirals

This guy Wilhelm is a supposed virologist, but in the discussions I've seen he's at best half-educated in the field.

Firstly he makes the old mistake of assuming that the nucleoside analogues (RTIs like AZT) are DNA chain terminators primarily. They are not, they are reverse-transcriptase inhibitors primarily, and they act by chain termination. Am I nit-picking? No - and here's why.

You probably have a car right? You probably use a key to get into and start your car, right? Does your key work on your neighbour's car? No? Why - because it fits only your car.

The same is true of drugs like AZT, they cannot possible act on a DNA chain unless they are placed in position and chemically altered to join the DNA chain. The positioning and altering is done by enzymes like HIV reverse transcriptase (RT) and cellular DNA polymerase. AZT doesn't fit DNA polymerase. AZT does fit RT. This can be shown in chemical assays and in tissue cultures - AZT and other similar drugs are many more times effective against the virus than against the cells (some cross-reactivity with cellular enzymes is almost inevitable, but even here AZT isn't even the worst...!)

So not only will AZT not work to chain-terminate unless HIV RT is present, it will ONLY work on the DNA chain that is linked to the viral enzyme! So antiviral drugs like AZT are very specific to the virus, and act directly against it.

Wilhelm speaks as if AZT acts on the proviral DNA. It can't possibly do that, because by the time the provirus is there, reverse-transcription has already finished. The only way you can reduce proviral load is to kill off infected cells. The Perth Group in fact try to argue this same point in their anti-AZT critique and state the obvious - if you close the stable door when the horse is in the pasture you can't reduce the number of horses in the pasture... Stupid bastards.

He's also obviously ignorant that the protease inhibitors were the first "designer drugs", drugs that were designed on a computer to chemically match the target enzyme (the viral protease) rather than any other similar enzyme. These drugs are the best example of virus-specific drugs out there! Viruses do indeed use the cell's machinery to replicate, but many viruses also carry their own essential enzymes that aren't found in the cells. HIV carries three of them, of which two are currently attacked by drugs (reverse transcriptase, protease, integrase). It also has several accessory proteins that aren't enzymes but are essential for HIV to replicate. These too can be targetted, at least in the lab. The most important two are called Tat and Rev. They may become future drug targets as well.

His comparison between bacteria and viruses is absurd. Bacteria do mutate, but their mutations are also completely random. What they do which many viruses do not is acquire large chunks of new DNA in the form of plasmids. These can spread antibiotic resistance very easily, even between different species of bacteria. Bacteria can no more "adapt" to a new environment than we can. Do we grow gills when we're drowning? No. But if you hand us a snorkel or scuba gear we can do quite well! Antibiotic resistance plasmids are the bacterial scuba gear.

All mutations are random, in bacteria, viruses and human beings. Viruses in fact are far superior to bacteria in the rate of mutation at the nucleotide level because they replicate at far higher rates. When you have several thousand progeny, it doesn't take many rounds of replication to come up with an advantageous mutation such as a drug-resistant enzyme. The defective viruses will die, and in the face of drug therapy so will the neutral viruses, leaving only the resistant ones. It's called Darwinian selection - survival of the fittest.

If a resistant bacterial colony appears on an agar plate it is not because the bacteria "developed" resistance, its because among the bacteria that were present all the non-resistant ones died off, leaving the resistant one to take over.

What is most striking is that you can these days predict which drugs HIV is resistant to by sequencing the virus from each individual patient. This feat alone should be impossible if HIV didn't exist, not least because why would the same mutations always appear with the same drug-resistances? People with HIV these days can change drugs with the knowledge that their HIV is NOT resistant to the new one, whereas in the old days it was mostly trial and error. You can correlate drug resistances to treatment success or failure - again, this makes no sense if the virus is meaningless and the drugs non-specific. This simple, common practise every day in HIV clinics all over the world, disproves the dissident views on so many counts.

Not least the views of this guy, apparently the closest thing they have on the forum to a scientist. I wonder what he would think of Aciclovir acting against herpes viruses....

9 Comments:

Blogger Brad said...

Hi there,

I wasn't sure if you had come across this article yet. It's relevent to your subject matter, so I wanted to share it with you:

Mother who denied Aids link faces police investigation after death of daughter

Cheers,
-Brad

4:56 PM  
Blogger Bennett said...

Oh dear - this is actually kind of sad. Most dissidents and orthodoxy alike know of Christine Maggoire and the recent death of her daughter. This is the first I've heard of any definitive diagnosis about her death. You can tell I've been out of the loop recently..

