San Francisco Chronicle - Friday, June 22, 2007
Sabin Russell, Chronicle Medical Writer, srussell@sfchronicle.com

That battle left chimps, gorillas and old world monkeys vulnerable to the virus 4 million years ago, but our human forebears evolved instead a natural antiviral protein that protected against it.

That evolutionary path, which gave us immunity to the ancient virus, nevertheless may have made human beings -- and not apes - vulnerable to the modern scourge of HIV.

Such are the startling conclusions of a study published in Friday's issue of the journal Science by researchers at the Fred Hutchison Cancer Research Center in Seattle.

"We did a really great job 4 million years ago, but now we have a major new retrovirus to deal with," said Shari Kaiser, a Fred Hutchison researcher and lead author of the report.

Her findings are the latest in the burgeoning new field of paleovirology, in which scientists have found etched into the genes of plants and animals something akin to a medical record that dates back millions of years.

"It is an absolutely fascinating story in evolutionary biology," said Dr. Warner Greene, director of the Gladstone Institute for Virology in San Francisco. Greene had seen a presentation of the study at an academic conference earlier this year.

The virus responsible for this ancient mayhem is long extinct, but Kaiser and her colleagues made their case by resurrecting a living version of it using the genetic instructions planted by the bug into the chimpanzee genome about 4 million years ago.

Retroviruses are a primitive microbes containing their own genetic information in a single strand of RNA -- a flimsier chain of molecules than DNA, but one that is able to transmit instructions on how to make proteins or copies of itself.

When a retrovirus infects a cell, it plants a copy of its genetic instructions directly into the genes of the cell it has invaded. These instructions, which are also converted into more stable DNA, can be passed down through generations if an egg cell, for example is infected. HIV is a retrovirus. So was this ancient bug, Pan troglodyte endogenous retrovirus, which scientists call PtERV, or PERV for short.

By counting the number of mutations in a modern stretch of PERV found in a chimpanzee genome, scientists can calculate how long ago the ancient chimps were infected. That's because mutations occur at a predictable rate over time. About 4 million years ago, just as apes and humans were diverging, about 100 different versions of PERV were planted in the ape genome -- signs of a persistent viral assault that may have lasted thousands of years.

A hobbled version of that ancient retrovirus was reconstructed in the laboratory and promptly showed it could infect cells in a lab dish. The Frankenstein-like lab virus contained only parts of the ancient microbe, and was genetically engineered so it could not replicate after it infected cells, making it safe, according to Kaiser.

Further lab experiments zeroed in on an antiviral protein, called TRIM5, which both apes and humans manufacture routinely. But human TRIM5 is different from the TRIM5 made by gorillas, chimps and old world monkeys -- and that may have made all the difference.

Kaiser's lab tests showed that cells carrying human TRIM5 could not be infected by the resurrected virus, while cells carrying the ape and monkey TRIM5 were vulnerable.

The importance of human TRIM5 in warding off the virus 4 million years ago is uncertain. Kaiser said it is unlikely that this single virus was responsible for taking humankind on a separate evolutionary path from apes. Nor is it certain that early humans were unscathed by PERV. "It could be that lots of humans died, and the only ones who survived had this form of TRIM5," Kaiser said.

However, the different forms of TRIM5 carried by humans and apes have a bearing on modern medicine: Human TRIM5 is a natural antiviral defense, but it does not block HIV. The TRIM5 proteins carried by chimpanzees and rhesus monkeys, however, are powerfully protective against HIV -- a virus these primates do not contract.

So the defense that evolved to protect humans against the ancient virus may, in fact, have weakened a natural defense against HIV.

UCSF virologist Dr. Jay Levy called the paper enticing, but said it was very speculative to suggest that the gene that protected human from the ancient virus left us susceptible to HIV.

"It will lead to further evaluation of this idea by other researchers in the field," he said.

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