August 20, 2001
Researchers uncover how a pox virus fools the immune system
By Erica Klarreich
Research on a rabbit pox virus has shed light on how some viruses sneak past our
immune defenses. UCSC scientists have found three separate mechanisms by which the
pox virus, myxoma, silences the messengers that would normally alert the immune system
when a cell is infected. Some of these techniques are also used by herpes viruses
and by HIV, the virus that causes AIDS.
Most viruses betray themselves to the immune system by their own activities within
an infected cell. Viruses cannot replicate on their own, but use the cells they invade
as factories to reproduce themselves. Hijacked cellular machinery replicates the
virus's genetic material and builds viral proteins.
But these viral proteins tip off the host organism's immune system that something
is wrong. Specialized molecules in the infected host cells, called major histocompatibility
complex (MHC) molecules, carry pieces of the viral proteins to the cell surface,
where the immune system's T-cells recognize the proteins as foreign and kill the
infected cell.
One class of viruses, called DNA viruses, has evolved special genes to block the
action of the MHC molecules.
"In streamlined viruses, most genes are for virus reproduction," said Martha
Zúñiga, an associate professor of molecular, cell and developmental
biology at UCSC who directed the research. "But in DNA viruses, much of the
genome is devoted to evading the host immune system."
In the myxoma research, Zúñiga and her coworkers found that during
the early stages of an infection, the viral DNA produces proteins that pull MHC molecules
on the cell surface back inside the cell, where they disintegrate. As the infection
progresses, the virus also manages to hold new MHC molecules prisoner within the
organelle that makes them. And in the late stages of infection, the virus prevents
fragments of its proteins from attaching to transporter molecules that would ordinarily
carry protein pieces to the MHC molecules.
"It's as if it is covering all its bases for preventing MHC molecules from making
it to the cell surface," Zúñiga said. She has summarized several
years of her research on myxoma in a review article published in July in Recent
Research Developments in Virology.
Understanding how viruses slip past immune defenses may help researchers learn
how to "tweak the system" to control viral infections, Zúñiga
said.
"A treatment is much more likely to work if we know all the tricks a virus has
up its sleeve," she said.
Myxoma doesn't infect humans, but it shares its evasion techniques with several viruses
harmful to humans. HIV also causes MHC molecules on the cell surface to be drawn
inside the cell. Adenovirus, a virus that causes respiratory illness, retains MHC
molecules in the cellular compartment where they are made. And herpes viruses block
pieces of viral protein from being carried to the MHC molecules.
But although these viruses produce similar effects, the causes appear to be different.
A close examination of myxoma's DNA has revealed that the genes that regulate myxoma's
evasion mechanisms are different from those of HIV, adenovirus, and herpes, suggesting
that the viruses did not all inherit the same evasion genes from a common ancestor.
"They seem to have evolved separately," Zúñiga said.
Observing myxoma's evasions teaches researchers as much about MHC as about myxoma,
Zúñiga added.
"A lot of what we know about MHC comes from viruses," she said. "You
can learn a lot about how something works by seeing how it gets broken."
A better understanding of MHC transport might allow scientists to block MHC in the
rare situations when its activity is harmful instead of helpful. When a patient receives
an organ transplant, for instance, the grafted organ's MHC molecules are among the
factors that prompt the body to reject the organ as a foreign object.
"If we could selectively manipulate MHC expression, we could turn it on and
off at will," Zúñiga said.
