Jefferson scientists uncover HIV escape route from drugs and vaccines

May 29, 2003

Virologists at Jefferson Medical College may have discovered a new way by which HIV, the AIDS virus, can evade both anti-viral drugs and vaccines.

Researchers had reported last summer that a protein called CEM15 is a natural inhibitor of HIV, acting as a brake on HIV's replication. They also showed that an HIV-encoded protein, Vif, or Virion infectivity factor, counteracts CEM15. Vif, in effect, is a shield to protect HIV from a host cell's defenses.

But how CEM15 worked was something of a mystery. Now, Hui Zhang, M.D., Ph.D., Bin Yang, Ph.D., and their colleagues at Jefferson Medical College of Thomas Jefferson University in Philadelphia have found that CEM15 renders HIV essentially dead by altering newly made HIV DNA, causing mutations and preventing replication.

At the same time, the researchers showed that HIV and Vif can subvert this system, enabling the virus to instead make myriad mutations of itself. The major obstacle to creating anti-HIV drugs and vaccines is the virus' propensity to mutate quickly and often. The researchers report their findings this week in an advanced online publication in the journal Nature.

"This is an important finding because it may be a reason why HIV can escape from vaccines and develop resistance to antiviral drugs," says virologist Roger J. Pomerantz, M.D., professor of medicine, biochemistry and molecular pharmacology and director of the Center for Human Virology and Biodefense at Jefferson Medical College and a co-author on the Nature paper.

According to Dr. Zhang, who is an associate professor of medicine at Jefferson Medical College, Vif is a regulatory protein needed for the virus to grow and make infectious viruses from certain cells. CEM15 is relative newcomer to the known array of host defense systems.

But little was known about how CEM15 inhibited viral replication. In the Nature paper, he and his colleagues describe results from work in their laboratory showing that CEM15 attacks newly synthesized viral DNA. CEM15 works by either biochemically degrading such DNA or alternatively, causing a "lethal hypermutation," killing the virus.

In the process of replicating, HIV mutates at a rate 1,000 times higher than normal cells. This high rate of mutation during replication, Dr. Zhang says, has been thought to be the driving force behind viral genetic variation - and the reason it has been so difficult to create treatments against - or prevent - HIV infection.

"No one knew the entire reason why HIV makes a hypermutation," he says, explaining that during a process called reverse transcription (RT) that occurs in replication, the HIV mutation rate greatly increases. "This paper shows that hypermutations aren't only caused by HIV RT, but are also made by CEM15, a host defense system.

"HIV is smart," he says. "The virus sees CEM15 is going to use hypermutation as a way to defeat and kill it. The virus uses a shield, Vif, to protect itself. At the same time, the virus hijacks the antiviral defense system and uses a 'non-lethal' hypermutation process to make more mutations. It turns it into its own weapon."

Accumulating such non-lethal hypermutations means HIV is essentially "using CEM15 to drive genetic variation," Dr. Zhang says.

"These are preliminary data, but it is a beginning," he says. "It is not an answer, but opens the door for more research. People have to think about the fact that host defense-caused hypermutation may play a role in genetic variation. It could be a key to know how HIV resists drugs and escapes from immunosurveillance and vaccines.

The researchers are now working on trying to better understand how HIV Vif fights back against CEM15.
-end-
Contact: Steve Benowitz or Phyllis Fisher
215/955-6300
After Hours: 215/955-6060
E-Mail: steven.benowitz@mail.tju.edu

Thomas Jefferson University

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