title: APOBEC3D and APOBEC3F potently promote HIV-1 diversification and evolution in humanized mouse model.
abstract: Several APOBEC3 proteins, particularly APOBEC3D, APOBEC3F, and APOBEC3G, induce G-to-A hypermutations in HIV-1 genome, and abrogate viral replication in experimental systems, but their relative contributions to controlling viral replication and viral genetic variation in vivo have not been elucidated. On the other hand, an HIV-1-encoded protein, Vif, can degrade these APOBEC3 proteins via a ubiquitin/proteasome pathway. Although APOBEC3 proteins have been widely considered as potent restriction factors against HIV-1, it remains unclear which endogenous APOBEC3 protein(s) affect HIV-1 propagation in vivo. Here we use a humanized mouse model and HIV-1 with mutations in Vif motifs that are responsible for specific APOBEC3 interactions, DRMR/AAAA (4A) or YRHHY/AAAAA (5A), and demonstrate that endogenous APOBEC3D/F and APOBEC3G exert strong anti-HIV-1 activity in vivo. We also show that the growth kinetics of 4A HIV-1 negatively correlated with the expression level of APOBEC3F. Moreover, single genome sequencing analyses of viral RNA in plasma of infected mice reveal that 4A HIV-1 is specifically and significantly diversified. Furthermore, a mutated virus that is capable of using both CCR5 and CXCR4 as entry coreceptor is specifically detected in 4A HIV-1-infected mice. Taken together, our results demonstrate that APOBEC3D/F and APOBEC3G fundamentally work as restriction factors against HIV-1 in vivo, but at the same time, that APOBEC3D and APOBEC3F are capable of promoting viral diversification and evolution in vivo.
authors.affiliation: Laboratory of Viral Pathogenesis, Institute for Virus Research, Kyoto University, Kyoto, Kyoto, Japan.
authors.forename: Kei
authors.initials: K
authors.lastname: Sato
authors.affiliation: Laboratory of Viral Pathogenesis, Institute for Virus Research, Kyoto University, Kyoto, Kyoto, Japan.
authors.forename: Junko S
authors.initials: JS
authors.lastname: Takeuchi
authors.affiliation: Laboratory of Viral Pathogenesis, Institute for Virus Research, Kyoto University, Kyoto, Kyoto, Japan.
authors.forename: Naoko
authors.initials: N
authors.lastname: Misawa
authors.affiliation: Viral Mutation Section, HIV Drug Resistance Program, Center for Cancer Research, National Cancer Institute-Frederick, Frederick, Maryland, United States of America.
authors.forename: Taisuke
authors.initials: T
authors.lastname: Izumi
authors.affiliation: Laboratory of Viral Pathogenesis, Institute for Virus Research, Kyoto University, Kyoto, Kyoto, Japan.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Kobayashi
authors.affiliation: Laboratory of Viral Pathogenesis, Institute for Virus Research, Kyoto University, Kyoto, Kyoto, Japan.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Kimura
authors.affiliation: Department of Biology, Faculty of Sciences, Kyushu University, Fukuoka, Fukuoka, Japan.
authors.forename: Shingo
authors.initials: S
authors.lastname: Iwami
authors.affiliation: Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Kyoto, Japan.
authors.forename: Akifumi
authors.initials: A
authors.lastname: Takaori-Kondo
authors.affiliation: Viral Recombination Section, HIV Drug Resistance Program, Center for Cancer Research, National Cancer Institute-Frederick, Frederick, Maryland, United States of America.
authors.forename: Wei-Shau
authors.initials: WS
authors.lastname: Hu
authors.affiliation: Institute of Industrial Science, The University of Tokyo, Meguro-ku, Tokyo, Japan; Graduate School of Information Science and Technology, The University of Tokyo, Meguro-ku, Tokyo, Japan.
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Aihara
authors.affiliation: Central Institute for Experimental Animals, Kawasaki, Kanagawa, Japan.
authors.forename: Mamoru
authors.initials: M
authors.lastname: Ito
authors.affiliation: Division of Hematology and Oncology, University of California, Los Angeles, Los Angeles, California, United States of America; School of Nursing, University of California, Los Angeles, Los Angeles, California, United States of America; AIDS Institute, University of California, Los Angeles, Los Angeles, California, United States of America.
authors.forename: Dong Sung
authors.initials: DS
authors.lastname: An
authors.affiliation: Viral Mutation Section, HIV Drug Resistance Program, Center for Cancer Research, National Cancer Institute-Frederick, Frederick, Maryland, United States of America.
authors.forename: Vinay K
authors.initials: VK
authors.lastname: Pathak
authors.affiliation: Laboratory of Viral Pathogenesis, Institute for Virus Research, Kyoto University, Kyoto, Kyoto, Japan.
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Koyanagi
mesh_terms: D000818:Animals; D005075:Biological Evolution; D002874:Chromosome Mapping; D003564:Cytidine Deaminase / Q000378:metabolism*; D043525:Cytosine Deaminase / Q000378:metabolism*; D004195:Disease Models, Animal; D014644:Genetic Variation / Q000235:genetics; D015497:HIV-1; D006801:Humans; D051379:Mice; D009154:Mutation / Q000235:genetics*; D012367:RNA, Viral / Q000235:genetics*; D019718:Receptors, CXCR4 / Q000235:genetics; D014779:Virus Replication / Q000502:physiology
chemical_list: D012367:RNA, Viral; D019718:Receptors, CXCR4; C492906:APOBEC3F protein, human; D043525:Cytosine Deaminase; C578087:APOBEC3D protein, human; D003564:Cytidine Deaminase