The HIV NEF protein plays both offense and defense in the battle between the AIDS virus and the body

By Laura Lane

In fighting the body’s immune system, HIV owes part of its success to its
ability to destroy those cells normally recruited to mount the body’s
counter-attack against the HIV-infected cells. Lying at the crux of such
success is a viral protein called Nef, which protects its infected host while
simultaneously destroying the neighboring uninfected cells of the immune
system, according to scientists at the Gladstone Institute of Virology and
“It’s HIV going both ways, playing offense and defense,” said Warner C.
Greene, MD, PhD, director of the Gladstone Institute of Virology and Immunology
and UCSF professor in the departments of medicine and microbiology and
immunology. “It is a rather remarkable example of the cunning strategy the AIDS
virus employs to help ensure its survival and spread.”

Researchers have long known that cells surrounding an HIV-infected cell are
eliminated by way of a programmed self-destructive process known as apoptosis.
And Nef, the researchers knew, somehow plays a key role in triggering this
destruction. Now in a study published in the April 12, 2001 issue of Nature,
Gladstone scientists have discovered that Nef also protects its infected host
cell from the detrimental effects by using the same trigger. The new study
shows that Nef does this by binding to and inhibiting a protein called ASK1, a
key player in apoptosis.
“If we could effectively block the assembly of Nef and ASK1, it could lead to
the premature death of the HIV-infected host cell,” Greene said. “The HIV
infection process would then be short-circuited and the virus might simply die
out because it would not have sufficient time to fully reproduce itself.”

Achieving such a block will require discovering and developing a molecule that
interrupts the assembly of Nef and ASK1, helping to “tip the balance in favor
of the body effectively dealing with the virus,” he said.

Identifying such a molecule could lead to the development of a new class of
drugs to fight HIV infection-an entirely new approach in the anti-HIV arsenal,
Greene said. Current drugs, such as reverse transcriptase and protease
inhibitors, stop key viral protein enzymes from catalyzing reactions necessary
to maintain the HIV viral life cycle. But scientists are coming close to
exhausting the number of viral protein enzymes as potential drug targets.
Greene and his research team are among the first to focus on non-enzymatic
viral proteins, such as Nef, which interact with host cell proteins that HIV
needs for its own growth.

Strong support for developing drugs that specifically target Nef comes from the
observation that people infected with HIV strains lacking the nef gene-a rarity-
develop AIDS symptoms much more slowly than those infected with HIV strains
containing the nef gene.
“If we can win the battle at the single cell level, then we will be in a
better position to win the war in the millions of HIV infected patients,”
Greene said.

Co-investigators in the study include Romas Geleziunas, PhD, formerly at
Gladstone and now a principal research scientist in the Discovery Virology
Department at the DuPont Pharmaceuticals Company; Weiduan Xu, MD, PhD, formerly
at Gladstone and now associate scientist at Rigel in South San Francisco;
Hidenori Ichijo, DDS, PhD, professor at the Tokyo Medical and Dental University
in Japan; and Kohsuke Takeda, DDS, PhD, assistant professor also at the Tokyo
Medical and Dental University.

Both the National Institutes of Health and the Center for AIDS Research, a
collaboration of UC San Francisco and the Gladstone Institute for Virology and
Immunology, funded this study.

The Gladstone Institute for Virology and Immunology is one of three premier
research institutes that comprise the J. David Gladstone Institutes, a private
biomedical research institution affiliated with UC San Francisco. The
institution is named for a prominent real estate developer who died in 1971.
His will created a testamentary trust that reflects his long-standing personal
interest in medical education and research.