Prospects for an HIV vaccine

Unfortunately, they're extremely poor. Even if they produce one, it's unlikely to be of any use. But to explain why I'm going to have to introduce a lot of background, because you have to understand how viruses work, how our bodies defend against them, what a vaccine does. Then I'll have to talk about how HIV works and how it is unusual.

Whenever anyone tries to define "life", the virus always straddles the dividing line between living and unliving. Looking at its behavior without knowing what it is, it seems to act as if it were living. But in actuality it's little more than a protein coat surrounding some nucleic acids. It doesn't have the ability to do anything we would refer to as "live" on its own; it's completely static when it's outside a cell. The protein coat defends the nucleic acids inside, and also facilitate entry through the wall of a cell which it will try to infect. Once inside, the coat bursts and releases the nucleic acids. These then take over the cell's normal processes and use them to create new viruses. Eventually this kills the cell but only after thousands of new viruses have been created. The cell bursts, spilling the viruses back into the blood to infect other cells. Some of the viruses will be shed into the environment in any of a number of ways, to infect other creatures.

Our bodies contain elaborate defenses against this kind of thing. First, there are cells whose job is to detect that an invasion is in process. When one of them discovers this, it uses a genetic toolbox of about a thousand DNA fragments, and through mechanisms which are not yet well understood it will figure out the genetic description of an appropriate antibody. This is really a custom protein which has a section on one side which is exactly the right shape to connect to something on the invader, which is called an antigen. Once the white cell gets it right, it will start reproducing like mad, creating and releasing antibodies and also creating certain signal hormones to alert the rest of the body that an attack is in progress.

Then there's a pitched battle. Antibodies connect to the invaders, which not only deactivates them if they're viruses but also tags them so that other white cells can engulf them and destroy them with enzymes.

The recognition process is slow. From initial infection it typically takes three days for one or more white cells to get the combination right. After that, they reproduce over a period of a few hours and then battle is joined.

During that initial period, the invading virus is free and clear to do what it will. So it reproduces and its numbers grow exponentially. By the time the immune system is ready for battle, there are a lot of viruses. So eradicating them takes a while. How long it takes depends on the virus in question.

Now it's important to understand the underlying design philosophy behind all this: it all assumes that there's a threshold viral load which is not dangerous, and it only girds for a fight when the load exceeds that amount. When you "get over" a cold, it's not the case that you have no viruses left. Rather, you have so few that they no longer represent a danger to you. The body can't remain in full-scale battle mobilization over long periods; it would seriously harm other things and could kill you. So it gears up when an invasion starts, but stands down once most of the battle is won.

But not totally. After the battle ends, some of the T4 cells, the ones which recognize an invader and create antibodies, remain behind. The immune system has a kind of memory about this, embodied in T4 cells which have already adapted to recognize invaders.

If you are ever infected again with a virus you've already had, the immune system is ready to go. Instead of taking three days to recognize the invasion, the T4 cells already knowing about it start reproducing immediately, producing antibodies. It cuts a process which ordinarily takes maybe three days to less than six hours. And since the number of viruses grows exponentially, it means that the peak viral load in your blood will only be a fraction of a percent of what it would otherwise have been. Indeed, this response is so fast and so efficient that you won't even realize that you've gotten sick again.

But with some viruses, there is substantial damage done before the immune system gets ready for the fight, and in some cases the victim can die. In some cases it takes a lot longer to recognize the invader, for instance. The most fatal disease known in humans is rabies. Everyone who gets rabies and isn't treated for it will die from it; fatality rate is 100%. This is greater than Ebola, which has a fatality rate of about 95%, or Marburg, about 70%.

That's where vaccines come in. The first vaccine was developed nearly three hundred years ago, to fight smallpox. But it wasn't until late in the 19th century that they began to even get an idea how they worked, and they didn't really become practical until early in the 20th century.

