SAN FRANCISCO—After years of attempting to stimulate neutralizing antibodies with HIV vaccines, scientists from the Gladstone Institute of Virology and Immunology (GIVI) and the National Institutes of Allergy and Infectious Diseases (NIAID) have identified a gene that may influence the production of antibodies that neutralize the virus.
According to the scientists, finding a link between the gene, Apobec3, and the production of neutralizing antibodies came as a complete surprise. The discovery, reported Sept. 5 in the American Association for the Advancement of Science journal Science, may spur a new approach for making an HIV vaccine that may stimulate antibodies to attack and control an infecting virus, the scientists say.
"We now have a host factor needed for the production of neutralizing antibodies that HIV targets and destroys," says Gladstone scientist Dr. Mario Santiago. "This offers a fresh perspective on how to strengthen this arm of the immune response against HIV, with direct implications for immunotherapy and vaccine development."
The search for a gene with these properties began in 1978, when researchers at the National Institutes of Health (NIH) studying a similar retrovirus in mice discovered a gene called Rfv3 that influenced the production of neutralizing antibodies that allowed the animals to recover. By 1999, they had narrowed the location of Rfv3 to a relatively small region on mouse chromosome 15, but that region contained more than 60 genes.
Conducting a series of genetic experiments by mating mice with different Rfv3 and Apobec3 profiles, the researchers demonstrated that Apobec3, like Rfv3, contributes to the early control of retroviral infection in mice, and also influences specific retroviral antibody responses. They also discovered that Rfv3 susceptible mouse strains that fail to make antibody responses have a natural defect in Apobec3.
These results provide convincing evidence that Rfv3 and Apobec3 are the same gene, the scientists say. The discovery also bolsters other recent studies of people who somehow resist HIV infection despite years of frequent exposure to the virus. These individuals produce a particular type of antibody recognizing the virus and genetic mapping studies of their resistance points to a chromosomal region where the human Apobec3 genes are clustered.
The research group will now investigate Apobec3 differences in these individuals and is currently screening for compounds that would rescue Apobec3 function during HIV infection.
"Genome-wide studies of the entire human Apobec3 locus, with particular emphasis on functional differences induced by alternative splicing, are clearly merited to fully explore the potential contribution of this gene family to HIV resistance, neutralizing antibody production, and disease progression," the scientists wrote.
The study, Apobec3 encodes Rfv3, a gene influencing neutralizing antibody control of retrovirus infection, was co-authored by Mauricio Montano, Robert Benitez, Ronald J. Messer, Wes Yonemoto, Bruce Chesebro, Kim J. Hasenkrug and Warner C. Greene. DDN
