Different modes of retrovirus restriction by human APOBEC3A and APOBEC3G in vivo.
The apolipoprotein B editing complex 3 (A3) cytidine deaminases are among the most highly evolutionarily selected retroviral restriction factors, both in terms of gene copy number and sequence diversity. Primate genomes encode seven A3 genes, and while A3F and 3G are widely recognized as important in the restriction of HIV, the role of the other genes, particularly A3A, is not as clear. Indeed, since human cells can express multiple A3 genes, and because of the lack of an experimentally tractable model, it is difficult to dissect the individual contribution of each gene to virus restriction in vivo. To overcome this problem, we generated human A3A and A3G transgenic mice on a mouse A3 knockout background. Using these mice, we demonstrate that both A3A and A3G restrict infection by murine retroviruses but by different mechanisms: A3G was packaged into virions and caused extensive deamination of the retrovirus genomes while A3A was not packaged and instead restricted infection when expressed in target cells. Additionally, we show that a murine leukemia virus engineered to express HIV Vif overcame the A3G-mediated restriction, thereby creating a novel model for studying the interaction between these proteins. We have thus developed an in vivo system for understanding how human A3 proteins use different modes of restriction, as well as a means for testing therapies that disrupt HIV Vif-A3G interactions.
Department of Microbiology, Institute for Immunology and Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
Spyridon
S
Stavrou
Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
Daniel
D
Crawford
Department of Microbiology, Institute for Immunology and Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
Kristin
K
Blouch
Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.
Edward P
EP
Browne
Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
Rahul M
RM
Kohli
Department of Microbiology, Institute for Immunology and Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
Susan R
SR
Ross
D000071480:APOBEC-3G Deaminase; D000818:Animals; D002478:Cells, Cultured; D003564:Cytidine Deaminase / Q000502:physiology*; D015497:HIV-1 / Q000502:physiology; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D041681:NIH 3T3 Cells; D011506:Proteins / Q000502:physiology*; D012190:Retroviridae / Q000502:physiology; D012192:Retroviridae Infections / Q000235:genetics* / Q000821:virology*; D019562:Viral Load / Q000235:genetics*; D019065:Virus Assembly / Q000235:genetics; D053586:Virus Internalization; D014779:Virus Replication / Q000235:genetics; D054320:vif Gene Products, Human Immunodeficiency Virus / Q000235:genetics
D011506:Proteins; D054320:vif Gene Products, Human Immunodeficiency Virus; C514847:vif protein, Human immunodeficiency virus 1; D000071480:APOBEC-3G Deaminase; C121399:APOBEC3A protein, human; C464924:APOBEC3G protein, human; D003564:Cytidine Deaminase