A vaccine is, in essence, a benign disease. Its purpose is to introduce antigens into your body which are close to those on a real disease you haven't had. By doing this, your body goes through that three day recognition-and-create-antibody process, only to find that there's nothing to fight. Still, primed T4 cells remain afterwards, and if you then get infected for the first time with the disease, your body reacts as if it had already had it. The response is rapid and effective and the viral load never gets great. In most cases, again, you won't even realize you've been infected.

But you are infected. That's the critical point. A vaccine doesn't keep you from getting a disease. What it does do is make it so that your body responds to the disease far more rapidly so that the peak viral load is vastly lower, which means that the virus has far less opportunity to do permanent harm.

HIV is a ferocious disease with truly pernicious strategies. Viruses do all sorts of weird things, and HIV is one of the worst. It's actually not very infections; unlike adenoviruses it is killed by exposure to oxygen, for instance. So it can only pass from one person to another in body fluids, primarily blood. It cannot be passed by casual contact.

But it can be passed by a number of other activities, like sex and sharing hypodermic needles.

When you get HIV, it initially acts like any other virus and starts to reproduce by entering cells, taking over their systems, making lots of viruses, killing the cells and bursting back out into the blood.

Your body recognizes this and mounts an immune response just as it would against a cold and flu. In a few days T4 cells have recognized the disease and started creating antibodies against it, and you have a battle which the immune system wins. You get over the disease!

But...

But, during that time, HIV plays its trump card. HIV is a "retrovirus" which means that in addition to its normal life cycle, it has the ability to transcribe its genetic information into the cell it infects. In some cases this happens without the cell reproducing viruses, and such an infected cell is a timebomb. There are no viruses in it, but if in future that genetic information gets activated then the cell will start creating HIV. And most insidiously of all, it does this preferentially to the T4 cells, the point men of the immune system.

So what happens is that after the first infection, when HIV hit a high blood load and then collapsed, it becomes chronic. Most of the immune response to it goes away, and it achieves a low but continuous level in the blood. Good enough, by the standards of the immune system; that's the goal. There are a small number of viruses and a low level of activity against it, and the viral load is low and stays low. Every once in a while, one of the transcribed T4 cells activates and starts producing HIV; this kills the T4 cell, which burst and spills a small pulse of HIV into the blood stream. The immune system kills most of them, but a few manage to find and infect other T4 cells, transcribing their information into the chromosomes.

So over a long period of time, the number of T4 cells declines because they're slowly being destroyed by HIV. Eventually there are too few to make any difference. Without T4 cells, the rest of the immune system is useless; they never see a signal indicating that there's an infection, so they never respond to it. The patient has AIDS, and there's no hope.

The problem is that the fundamental assumption of the immune system is wrong for HIV: there is no safe level of the virus. Any level will eventually kill you.

So what if we have a vaccine? Well, the immune system would be preprogrammed to recognize HIV which would speed a response up from three days to six hours. But during that six hours the virus would still be reproducing, and at least some T4 cells would get infected. Then the immune system would stomp on the others. The patient would not notice an infection -- but an infection would take place nonetheless. So all that happens is that the patient skips the initial big pulse of viruses and goes directly into the second stage of chronic low-level infection which slowly destroys the immune system. How is this really better?

The vaccine would not prevent AIDS, because a vaccine doesn't prevent infection. It keeps the viruses from getting above a dangerous threshold -- except that for HIV, there appears to be no safe level of the virus.

So why are they working on one? Because there isn't anything else they can do. Modern medicine is very impressive, but it's largely based on a relatively small number of basic discovery. Really very few, and of those only one is effective against viruses. Antibiotics, for instance, are useless against viruses. Antibiotics are selective poisons which interfere with certain cell functions, and they happen to be functions present in bacteria but not in us. So if you've got syphilis and you take penicillin, it doesn't affect you but it kills the bacteria which have infected you. That's because the bacteria really are alive, and penicillin interferes with essential life functions.

But a virus really isn't quite alive; when it's not in a cell it doesn't have any life function. It's just information; the life comes from the cell it infects and takes over. So chemical poisons have no effect on it; there isn't anything to poison.

