New Model for Testing and Discovery of Anti-HIV Drugs
Researchers at the University of Pennsylvania School of Medicine are the first to show that a mouse protein, whose human equivalent is related to defense against HIV-1, inhibits the infection and spread of a mouse tumor virus. The study, which appeared online January 28 in advance of its print publication in Nature, provides a new model for the discovery and evaluation of anti-HIV drugs. HIV-1, like the mouse tumor virus, is a retrovirus which infects immune system cells. However, unlike HIV-1, the mouse virus causes breast cancer in mice.
"Our study is the first to show that the mouse equivalent to the human protein, called APOBEC3, actually inhibits a retrovirus in a live animal," says lead author Susan R. Ross, PhD, Professor of Microbiology. The study is based on a mouse strain that does not have the gene for mouse APOBEC3, developed by co-author Boris Matija Peterlin, PhD, University of California at San Francisco.
In this study, normal mice and mutant mice were injected with mouse mammary tumor virus (MMTV). Using a sensitive test for virus infection, the researchers found that lymph nodes from mutant mice were more infected than normal mice. At six days after injection, the lymph nodes near the injection site in mutant mice had four times more of the breast cancer-causing virus. By 18 days after infection, the virus had spread to other sites in the mice, and spleen cells from the mutant mice were seven-fold more infected by MMTV than spleen cells from normal mice. The research team is currently waiting to see if mutant mice develop breast cancer at a greater rate than normal mice.
"Although this study was performed with mice and used a mouse tumor virus for which there is no human counterpart, the mouse model of infection we have developed may be useful as a test system for evaluating drugs that augment the role of human APOBEC3 in defending against HIV," says Ross. Since its discovery in 2002, the human equivalent to mouse APOBEC3 has been shown to defend some cell types against HIV-1 infection.
Some unanswered questions remain about APOBEC3 and how it can prevent virus replication and spread. Some cells cannot be infected with a retrovirus unless the virus has viral infectivity factor (Vif). Vif is a protein made by viruses like HIV that binds to APOBEC3 and marks it for destruction.
On the other hand, if APOBEC3 is not degraded by binding with Vif, it gets packaged into new virus particles. When these virus particles infect new cells, APOBEC3 causes mutations in virus RNA and DNA by a process called deamination. The mutations are so extensive that the new viruses cannot infect more cells, thus stopping the spread of the virus.
However, in the Nature study, no mutated MMTV virus was detected in the normal mice. "Thus, APOBEC3 must not use the deamination activity to mutate and limit the spread of MMTV," says Ross. "We plan to study the mechanism of the antiviral activity in our model system."