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Researchers at the Gladstone Institute of Virology and Immunology have discovered the mechanism that enables some T cells--the main target of HIV--to escape infection. Scientists, led by institute director Warner C. Greene, found that a key antiviral factor called APOBEC3G helps protect resting T cells from infection. APOBEC3G exists in two forms--a large form that is ineffective in preventing cellular infection and a shorter form that repels the virus. Activated T cells have the longer form of the antiviral compound and as such are easily infected by HIV. But resting T cells--immune system cells that are dormant in the body and come to life only when they detect a particular invading pathogen--carry the smaller form of the compound, which makes them impervious to HIV infection. Lab tests showed that blocking the small form of APOBEC3G in resting T cells suddenly made them susceptible to HIV infection. "Until now, the prevailing belief has been that HIV failed to infect resting T cells due to a simple lack of some essential factor or nutrient," says Greene, a professor of medicine, microbiology, and immunology at the University of California, San Francisco, in a press release. "This study now shifts the paradigm, showing that resting CD4 T cells actively repel HIV infection through the action of the small, enzymatically active form of APOBEC3G, which stops the virus in its tracks." Roughly 95% of T cells in the bloodstream exist in a resting, inactive state, awaiting the appearance of their specific antigen. When they detect its presence, they spring into action--growing and dividing, releasing cytokines (proteins that the immune system uses to communicate between cells), and recruiting and activating additional T cells. The new study shows that this activation process dismantles the highly effective APOBEC3G antiviral shield, making these cells highly susceptible to HIV infection. Greene's group is now looking at ways to use this new knowledge therapeutically. One approach would involve converting the ineffective, large form of APOBEC3G into the protective, small form in activated T cells. A parallel strategy would involve finding ways to prevent the small form of APOBEC3G from converting to the large form during the process of T cell activation. "The possibility of exploiting the natural and potent antiviral properties of APOBEC3G to control HIV infection is very exciting," says Greene in a press release. "We have learned a great deal from our studies of how the resting CD4 T cell resists HIV. Now the challenge is for scientists at the Gladstone Institute of Virology and Immunology and elsewhere to translate these basic discoveries into novel treatments that could benefit HIV-infected patients around the world." The Gladstone study, titled "Cellular APOBEC3G Restricts HIV-1 Infection in Resting CD4 T Cells," appears in the April 13 online edition of the journal Nature.