Only vaccines work, and they've performed miracles. Indeed, the granddaddy of them all, vaccinia, was used to completely eradicate for the very first time in history a disease which has afflicted humans all through recorded history. It's a modern miracle: for at least ten years there hasn't been a single case of smallpox anywhere on earth, and there won't ever be again.

But for nearly all known diseases, there is a threshold of infection which is not dangerous. What a vaccine does is to keep the disease below that threshold.

If a vaccine doesn't work against HIV, then nothing will. Antiviral drugs aren't quite like antibiotics and there's strong evidence that they don't cure. A victim has to take them forever and even then eventually the disease will kill them. Antiviral drugs are also expensive and have to be taken several times per day. If a vaccine works, it will be a one-time treatment which could be administered even before infection to prevent it.

If it works -- only it won't. But the researchers don't want to surrender without a fight, so they're trying it anyway in hopes that there will be a miracle. I don't think there will be.

The only solution for HIV is prevention, and that's unlikely. This plague is with us for the long haul; it's going to be, in the long run, one of the great killers of humans. The history of the 21st century will be changed by it, just as the history of the 14th century was changed by Bubonic Plague (the "Black Death"). And it will take a breakthrough in theory to do anything about it. Right now no-one knows what that might be.

I don't like this answer, but the universe didn't promise to please me.

Sickle Cell Anemia: a case study in evolution

Summary: Sickle cell anemia, while a horrible disease, is a product of evolution. Sickle cell in general prevents the majority of carriers from dying of malaria, but renders some excruciatingly and fatally ill.

Actually, we're not going to be talking about sickle cell anemia here for quite a while, because we've got a lot to cover first. Sickle Cell Anemia is far more complicated than most people realize. For instance, most people don't realize that it's an advantage to the vast majority of people who carry the gene. But explaining why takes a lot of background. So let's get started.

For a moment, I want you to stop thinking of yourself as a businessman or poet or mother or football star or potential model or angel in training or whatever and start thinking of yourself as a whole bunch of meat. Because to a disease that how you look: you're lunch.

Diseases, including parasites, have existed for hundreds of millions of years, and the reason we have an immune system is to protect ourselves against all the very tiny creatures who want to eat us.

By analogy our defenses are in two levels, a passive one and an active one. Think of a medieval castle filled with soldiers armed with spears. (Sorry, no crossbows.) The first defense is the castle wall, in this case our skin. And it is extremely effective, which is why burn patients who lose large parts of their skin are in such danger.

However, the castle wall has several entrances which are not well guarded. By far the best from the point of view of diseases is our respiratory systems, where the lining of the nose and the lung are thin and easily invaded. The second best one is our digestive tract, but that one's harder because the disease has to run a fairly stiff gauntlet in the stomach before it can reach the small intestine and finally reach a thin part of the wall.

Once inside, however, there are all those soldiers with spears; white T-cells and B-cells and antibodies which do not like invaders and are ready to fight to the death to destroy them. It does however take a couple of days before the immune system recognizes a new disease and gears up to fight it. What happens is that one kind of white blood cell recognizes the invader, learns how to make appropriate antibodies, and the reproduces like mad so that there are millions of them pouring out antibodies.The antibodies attach themselves to the invaders, and that becomes a signal for other white blood cells to attack, engulf and destroy the invader. And with most diseases what then happens is a pitched battle between the disease and the immune system, which the immune system ultimately wins over the course of a few days, and you get over the disease (but usually not until you've given it to a couple of friends).

But there are other ways in. Mosquitos have the ability to burrow through our skin to reach the blood which they suck. But if they immediately started to suck, the blood would clot in their proboscis, clogging it, which would do them no good at all. So after they've finally penetrated the skin, the first thing they do is inject some saliva. The saliva contains a very powerful anticoagulant. Then as the mosquito sucks out blood, the blood it gets contains some of this saliva, and thus does not clot and clog the proboscis.

