DURHAM, N.C. - Much like archeologists who search the fossil
record looking for clues about the past, Duke University
Medical Center researchers have done their own genetic sifting
and have found a striking similarity between viral genetic
material that has always existed in humans and HIV, a
relatively new virus to infect humans.

The data show surprising evidence for an evolutionary link
between HIV-1, the virus that causes AIDS, and a group of
retroviruses that first entered the human genome up to 30
million years ago, the researchers report in the Nov. 9 issue
of the Proceedings of the
National Academy of Sciences. Retroviruses are those that
use RNA as their basic genetic template, rather than DNA as in
most organisms.

The genetic makeup, or genome, of every human being contains
genes that were first introduced through infections by
retroviruses, which, like HIV, inject their genetic material
into the target cell, where, converted to DNA, it becomes a
permanent part of the cell's DNA. If the infected cell happens
to be the precursor of a germ cell, like sperm, the largely
benign viral genetic material has the potential to be passed
from generation to generation.

While studying one particular ancient virus found in the
human genome, named "human endogenous retrovirus K (HERV-K),"
lead researcher Bryan Cullen, a Howard Hughes Medical Institute
(HHMI) investigator, found that a protein produced by HERV-K is
virtually identical to one made by the more modern HIV-1, the
form of HIV most commonly found in the Western Hemisphere and
in east, south and central Africa.

The protein, called REV, is responsible for shuttling
messenger RNA from the cell's nucleus, where it has been copied
from DNA, to the cytoplasm that surrounds it. The messenger RNA
then directs the production of proteins that make up the cell's
structure and enzymatic machinery. Cullen was surprised that
REV from present-day HIV functions exactly like the ancient REV
from HERV-K because the two viruses are from different families
of retroviruses and are separated in age by millions of
years.

"It is a fairly simple task to determine when the
approximately 100 HERV-Ks entered the genome," Cullen said,
"When viral genes enter the genome, it is very precise, much
like putting a word into a book. Once in the book, the word
never leaves. We can then look at the 'book' and see exactly
where and when the word entered."

Not only do the two viral REV proteins appear to have the
same biological activity, they can to some degree cross-react
with each other, Cullen said.

"This raises the possibility that HIV-1 infection, and
perhaps HIV-1 REV expression, is able to induce the expression
of HERV-K structural proteins," Cullen said. "While it is
unclear at this point how this may affect the pathogenic
potential of HIV-1, it does raise the possibility of
interaction between an extremely old virus and the relatively
new HIV."

Although Cullen doesn't see any immediate applications of
this understanding to the treatment of AIDS, he does think that
these findings could help in the future development of vectors,
or viral "shuttles," to carry gene therapy to target cells.

"Our genome is full of these old viral genes that entered
our genome millions of years ago and over time they've lost
their infectivity and don't really do anything detrimental, but
they're still there," Cullen said. Researchers estimate that a
small but significant percentage of the human genome originated
from HERVs.

Interestingly, while REV is essential for the ability of
HIV-1 to replicate itself, most viruses do not have it, he
said.

Of the known HERVs in the human genome, HERV-K is the most
intact, Cullen said. While the virus is no longer infectious,
the genetic material that has survived can still make viral
particles that can be detected in some testicular cancers,
though it is uncertain whether or not these particles play any
role at all in the malignancy, he added.

In order for the genetic material to enter the genome, the
viruses must first enter cells that are actively dividing. The
most likely target would have occurred in the cells that give
rise to germ cells, probably sperm cell precursors, according
to Cullen.

"Since females are born with their complement of eggs, it is
highly unlikely that eggs were the targets," Cullen said.
"However, since males are continuously producing sperm, it
seems probable that these early viruses infected sperm cell
precursors."

The earlier that HERV-K entered the genome, the more
branches of the family tree will carry the gene, beginning with
the New World monkeys through Old World monkeys, gibbons,
orangutans, gorillas, chimpanzees and finally man.

"It appears that all the infections that led to the viral
genes being in our genome occurred before we became 'human' a
few hundred thousand years ago," Cullen said. As a comparison,
it is estimated that HIV-1 emerged from chimpanzees about 100
years ago, he added.