September 4, 2008
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 NIAID's 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 study's 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 NIAID's Rocky Mountain Laboratories and the study's 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."
ML Santiago et al. Apobec3 encodes Rfv3, a gene influencing neutralizing antibody control of retrovirus infection. Science DOI 10.1126/science.1161121 (2008).