I dunno exactly what they've called "HIV related pneumonia". If it's something like CMV or PCP then I'd have to, unfortunately, agree with that label. However kids can and do get other pneumonias like streptococcal. Right now no-one seems to have the facts to hand, except the coroner, and he's not talking.

Thanks for the link.

Bennett

7:51 PM  
Blogger ┬┐Que fue loco? said...

You defend AZT eloquently, yet do not mention what happens with nucleic acids in the mitochondria in the presence of AZT: as a drug it is hard to defend - but Duesberg's relentless attack on it can be justified by a non-scientist just by reading some of this 'orthodox' AZT literature:

Could valproic acid eradicate HIV from the body?

http://www.aidsmap.com/en/news/7E9AE4D0-FA87-432E-837F-7A350A8F4E94.asp

None of the patients experienced severe adverse effects during the trial, although all had mild irritation at the sites of T-20 injection, a well-known side-effect of this drug. In addition, one patient taking AZT (zidovudine, Retrovir) experienced anaemia, possibly due to increased AZT levels caused by addition of valproic acid.

Drugs at a Glance: AZT What are the side effects?

http://www.thewellproject.org/Treatment_and_Trials/Anti_HIV_Meds/Drugs_at_a_Glance_AZT.jsp

Low white blood cell count (neutropenia)
low red blood cell count ( anemia)
Myopathy
blood (lactic acidosis),
enlarged liver,
liver failure,

Authors
Lamperth L. Dalakas MC. Dagani F. Anderson J. Ferrari R.
Institution
National Institute of Neurological Disorders and Stroke, National
Institutes of Health, Bethesda, Maryland.
Title
Abnormal skeletal and cardiac muscle mitochondria induced by zidovudine
(AZT) in human muscle in vitro and in an animal model.
Source
Laboratory Investigation. 65(6):742-51, 1991 Dec.
Abstract
To examine the mechanism of mitochondrial myocytotoxicity caused by
long-term administration of zidovudine (AZT) in human immunodeficiency
virus-positive patients, we examined the effect of AZT in vitro on human
muscle in tissue culture and in vivo in rats treated with daily
intraperitoneal injections of AZT at doses equivalent to the total daily
dose used in acquired immunodeficiency syndrome patients. After 19 days,
the AZT-treated myotubes in tissue culture exhibited abnormal mitochondria
characterized by proliferation (mean +/- SD, 27.5 +/- 8 mitochondria/16
microns2 surface area, compared with 12.8 +/- 4 in the control cultures (p
less than 0.001], enlarged size, abnormal cristae and electron-dense
deposits in their matrix. The changes were partially reversible after AZT
withdrawal. Rats treated with AZT developed weight loss, 100-fold
elevation of creatine kinase, and increased serum lactate and glucose. In
tissues, AZT had its highest concentration in the skeletal muscle and the
heart. Skeletal and heart muscles from the treated animals, but not the
controls, showed enlarged mitochondria with disorganized or absent cristae and electron-dense deposits in their matrix. Study of the mitochondrial functions assessed by evaluating stimulated oxygen consumption rate, enzymatic activities of electron transport chain and coupling state of oxidative phosphorylation (respiratory control ratio) revealed a decrease in rotenone-sensitive NADH cytochrome C reductase (complex I + III) and an
uncoupling effect demonstrated by decreased respiratory control ratio. We
conclude that AZT, a DNA chain terminator, is a muscle mitochondrial toxin
that affects the oxidation-phosphorylation coupling and the activity of
complex I and III of the mitochondrial respiratory chain.


Unique Identifier
91113257
Authors
Shaw DR. Knight DR. Waterman AL. Sommadossi JP.
Institution
Comprehensive Cancer Center, University of Alabama, Birmingham 35294.
Title
3'-Azido-3'-deoxythymidine inhibition of human lymphocyte cytolytic
function in vitro.
Source
Biochemical Pharmacology. 41(2):287-91, 1991 Jan 15.
Abstract
Despite administration of 3'-azido-3'-deoxythymidine (AZT, Zidovudine) to
seriously immunocompromised patients, little has been reported regarding
effects of AZT on specific immune functions. This study analyzed the in
vitro effect of AZT on normal human lymphocyte cytolytic activity. AZT at
concentrations up to 100 microM had no effect when added directly to
cytotoxicity assays with lymphocyte effector cells and natural killer
(NK)-sensitive or NK-resistant target cells. In contrast, addition of AZT
to lymphocytes cultured for 4-10 days with interleukin-2 (IL-2) prior to
cytotoxicity assays produced a concentration- and time-dependent
inhibition; this effect was not mimicked by acyclovir or ganciclovir.
Lymphocyte cell numbers and viability were not reduced in parallel to
inhibition of cytolytic activity by AZT. Furthermore, AZT inhibition of
IL-2-dependent cytolytic activity was not correlated with alterations in
lymphocyte cell surface phenotypes by flow cytometry, and lymphocyte
culture supernatant levels of interferon-gamma were not reduced by AZT.
These results suggest that AZT may selectively inhibit human lymphocyte
functions and thus may have implications for long-term therapeutic
administration of AZT in chronic immunodeficiency states.

