title: Natural polymorphisms in human APOBEC3H and HIV-1 Vif combine in primary T lymphocytes to affect viral G-to-A mutation levels and infectivity.
abstract: The Vif protein of HIV-1 allows virus replication by degrading several members of the host-encoded APOBEC3 family of DNA cytosine deaminases. Polymorphisms in both host APOBEC3 genes and the viral vif gene have the potential to impact the extent of virus replication among individuals. The most genetically diverse of the seven human APOBEC3 genes is APOBEC3H with seven known haplotypes. Overexpression studies have shown that a subset of these variants express stable and active proteins, whereas the others encode proteins with a short half-life and little, if any, antiviral activity. We demonstrate that these stable/unstable phenotypes are an intrinsic property of endogenous APOBEC3H proteins in primary CD4+ T lymphocytes and confer differential resistance to HIV-1 infection in a manner that depends on natural variation in the Vif protein of the infecting virus. HIV-1 with a Vif protein hypo-functional for APOBEC3H degradation, yet fully able to counteract APOBEC3D, APOBEC3F, and APOBEC3G, was susceptible to restriction and hypermutation in stable APOBEC3H expressing lymphocytes, but not in unstable APOBEC3H expressing lymphocytes. In contrast, HIV-1 with hyper-functional Vif counteracted stable APOBEC3H proteins as well as all other endogenous APOBEC3s and replicated to high levels. We also found that APOBEC3H protein levels are induced over 10-fold by infection. Finally, we found that the global distribution of stable/unstable APOBEC3H haplotypes correlates with the distribution a critical hyper/hypo-functional Vif amino acid residue. These data combine to strongly suggest that stable APOBEC3H haplotypes present as in vivo barriers to HIV-1 replication, that Vif is capable of adapting to these restrictive pressures, and that an evolutionary equilibrium has yet to be reached.
authors.affiliation: Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, Minnesota, United States of America; Institute for Molecular Virology, University of Minnesota, Minneapolis, Minnesota, United States of America; Center for Genome Engineering, University of Minnesota, Minneapolis, Minnesota, United States of America; Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota, United States of America.
authors.forename: Eric W
authors.initials: EW
authors.lastname: Refsland
authors.affiliation: Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, Minnesota, United States of America; Institute for Molecular Virology, University of Minnesota, Minneapolis, Minnesota, United States of America; Center for Genome Engineering, University of Minnesota, Minneapolis, Minnesota, United States of America; Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota, United States of America.
authors.forename: Judd F
authors.initials: JF
authors.lastname: Hultquist
authors.affiliation: Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, Minnesota, United States of America; Institute for Molecular Virology, University of Minnesota, Minneapolis, Minnesota, United States of America; Center for Genome Engineering, University of Minnesota, Minneapolis, Minnesota, United States of America; Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota, United States of America.
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Luengas
authors.affiliation: Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, Minnesota, United States of America; Institute for Molecular Virology, University of Minnesota, Minneapolis, Minnesota, United States of America; Center for Genome Engineering, University of Minnesota, Minneapolis, Minnesota, United States of America; Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota, United States of America.
authors.forename: Terumasa
authors.initials: T
authors.lastname: Ikeda
authors.affiliation: Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, Minnesota, United States of America; Institute for Molecular Virology, University of Minnesota, Minneapolis, Minnesota, United States of America; Center for Genome Engineering, University of Minnesota, Minneapolis, Minnesota, United States of America; Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota, United States of America.
authors.forename: Nadine M
authors.initials: NM
authors.lastname: Shaban
authors.affiliation: Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, Minnesota, United States of America; Institute for Molecular Virology, University of Minnesota, Minneapolis, Minnesota, United States of America; Center for Genome Engineering, University of Minnesota, Minneapolis, Minnesota, United States of America; Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota, United States of America.
authors.forename: Emily K
authors.initials: EK
authors.lastname: Law
authors.affiliation: Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, Minnesota, United States of America; Institute for Molecular Virology, University of Minnesota, Minneapolis, Minnesota, United States of America; Center for Genome Engineering, University of Minnesota, Minneapolis, Minnesota, United States of America; Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota, United States of America.
authors.forename: William L
authors.initials: WL
authors.lastname: Brown
authors.affiliation: Institute for Molecular Virology, University of Minnesota, Minneapolis, Minnesota, United States of America; Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis, Minnesota, United States of America.
authors.forename: Cavan
authors.initials: C
authors.lastname: Reilly
authors.affiliation: Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
authors.forename: Michael
authors.initials: M
authors.lastname: Emerman
authors.affiliation: Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, Minnesota, United States of America; Institute for Molecular Virology, University of Minnesota, Minneapolis, Minnesota, United States of America; Center for Genome Engineering, University of Minnesota, Minneapolis, Minnesota, United States of America; Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota, United States of America.
authors.forename: Reuben S
authors.initials: RS
authors.lastname: Harris
mesh_terms: D000619:Aminohydrolases / Q000235:genetics*; D015496:CD4-Positive T-Lymphocytes / Q000473:pathology / Q000821:virology; D002460:Cell Line; D015658:HIV Infections / Q000235:genetics* / Q000473:pathology / Q000821:virology; D015497:HIV-1 / Q000235:genetics* / Q000472:pathogenicity; D006239:Haplotypes; D006801:Humans; D009154:Mutation; D011110:Polymorphism, Genetic; D014779:Virus Replication / Q000235:genetics; D054320:vif Gene Products, Human Immunodeficiency Virus / Q000235:genetics*
chemical_list: D054320:vif Gene Products, Human Immunodeficiency Virus; C514847:vif protein, Human immunodeficiency virus 1; C529313:APOBEC3H protein, human; D000619:Aminohydrolases