|Study Reveals Link between Apobec3 Gene
and Neutralizing Antibody Response to Retrovirus
Scientists have uncovered new evidence that strengthens the link
between a host-cell gene called Apobec3 and the production of neutralizing
antibodies to retroviruses. Published in the Sept. 5 issue of Science,
the finding adds a new dimension to the set of possible explanations
for why most people who are infected with HIV do not make neutralizing
antibodies that effectively fight the virus.
Antibodies are key to warding off viral infections, and most vaccines
against viral diseases stimulate the body to make antibodies against
the target virus. Yet no one knows how to make a vaccine that artificially
stimulates the production of antibodies that can readily neutralize
HIV, largely because so few HIV-infected people naturally exhibit
this immune activity. The new finding about Apobec3 suggests that
this gene may influence anti-HIV antibody production and may help
explain why some people who are repeatedly exposed to the virus
never become infected.
HIV is a retrovirus, a type of virus that incorporates its genetic
material into the DNA of its host cell. Retroviruses infect many
mammals, and mice are susceptible to a retrovirus called Friend
virus. A single gene controls the ability of mice to make neutralizing
antibodies against this retrovirus and to recover from the viral
infection. New research sponsored by the National Institute of
Allergy and Infectious Diseases (NIAID), part of the National Institutes
of Health, demonstrates that this single, powerful gene is Apobec3,
a gene found in matching locations in mice and humans. The scientists
who conducted the study hypothesize that Apobec3 in humans might
play a similar role in helping shape the neutralizing antibody
response to human retroviruses such as HIV. Their thinking is supported
by previous studies showing that human Apobec3 proteins exert anti-HIV
activity and that the human chromosomal region containing Apobec3
genes influences the ability of the virus to establish infection.
"This research delineates a potential genetic mechanism behind
the production of neutralizing antibodies to HIV, which are critical
to preventing HIV infection," says NIAID Director Anthony
S. Fauci, M.D. "Further research on the function of human
Apobec3 could yield promising insights that inform the discovery
of HIV drugs and vaccines."
Scientists from the Gladstone Institute of Virology and Immunology,
which is affiliated with the University of California, San Francisco,
and from NIAIDís Rocky Mountain Laboratories in Hamilton, Mont.,
conducted a series of genetic experiments by mating mice with different
genetic profiles of Apobec3 and Rfv3, a gene critical to recovery
from retroviral infection in mice. The researchers demonstrated
that Apobec3, like Rfv3, contributes to the early control of retroviral
infection in mice and also influences specific retroviral antibody
responses. In addition, the scientists discovered that versions
of Rfv3 that fail to make antibody responses correlate with a natural
defect in Apobec3. These results provide convincing evidence that
Rfv3 and Apobec3 are the same gene.
"These findings add a new and quite unexpected dimension
to our understanding of Apobec3 biology that might help us attack
the HIV neutralizing antibody problem, an area where scientific
progress has been slow," says Warner C. Greene M.D., Ph.D.,
director of the Gladstone Institute of Virology and Immunology
and the studyís principal investigator.
The idea that Apobec3 can influence not only the ability of HIV
to cause infection but also antibody responses to the virus is
supported by a previous study demonstrating that the human chromosomal
region containing several Apobec3 genes is linked to anti-HIV antibody
responses in a group of Italian subjects who were repeatedly exposed
to the virus by their HIV-infected partners but remained uninfected.
The new research by the Gladstone Institute and NIAID is also
intriguing in light of an earlier study demonstrating that HIV
uses one of its own proteins, Vif, to destroy two human Apobec3
proteins. Given that Apobec3 seems to help the immune system make
neutralizing antibodies against retroviruses, the destruction of
Apobec3 proteins by Vif might help explain why most people do not
make neutralizing antibodies against HIV.
"Our mouse studies suggest that neutralization of Vif could
provide the unexpected benefit of better antibody responses to
HIV and therefore better control of HIV infection," says Dr.
Kim Hasenkrug, chief of the retroviral immunology section at NIAIDís
Rocky Mountain Laboratories and the studyís lead NIAID investigator. "We
knew that Apobec3 had very interesting antiviral properties, but
this new discovery that it affects antibody responses will generate
even greater interest in both Apobec3 and Vif."
NIAID conducts and supports research — at NIH, throughout
the United States, and worldwide — to study the causes of
infectious and immune-mediated diseases, and to develop better
means of preventing, diagnosing and treating these illnesses. News
releases, fact sheets and other NIAID-related materials are available
on the NIAID Web site at http://www.niaid.nih.gov.
The National Institutes of Health (NIH) — The Nation's
Medical Research Agency — includes 27 Institutes and Centers
and is a component of the U.S. Department of Health and Human Services.
It is the primary federal agency for conducting and supporting basic,
clinical and translational medical research, and it investigates
the causes, treatments, and cures for both common and rare diseases.
For more information about NIH and its programs, visit www.nih.gov.
Reference: ML Santiago et al. Apobec3 encodes Rfv3,
a gene influencing neutralizing antibody control of retrovirus infection. Science DOI