Why No HIV Vaccine?

This week's Science magazine has a review article titled, "Toward an AIDS Vaccine" (subscription required), by Bruce Walker and Dennis Burton--both of which are prominent in the field of HIV research. Despite 25 years of research and the infamous prediction by a U.S. Health Secretary in 1984 that a vaccine would be available within two years, we still lack a vaccine for HIV. The article summarizes why that is, and I thought that I would summarize the summary here.

Before I continue, I need to provide an extremely quick and painless (I promise) introduction to immunology. The immune system can be broadly divided into 'innate' and 'adaptive'. The innate immune system is quick, but lacks specificity and has no memory. The adaptive immune system is slower to respond--the first time, but it is powerful, specific, and has memory. If the bug shows up again, the adaptive immune system will act swiftly. Vaccines are designed to stimulate the adaptive immune system.

(Not bad eh? Just one more paragraph.) The central players in the adaptive immune system are B cells and T cells. B cells make antibodies, which are Y-shaped proteins that bind specific 3-dimensional protein surfaces. The shape of that surface is determined randomly for each B cell when it is made. Imagine attacking Godzilla with thousands of bear traps; that's sort of like what antibodies do. For our purposes here, there are two kinds of T cells. One kind acts as a surgical strike team to kill cells infected with virus. The other kind acts as central command; these cells give (or deny) B cells and the killer T cells permission to attack. (You can wake up now.)

The basic vaccine problems are summarized in a table that I will adapt for use here as numbered headings.

1. Sequence diversity. HIV mutates a lot--even within an individual. I already knew that, but this sentence caught my attention:

Indeed, the amount of HIV diversity within a single infected individual can exceed the variability generated over the course of a global influenza epidemic, the latter of which results in the need for a new vaccine each year.

Any vaccine worth doing needs to protect across a broad range of strains. Given the diversity found in an individual person, that's a tall order.

2. Infection of critical immune cells. Remember those T cells that act as central command? HIV infects and kills them. In fact, there is a large slaughter of them within days after initial infection. Remember, people don't die from HIV; they die from other infections after HIV has wiped out the immune system. That's why it is called Acquired Immune Deficiency Syndrome (AIDS).

3. Immune Avoidance.

3a. Masking of neutralization epitopes. Remember my Godzilla analogy above? Well Godzilla has lots of scales protecting him, so what you really want to do is to get at his sensitive places--like his Achilles heel, to mix metaphors. The problem with HIV is that its sensitive places--particularly those that are the same among different strains--are covered very well.

3b. MHC down-regulation. Metaphorically, when cells get infected with a virus they have a special flag (the MHC protein) that they can wave around to get the attention of the killer T cells. HIV prevents cells from waving that flag.

3c. Immune escape through viral mutation. This was touched on above; just as the adaptive immune system gets revved up and starts to make some progress, the virus mutates and the adaptive immune system has to start over with the new mutants.

3d. Counter-immunoregulatory mechanisms. This is the same kind of thing as 3b above.

4. Latency. Like other retroviruses, as part of its life-cycle HIV integrates its genome into the host cell's chromosomes. In other words, HIV becomes part of the cell's DNA. Even if you could eliminate every single viral particle from the body, there would still be these cells--sleeper cells, if you will--that would eventually begin making new virus.

Another problem they mention is a good animal model. Since they obviously can't experiment on people, scientists have had to make due with monkeys. Not only is this expensive, but it is not always clear how well the results will translate into humans.

In the wake of a recent trial vaccine failure, HIV experts are calling for the field to get back to basics--basic research. The rest of the article is about future strategies and questions that need to be addressed. I haven't finished reading that part, and it's geek-talk anyway.

Clearly we have major challenges to overcome in order to have a decent HIV vaccine. Given the magnitude of the difficulty, should we just give up and work on something else? I think that would be a mistake for (off the top of my head) two reasons. First, AIDS is a big problem throughout the world and I just can't see giving up on the millions of people who will die. A cheap vaccine is the only hope many poor people will ever have. (Spare me a lecture about lifestyle. Plenty of innocent people get HIV.) Second, HIV research not only teaches us about HIV, it also teaches us about immunology and vaccinology, virology, biochemistry, genetics, etc. These disciplines cannot be walled off from one another. Just to use an example I know something about, research into how HIV gets into cells is successfully being applied to other unrelated viruses. It is not hyperbole to say that HIV research may lead to treatments for other diseases (and vice versa). The benefits of basic research are often unseen at the outset.

So there you go. Now you will have something to talk about during quiet moments at parties.


Science 9 May 2008: Vol. 320. no. 5877, pp. 760 - 764

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