But if the mosquito were to suck all the saliva out then it would be sucking blood without the anticoagulant and it would clot. So the mosquito stops before then, and as a result leaves some of the saliva behind. And that's why a mosquito bite is annoying; because it leaves behind some things which cause a local immune reaction; so you get a lump and it itches for a couple of days.

Some diseases have gotten a comensal relationship with the mosquito: when the mosquito sucks blood from a victim who is infected with that disease, the disease travels through the mosquito's blood system from its stomach to its saliva glands, and there it waits. And when the mosquito bites someone else, the disease pathogen hitches a ride on the saliva which gets injected. A lot of it gets sucked back out, but as mentioned some is left behind and thus some of the disease pathogens remain, right there in the blood, on the inside side of the wall, in the yummy juicy part of you.

But there are still all those soldiers. The second trick is to figure out how to fool them, and various diseases and parasites have found interesting ways of doing that. There's a rather large parasite called a fluke; one version lives in your liver, another in your lungs, another in your heart, and they can be there for years and the immune system ignores them completely. That's because they coat themselves in a layer of your own cells. So when the immune system takes a look at one of these monsters, it sees "self" not "invader". It's as if the fluke is wearing a stolen a uniform from one of your own soldiers.

Another trick is to hide where the immune system cannot go; the favorite being to cross the "blood-brain barrier" which despite the name actually applies to the entire nervous system everywhere. Herpes does this. When you get herpes, it reproduces in your blood, and your immune system fights back and wins. But before it's done so, some herpes viruses have crossed the blood-brain barrier and gone dormant in nerve cells and the immune system cannot follow them there, because it does not cross the blood-brain barrier. Every once in a while, for no reason anyone has ever determined conclusively (though a weakening of the immune system through, say, a cold, is the most likely cause, thus the term 'cold sore'), the herpes viruses decide to come out for a rematch and again they battle the immune system, and again the immune system wins. But in the mean time the supply of viruses in the nerves has been replenished, and this keeps happening all your life, which is why Herpes has no permanent cure, and why a person infected with it will suffer many attacks. Herpes is not the only virus which does this; there are many. The one which causes warts does exactly the same thing.

But the disease I'm most interested in for this discussion is malaria. You get it by being bitten by a mosquito who had previously bitten someone else who was infected; malaria does that trick of moving from the mosquito stomach to the mosquito saliva gland. (However, it's very specific; it has to be the Anopheles mosquito. No other will do. The Anopheles mosquito is a friendly beast and loves to share; it also spreads yellow fever.)

The malarial parasite is extremely small, and inside you its life cycle consists primarily of invading red blood cells (which are huge by comparison) and eating out the insides and using that material to make more malarial parasites. Eventually you have a loose bag filled with parasites, and it bursts.

While the parasites are out in the blood plasma, the immune system is capable of recognizing and attacking them. But they don't have to search far to find a new red blood cell to invade, and while they're inside the red blood cell they've vanished as far as the immune system is concerned.

Malaria is a vicious disease and while it often doesn't directly kill its victim it so seriously weakens him that he's liable to die from many other things which ordinarily would not be fatal.

Now the malarial parasite has a normal metabolism just like any other living thing; it utilizes oxygen and generates carbon dioxide as a waste. This is critical.

I'm afraid I need to define some technical terms because we'll be using them extensively. The first two words we need are homozygous and heterozygous. Everyone knows that humans have 23 pairs of chromosomes and except for the sex pair, each pair is essentially identical in gross. But they are not neccesarily identical in detail. A given chromosome may contain the formula for hair color at a certain location, and if so, its compatriot will also contain the formula for hair color at that same location. But they may contain the same formula or different ones.

If the two chromosomes contain exactly the same formula at that point, then the individual is referred to as being homozygous for that gene, which means that the zygote (the person) only has one ("homo") formula. If the two chromosomes are different at that location then the individual is referred to as being heterozygous which means the zygote (the person) has multiple ("hetero") kinds of gene. (Just to clarify, the words have nothing whatever to do with sexual preference.)

