Wednesday, August 17, 2005


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....

Monday, August 15, 2005

Latency Confusion

I've noticed a lot of confused/conflicting posts over the last week or two regarding the old doozy of HIV latency. The concept isn't helped by the fact that the word has two meanings, and BOTH apply to HIV and AIDS. One article talking about latency may have nothing at all in common with another. The difference is explained during undergraduate virology classes, but since so many of the dissidents are either untrained or deliberately choose to mislead their readers, this makes excellent fodder for anti-HIV "logic".

Clinical Latency
HIV infection has a well known asymptomatic period, in between the seroconversion illness (which doesn't always happen - 50% of the time) and end-stage disease (AIDS, which nearly always does happen - 95% of the time). This period is known as clinical latency, because clinically (meaning, in terms of wellness, signs and symptoms) there isn't much going on. Generally speaking, only lab tests will give a hint that something is amiss, such as depressed CD4 T cells, and of course virus-specific tests like antibodies and viral load.

However, it is now well established that during this time "the virus" is replicating at a significant rate. This rate is reflected in the amount of virus in the peripheral blood, the viral load. Although the virus replicates in lymph nodes, of course some gets out into the blood, and this can be detected using standard tests like RT-PCR (the RT bit refers to the fact that the virus is made of RNA, and so as to be converted to DNA for the PCR to work). If the virus were dormant then there would be no viral load. The only reason why the infection doesn't become run-away is that the immune system is able to partially control it. Contrary to popular dissident belief, it is not due to antibodies. As with most viruses, it is the CD8 T cells than control the infection. In an ideal situation the CD8 response would be able to clear the infection, but HIV has the ability to persist. That ability is tied into the following:

Virological Latency
Now, on the level of the individual infected cells, some will NOT be producing viruses. And by producing viruses, we're talking thousands at a time. Viruses do not replicate by multiplying, like bacteria, or through offspring like sexual animals or plants. Rather they literally turn an infected cell into a virus factory. One virion can result in thousands or millions of other virions, depending on what virus we're talking about. This is required because we know that not all viruses are active, in the case of HIV it might only be 1 in 60,000 peripheral viruses - the others are either genetically defective or physically damaged.

Because HIV has the requirement for cellular transcription factors (NF-kB specifically) if that protein isn't around, it won't do anything. The provirus will be latent. This is virological latency, and is found also in herpes viruses. However, since in a population of many millions of T cells some will be producing NF-kB, say in response to a pathogen they recognise, not all the proviruses will be latent.

The analogy is perhaps a snowstorm on a TV screen. Some of the dots are white, some are black. Overall the image is a grey fuzzy mess! It doesn't mean that each virus is "half active", in fact there is good evidence that for HIV it really is an all-or-nothing response. Either the provirus is shut down, of it's fully active. Black, or White.

So when you hear people talking about "reactivating latent virus" they're referring to turning all the black dots white. When they're talking about "HIV replicating throughout infection" they're referring to the fact that it's a snowstorm rather than a black-out. As a virologist, this makes perfect sense to me, because comparing clinical and virological latency is like comparing chalk and cheese. Sometimes they might coincide (e.g. herpes breakouts) but there is no logical reason why they MUST coincide. The two concepts are not contradictory or confusing, although it's easy to see how they might be to some people!