APOBEC3G-Induced Hypermutation of Human Immunodeficiency Virus Type-1 Is Typically a Discrete "All or Nothing" Phenomenon

作者：Armitage Andrew E^*; Deforche Koen; Chang Chih hao; Wee Edmund; Kramer Beatrice; Welch John J; Gerstoft Jan; Fugger Lars; McMichael Andrew; Rambaut Andrew; Iversen Astrid K N

来源：PLoS Genetics, 2012, 8(3): e1002550.

DOI：10.1371/journal.pgen.1002550

The rapid evolution of Human Immunodeficiency Virus (HIV-1) allows studies of ongoing host-pathogen interactions. One key selective host factor is APOBEC3G (hA3G) that can cause extensive and inactivating Guanosine-to-Adenosine (G-to-A) mutation on HIV plus-strand DNA (termed hypermutation). HIV can inhibit this innate anti-viral defense through binding of the viral protein Vif to hA3G, but binding efficiency varies and hypermutation frequencies fluctuate in patients. A pivotal question is whether hA3G-induced G-to-A mutation is always lethal to the virus or if it may occur at sub-lethal frequencies that could increase viral diversification. We show in vitro that limiting-levels of hA3G-activity (i.e. when only a single hA3G-unit is likely to act on HIV) produce hypermutation frequencies similar to those in patients and demonstrate in silico that potentially non-lethal G-to-A mutation rates are similar to 10-fold lower than the lowest observed hypermutation levels in vitro and in vivo. Our results suggest that even a single incorporated hA3G-unit is likely to cause extensive and inactivating levels of HIV hypermutation and that hypermutation therefore is typically a discrete "all or nothing" phenomenon. Thus, therapeutic measures that inhibit the interaction between Vif and hA3G will likely not increase virus diversification but expand the fraction of hypermutated proviruses within the infected host.

• 出版日期2012-3
• 单位河北医科大学