Now genes like that are sometimes dominant or recessive or co-dominant.

The eye-color gene is the classic example of dominance and recessiveness. If a person is homozygous with the blue-eyed gene, then they will have blue eyes. If the person is homozygous with the brown eyed gene they will have brown eyes. But if the person is heterozygous, with one of each, he will still have brown eyes because the brown eye gene is dominant and the blue-eyed gene is recessive.

Yet two more odd words: genotype and phenotype. The genotype is the genes the person carries. The phenotype is what the resulting individual looks like.

A person whose genotype for eye color is homozygous brown and the person who is heterozygous for eye color both have the same phenotype: brown eyes. There is no external way to tell them apart.

Finally, one last word to define and perhaps the most important of all: co-dominant means that if the person is heterozygous, he will express in his phenotype both genes, and thus will be different than a homozygous individual with either of the genes. The reason this is important is that the sickle gene is codominant with the normal gene at that location.

Sorry about all the jargon, but we need it to talk precisely about what happens with malaria.

Hemoglobin is the critical compound in our red blood cells, which carries iron atoms and gives the red cells the ability to carry oxygen from the lungs to the tissues. This is necessary because oxygen does not dissolve very well in water, and the plasma alone is not capable of carrying enough oxygen to the tissues to keep you alive. Hemoglobin is horrendously complicated, consisting of two each of two different large proteins which wind together so as to hold a few iron atoms into certain very precise positions. There are hundreds of amino acids in Hemoglobin.

Another function of the blood is to carry back the CO2 to the lungs so it can be exhaled. But unlike oxygen, CO2 is readily soluble in water. It forms carbonic acid (H2C03) by combining with a water molecule. At the lungs it just as readily returns to its normal gaseous form and can be exhaled. So unlike oxygen, no special mechanism is needed to carry CO2 to the lungs. But while dissolved, it is an acid and actually a fairly potent one.

The sickle gene turns out to be a single change, the alteration of a single amino acid, in the formula for one of the two protein chains which makes up hemoglobin. It has no effect at all on the ability of the modified hemoglobin to carry oxygen.

And the sickle gene is co-dominant. So a person who is heterozygous with the sickle gene will have half their hemoglobin in the normal form and half with the modification.

The modification has one critical effect: it make the hemoglobin sensitive to high levels of acid. In the presence of high quantities of acid, the modified hemoglobin molecules stack up like poker chips and form long chains, and as a result the shape of the red blood cell changes fom the normal platelet shape to something more like a banana. This is called sickling.

And when this happens, the immune system labels the cell as aberrant, and a white blood cell will engulf and destroy it.

For a person who is heterozygous with the sickle gene, almost the only thing which can make this happen is the presence of malarial parasites inside the red blood cell. They are excreting CO2 and it is dissolving in the water inside the red blood cell and being converted to carbonic acid, and when the concentration reaches a certain point, the half of the hemoglobin which is modified forms its long chains, causes the cell to sickle, and makes the immune system engulf and destroy the cell.

Before the parasites get out. This is a Good Thing.

Not every single time, but most of the time, and the result is that the disease never gets out of control. It's a chronic infection which never really affects the health of the heterozygous individual.

That's the point: the sickle gene protects its heterozygous carriers against malaria. They're not immune to the disease, but it can't kill them because it doesn't reach sufficient quantity in their blood to do so.

But it's an imperfect solution because it protects the heterozygous individuals at the expense of everyone else. They're doing fine, but everyone else suffers because they exist.

First there is the disease we call "sickle cell anemia". That happens when both parents of a child are heterozygous, and the child gets the sickle gene from both of them, approximately one chance in four, thus becoming homozygous with the modified gene. The effect of this is to dramatically lower the amount of acid which is needed to set off a sickling attack.

