Pleistocene Medicine for Battling HIV

Last November, scientists announced they had revived a virus that had been dead for millions of years. The virus belongs to a special class that multiply by inserting their genetic code into the genome of their host cell. When the cell divides, it makes a new copy of the virus’s genes along with its own DNA. Once it has installed itself in a genome, the virus can liberate itself from time to time, creating new copies. These copies can infect the same cell again, or wander out of the cell to infect another one. Some of these viruses, known as human endogenous retroviruses, may be harmless, while others have been associated with diseases such as cancer. If one of these viruses happens to infect an egg or sperm, it has the chance to get in on the ground floor during the development of an embryo. The virus will be replicated in every one of the trillions of cells in the new growing body. It can then be passed down from one generation to the next along with the rest of the genome. Mutations may strike the DNA of these viruses, making them unable to jump out of the genome. But these dead copies will still be replicated for millions of years. Scientists are scanning the human genome to count up all of the endogenous retroviruses (or their dead remains and fragments). Roughly 100,000 pieces of DNA in our genomes started out as viruses, making up eight percent of the genome all told. A small fraction of them can still produce proteins; the rest are generally just coming along for the ride. Related versions of some viruses are residing in the genomes of our primate relatives, and a number of scientists are busy delving into the sixty-million year history of this viral evolution.

As I wrote in this November article in the New York Times, scientists could not find a fully-functioning human endogenous retrovirus. So they resurrected one instead. They drew an evolutionary tree for a group of closely related dead viruses, and used that tree to work their way backwards to the original genetic sequence of the ancestral virus that gave rise to them all. They then synthesized this genetic sequence and–voila–created a perfectly respectable virus. This particular virus probably died off several million years ago.

I had a feeling this paper marked the start of a new way to understand viruses and diseases. To understand one of today’s major medical disasters, such as HIV, scientists may need to look back to epidemics that took place millions of years ago. They will practice a kind of Pleistocene medicine.

HIV has not established itself in the human genome. But, like endogenous retroviruses, it does replicate by inserting its genetic material into host cells. What makes HIV particularly puzzling is that it is closely related to many other retroviruses that infect apes and monkeys. And yet many other species appear to be resistant to the most common kind of HIV, known as HIV-1.

In today’s issue of Science, scientists at the Fred Hutchinson Cancer Research Center in Seattle offer some fascinating evidence for why we might be susceptible to HIV. As our ancestors evolved a resistance to an ancient, vanished virus, they became vulnerable to a new one.

More below…

The scientists open their case by pointing out that our closest relatives, chimpanzees and gorillas, have many copies of a kind of endogenous retrovirus called PtERV1. We have none. To investigate why we don’t, the scientists turned to one of the defenses that primates like ourselves use against many different retroviruses, a kind of protein called TRIM5-alpha. TRIM5-alpha can attack retroviruses and cause them to be destroyed before they have a chance to insert their genetic material into the genome. Each primate species has its own version of TRIM5-alpha. Some are good against viruses and not so good against others. The macaque monkey, for example, has a version that’s very good at blocking HIV-1. Ours is not. It’s likely that the differences in these versions of TRIM5-alpha arose through the unique evolutionary history of each species, as it grappled with its own set of infections. When a new retrovirus attacked a primate species, natural selection favored versions of TRIM5-alpha that did a better job of warding it off.

There’s an intriguing connection between the human TRIM5-alpha protein and PtERV1, the virus found in chimpanzees and humans gorillas. In 2004 scientists discovered that human TRIM5-alpha is very good at blocking an endogenous retrovirus associated with leukemia in mice. And that mouse virus is closely related to PtERV1, the virus we lack and chimps and gorillas carry.

Perhaps, the scientists thought, we don’t have PtERV1 because our ancestors evolved a good defense against it. To test this idea, they had to resurrect the original PtERV1. They compared the dead versions of PtERV1 found today in chimpanzee and gorilla DNA. Those sequences allowed them to reconstruct the ancestral gene for the virus’s shell and another gene that plays an essential role in allowing the virus to infect a cell. They then engineered the mouse leukemia virus so that it produced these two genes instead of its own. They found that with those ancestral genes, the virus had all the tools it needed to infect cells.

It turns out that human TRIM5-alpha does an excellent job of wiping out this ancestral virus. Its superior performance depends on a short bit of one of the virus’s genes–a bit that shows signs of having experienced strong natural selection in our hominid ancestors. But evolving a strong resistance to PtERV1 meant giving up resistance to HIV. The viruses seem to force primates to make an evolutionary choice: defend against one or the other, but not both. In our ancestors, the scientists argue, TRIM5-alpha evolved into a powerful weapon against PtERV1–so powerful that we carry no trace of the virus in our genomes. But it left us with little protection against HIV.

It’s important to remember that this is not revealed truth, but a scientific hypothesis that can be tested in the future. If it does hold up to further study, it could help scientists who are trying to figure out how to fight HIV. If our ancestors did indeed lose a weapon against HIV millions of years ago, perhaps we can dig it up and use it as a model to build new ones.

Update 6 pm: The paper link is not up yet. Here’s the press release for now.

Update 6/22/07: One of the authors of the paper is not so sanguine about applications. Interviewed by the Seattle Post-Intelligencer, Michael Emerman said,

“This is more like archaeology or paleontology,” Emerman said. It explains how something may have happened, and when it happened, but he said it may not help us deal any better with what’s happening today.