Apobec3 May Restrict Retroviral Infection by Controlling Antibody Response
Researchers have found evidence indicating that a cellular antiviral factor called Apobec3, which is associated with anti-HIV activity, can restrict infection with another retrovirus called Friend virus in mice (Science 321, 1343, 2008; J. Virol. doi:10.1128/JVI.01311-08). The results of the Science study also suggest that Apobec3 may restrict infection with Friend virus by improving the production of virus-specific neutralizing antibodies, leading the authors of this study to suggest that in humans, Apobec3 might fight HIV infection at least in part by improving neutralizing antibody responses against the virus.
Human Apobec3G and 3F are among a growing number of cellular factors that are thought to naturally inhibit HIV infection. Apobec3G and 3F interfere with HIV’s reverse transcription process in several ways. They encode an enzyme thought to introduce mutations in the reverse transcribed cDNA made from the retroviral RNA, which inhibits retroviral replication by destroying the cDNA’s ability to encode viral proteins. However, HIV has evolved a factor called Vif (viral infectivity factor) that inhibits Apobec3G and 3F, in part by targeting it for accelerated degradation in the proteasome. The role of human Apobec3G as an anti-HIV factor and its inhibition by Vif were first described in 2002 (Nature 418, 646, 2002). Researchers are trying to find molecules that could inhibit Vif and therefore allow Apobec to perform its natural function.
The Science study suggests that in the absence of Vif, Apobec may also keep HIV at bay by improving neutralizing antibody responses against the virus. In a series of genetic experiments in mice, Warner Greene, director and senior investigator at the Gladstone Institute of Virology and Immunology in San Francisco who led the study in collaboration with researchers at the National Institute of Allergy and Infectious Diseases (NIAID), and colleagues showed evidence that Rfv3 (recovery from Friend virus 3), a genetic trait that has been known for 30 years to be important for the recovery of mice from Friend virus by promoting the formation of neutralizing antibodies, is encoded by the murine Apobec3 gene. “When you remove Apobec in the Rfv3 resistant strain, [the mice] become susceptible [to Friend virus],” Greene says.
People have been wondering about which gene encodes Rfv3 for 30 years, says B. Matija Peterlin, a professor of medicine, microbiology, and immunology at the University of California in San Francisco, who was not connected to the studies. Friend virus is only the second type of retrovirus that has been shown in in vivo animal experiments to be repressed by Apobec3, according to Peterlin, who showed last year that the absence of Apobec3 in mice leads to an increased susceptibility to infection with mouse mammary tumor virus (Nature 445, 927, 2007).
However, Peterlin says the new studies do not completely exclude the contribution of a gene other than Apobec3 in restricting Friend virus infection. Mario Santiago, a postdoctoral fellow at the Gladstone Institute and the first author of the Science study, however, says that “if those genes exist, their contribution would be negligible.”
Additionally, when Greene and colleagues infected Apobec3-deficient mice with Friend virus, they observed that these mice also produced fewer Friend virus-specific neutralizing antibodies, resulting in a higher titer of Friend virus. This is consistent with the previous observation that Rfv3 mediated recovery from Friend virus correlates with Friend virus-specific neutralizing antibody responses.
“For the first time we link [Apobec3] to the adaptive immune response and more specifically to [the production of virus-specific] neutralizing antibodies,” says Greene. But the authors of the other study showing that Apobec3 plays a role in inhibiting infection with Friend virus are more cautious. “We think there is no direct connection between the known Apobec3 functions and the control of antibody production,” says Masaaki Miyazawa, lead author of the Journal of Virology study and a professor and chairman at the department of immunology at Kinki University School of Medicine in Japan.
Greene says the next experiments will try to elucidate the mechanism of the Apobec3/neutralizing antibody connection. “Now the question is how Apobec is eliciting these neutralizing antibodies,” says Greene.
One possible mechanism is that simply by lowering virus levels, Apobec might make the immune system less overwhelmed, thereby allowing it to mount a better antibody response. “It’s a little counterintuitive,” Peterlin says. “If you have less virus, you make more antibodies and [a better] cytotoxic T lymphocyte response.” Another possibility is that Apobec may be limiting viral replication in immune cells important for the production of neutralizing antibodies like T cells or dendritic cells, Greene says. It’s also possible that Apobec3, which according to Greene is expressed in B cells, might have a direct role in shaping the antibody repertoire by increasing the mutation rate in the DNA encoding antibody immunoglobulins.
For HIV, a possible involvement of Apobec3 in the neutralizing antibody response could mean that Vif antagonists, should they be identified, would have the added benefit of eliciting a strong humoral immune response, according to Greene. And higher Apobec levels may explain why some individuals known as exposed seronegatives (ESNs) are able to resist HIV infection despite sometimes repeat exposure. A 2005 study of ESNs mapped their resistance to HIV and production of antibodies to the same chromosomal region as the Apobec locus (AIDS 19, 1015, 2005). Perhaps, Peterlin says, increased Apobec3 levels could protect ESNs from HIV infection because the virus might not be able to make enough Vif protein to counteract Apobec3 levels in these people. “It’s a very attractive notion,” he adds. —Andreas von Bubnoff