12:47 AM  
Blogger Bennett said...

Hi again Que.

I'm not saying that AZT is perfect - far from it, it is probably the second worst anti-HIV drug. I find it amusing that no-one really comments on the worst!

In the same vein, one can defend AZT using the same dissident literature - many if not all of the papers that state that AZT can kill cells also show that AZT can, at far lower concentrations, stop viral replication.

My point is not that AZT it perfect, but if you're going to criticise it then at least have some solid evidence. The stuff you present, that of mitochondrial toxicity, fits with all the evidence. Most neatly it is also interesting to note that the mitochondrial DNA polymerase (which is different from the cellular DNA polymerase) is similar to HIV reverse-transcriptase in several respects. The Perth Group even allege that Montagnier confused it with RT in his early work on HIV. It is not surprisingly in molecular terms that AZT, the first "selective" reverse transcriptase inhibitor, cross-reacts with this enzyme.

Duesberg simply states that AZT causes AIDS, which is ludicrous and makes no sense at all. There is certainly no evidence for that!

10:04 AM  
Blogger Trent said...

Dr. Bennett:

Your email is posted here som I am leaving this in the comments. I have posted a rebuttal of the refutation of the ME in the pediatric AIDS case mentioned above. It is here:

http://catallarchy.net/blog/archives/2005/11/29/hiv-dissidents-continued/

I have posted an update of it here:

http://catallarchy.net/blog/archives/2005/11/29/hiv-dissident-the-continuing-saga/

In the update I have linked to a paper you wrote for Orac at "Respectful Insolence" that I am hosting on my group blog. I understand you have given permission to do so, right?

Anyway, stop by and feel free to add your comments.

1:32 PM  
Blogger Bennett said...

Thanks Trent, I'll add a new post here with all the relevant links :o)

Bennett

2:20 PM  
Blogger Brian FInch said...

All I know is that I was getting quite sick before HAART, including AZT. My quality of life has improved and my counts have worked. Argue as you may about some of these issues, but this is what I care about as someone living with this. And yes I am aware how some of the medications affect mitrochondria (sp?). For me its better than the alternative!

6:44 PM  
Blogger Mark said...

Question: I thought AZT was created by Sigma Pharmaceuticals in 1969 as an oral chemotherapy, but then shelved because of extreme toxicity (warning labels indicate not to inhale or touch). Given its original intended use, wouldn't it have to be a DNA chain terminator if it was going to be effective against cancer? Or do cancer cells also make use of reverse transcriptase? I'm quite confused and would ask you to review the historical data on this drug, as most people don't know it's been around for decades and was shelved completely because of extraordinary toxicities.

9:38 AM  
Blogger Bennett said...

Hi Mark,

It's a complete fabrication that AZT was shelved because of toxicity. The myth originated from Duesberg's book, in which he states that AZT "must have" been shelved due to toxicity, because in his mind AZT was an indiscriminate DNA chain terminator.

In point of fact, AZT was shelved because of sheer lack of activity in laboratory and mouse models. It wasn't toxic ENOUGH to kill the tumors and was shelved. Duesberg's error is in not appreciating that AZT won't terminate a growing DNA chain until it is bound to the DNA polymerase enzyme and added to the chain. AZT quite simply doesn't bind very well to cellular DNA polymerases, but does bind well to viral reverse transcriptase. As such, it doesn't matter whether or not AZT is around our own DNA, as without attaching to the DNA polymerase it can't be inserted into a growing DNA chain.

I'm afraid your comment has to be turned around completely - most dissidents simply aren't aware that AZT was shelved due to a lack of efficacy (toxicity) and that the myth originated from a very simple misunderstanding.

Ironically enough this story is detailed on a dissident website, in an exchange between David Crowe and Dr Richard Beltz, who invented AZT. I wrote about it long ago on this blog.

AZT - Not toxic enough

11:23 AM  

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