HIV-1 seems to have unlimited ways to avoid our natural defense systems. It first targets the very immune cells that normally help fight off infections, the CD4 T cells. Fortunately, these cells have a powerful ally, a potent anti-retroviral enzyme called APOBEC3G that can stop HIV almost in its tracks. However, HIV encodes a protein called Vif (viral infectivity factor) whose function is to neutralize APOBEC3G.
Although what Vif does was well established, how it stops APOBEC3G from doing its job remained a critical question. Now scientists at the Gladstone Institute of Virology and Immunology have answered that question. Their study is published in the September 26 issue of the journal Molecular Cell.
"The interaction between Vif and APOBEC3G is fascinating and more complicated than we imagined" said Warner C. Greene, MD, PhD, institute director and senior author of the study.
APOBEC3G is normally found in CD4 T cells. During HIV-1 infection, it sneaks aboard new viral particles as they are made. Once a particle carrying APOBEC3G enters a new CD4 T cell, the enzyme springs into action. It massively mutates the new retroviral DNA, turning the viral genetic information into gibberish and halting the viral life cycle. These effects lead to a near complete loss of viral infectivity before the virus can commandeer the genetic machinery of the host cell and use it to churn out more viral particles. Unfortunately for the more than 40 million people infected with HIV, the Vif protein of HIV blocks these antiviral effects of APOBEC3G.
The Gladstone researchers showed that Vif almost completely eliminates the intracellular stores of APOBEC3G in two distinct ways. First, it partially blocks the translation of APOBEC3G mRNA into protein. Second, it causes the APOBEC3G that is produced to be rapidly destroyed by the 26S proteasome, the cell’s garbage disposal. In combination, these two effects essentially deplete the infected CD4 T cells of APOBEC3G. Thus, the enzyme is unavailable for incorporation into new viral particles budding from these cells.
Key to unraveling the APOBEC3G-Vif connection was the development of an antibody that specifically recognizes the endogenous APOBEC3G protein. The antibody was used to examine cells infected either with normal HIV-1 or with a mutant version of the virus lacking Vif. Nothing happened to APOBEC3G in cells infected with HIV lacking Vif. However, in cells infected with wildtype HIV expressing Vif, the levels of APOBEC3G were greatly reduced.
"Our findings have great potential clinical significance," said Kim Stopak, lead author of the study and a graduate student in the UCSF Biomedical Science Program. "It might be possible to devise new drugs that block the effects of Vif on APOBEC3G, which would make APOBEC3G available to exert its potent antiviral effect."
For example, small-molecule drugs might be developed that would stop the intracellular depletion of APOBEC3G by Vif. As a result, the antiviral factor would be packaged into the new virus and deliver its lethal blow to the virus in the next infected cell.
"We now understand a lot more about how Vif works. The next challenge is whether we can use this information to create an entirely new class of anti-HIV drugs," said Dr. Greene, who is also professor of medicine, microbiology, and immunology at UCSF.
Other authors of the study were Gladstone research scientist Dr. Carlos de Noronha and Wes Yonemoto, a senior research associate in the Greene laboratory.
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