In a person who is homozygous with the sickle gene, their own normal CO2 (in the form of carbonic acid in their blood plasma) can be sufficient to cause their red blood cells to sickle, and when it happens it happens to many if not most of the red cells all at once. At which point the immune system goes hog wild and starts destroying nearly every red cell it can find (which has sickled). And that's why it is called "anemia", because in fairly short order there aren't many red blood cells left. Modern medical treatment for such an attack is to put the person into a nearly pure oxygen atmosphere to permit them to utilize such oxygen carrying capacity as they have left, and once things have calmed down a bit, to treat with transfusion of normal red blood cells.

But in an impoverished community in Somalia in some obscure village out in the bush, for instance, that's simply out of the question. So all you can do is watch the child and feel bad because of the pain and hope it doesn't die. Few survive past age 12. Now because heterozygous individuals make up a minority of the population and even when they do marry each other, only a quarter on average of their children are homozygous with the sickle gene, it doesn't actually kill a very large proportion of the population. On the other hand, all those heterozygous individuals have been saved from malaria by the gene -- so it saves more lives than it costs in areas where malaria is endemic.

What's less obvious is that the heterozygous community also represent a serious health threat to the people who are homozygous with the normal gene for hemoglobin.

The heterozygous individuals are not immune to malaria. They get it. They don't get over it. It just doesn't severely affect them. So they represent a pool of infected individuals that the mosquitos can bite which causes the mosquitos themselves to become infected, which raises the chance that the mosquito which bites a homozygous normals will carry malaria and give it to him. So the presence in the population of a significant number of heretozygous individuals will raise the chance of the homozygous normals getting and dying from the disease.

Now it is mathematically impossible for every individual in the population to be heterozygous. Even if they began that way, the next generation would not be.

And that's why this is such an interesting case study in evolution. For any given gene, all that natural selection is interested in is whether it saves more lives than it costs, and this one does. Far more people are saved from malaria by this gene than are killed by sickle-cell anemia, and since natural selection is simply a statistical process, that's all it takes to select in favor of it. Natural selection doesn't care what effect it has on those who do not carry the gene.

Consider when the original mutation took place. Now since it is a single amino acid change, it is completely plausible; unlikely, but plausible. (Why Africa? Gold is where you find it. It just happened to be there. Rewind the tape and run it forward again, and it might have happened in Malaysia, or in Central America, or Sweden, or it might not have happened at all. But it did happen in Africa. Unlike natural selection, which is stochastic, mutation is random.)

The first individual to get the mutation was heterozygous! She (?) got all the advantages and none of the disadvantages. She marries and has children and on average half of them get the gene and they are all heterozygous (and the rest are homozygous normal). And again, the carriers get all the advantages but none of the disadvantages. So the gene wil spread for a long time; and you won't get a homozygous individual with the sickle gene until two people marry who are sufficiently distantly related so that they don't think they are violating the incest taboo but are both descended from the person who had the original mutation. And even then only one quarter of their children die a horrible death; half are heterozygous, and one quarter are homozygous normal.

And even then, since the majority are homozygous normal, the heterozygous individuals are more likely on average to pick a homozygous normal individual for a mate, and their offspring will be on average half heterozygous and half homozygous normal. A homozygous sickle gene offspring is impossible in such a pairing.

So for a really long time, the sickle gene was an advantage and natural selection would have favored it and caused it to spread. And indeed in many parts of Africa it still is mostly an advantage.

At least, that's the evolutionary explanation. It turns out from an evolutionary standpoint to make perfect sense, because evolution isn't looking for "perfect" answers; just for things which are better than before.


[Since this was written I've learned more about sickle cell anemia. It turns out that each of us has a set of genes for haemoglobin which are active in the womb (g-globin), and a different set (b-globin) which activate shortly after birth (while the former are deactivated again). It is the second set which is changed in people carrying the sickle cell gene, and work is underway to see if there might be a way to reactivate the fetal gene. If this can be done, then people with sickle cell disease could conceivably be cured. This is an extremely exciting prospect.]