Map of life expectancy at birth from Global Education Project.

Wednesday, August 06, 2008

Mr. Science

I'm not a real scientist, I'm a sociologist. But I'll try not to be too distracted by the demonstration against Abbot pharmaceuticals going in one direction, and the sex workers demonstration going in the other, and tell you what's going on these days in the hard science of HIV.

First of all, I'm not sure what practical value this may have, but it's becoming clear that the infection event, in most cases, consists of a single virion. This discovery comes from a study of sero-discordant couples (heterosexual, by the way) and mother to child transmission. In a person with established infection, the virus is extremely genetically diverse, but in newly infected people, they are usually all identical, or at most there may be two or three varieties. Think about that: there might be millions of copies in semen or genital secretions, but exactly one of them manages to infect a cell of the host and start the process of HIV disease.

Second, and here is the part that is probably much more important, the story we have all heard, which is all about CD4+ cells, is highly incomplete. The most important way HIV causes disease is by selectively infecting and destroying these key cells of the immune system. And the essential process of HIV viremia is replication of the virus inside this type of cell. Furthermore, it is this extraordinarily prolific replication that supports the rapid evolution of the virus and its ability to escape pharmaceutical control.

So why don't the anti-retroviral drugs cure HIV? Scientists have had a vague understanding for a long time, but now they're starting to tighten the focus, and the answers may be discouraging. Some people simply think that the ARVs don't completely suppress viral replication, but it turns out that regimens including protease inhibitors can indeed drive it down to zero.

But remember that HIV is a retrovirus -- it inserts the viral genome into the nuclear DNA of an infected cell. Activated CD4+ cells turn into virus factories, fill up with virus, and eventually burst and die, releasing the virions into the blood. But the viral genes in an infected cell can also just sit there and do nothing, or perhaps produce small amounts of virus without necessarily harming the cell. It has long been known that some infected CD4+ cells remain latent, and so form a reservoir for the virus even when replication is suppressed. These undergo very slow attrition, and so can provide a life-long reservoir.

One approach to actually curing HIV would then be to somehow stimulate all these latent cells to become active. They would then die, and the ARVs would eliminate the virus. Lamentably, HIV also infects the meninges -- the membrane surrounding the brain -- and macrophages -- blood cells that scour up foreign matter and detritus -- in this way. Infected macrophages from the meninges can enter the brain, and call in others of their kind. Over a long period of time, this process can cause brain damage, so even people with perfectly suppressed viral loads can still suffer AIDS-related dementia.

An even more discouraging finding is that HIV may infect hematic stem cells, the precursors of lymphocytes (including CD4+ cells and macrophages), and these cells constantly reproduce, creating new copies of the so-called provirus in their DNA, and ultimately sending infected lymphocytes into the blood stream. Somehow finding and eradicating these cells would probably be impossible.

So maybe there can never truly be a cure for HIV disease, even in principle. A vaccine that could lead to effective lifelong suppression of the virus by the immune system would do the job for all practical purposes, but that might be impossible also. On the odds of that rests the great current controversy in HIV research priorities, but this post is already too long.

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