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....