Regulated production and anti-HIV type 1 activities of cytidine deaminases APOBEC3B, 3F, and 3G.
APOBEC3G and 3F (A3G and A3F) cytidine deaminases incorporate into retroviral cores where they lethally hypermutate nascent DNA reverse transcripts. As substantiated here, the viral infectivity factor (Vif) encoded by human immunodeficiency virus type-1 (HIV-1) binds A3G and A3F and induces their degradation, thereby precluding their incorporation into viral progeny. Previous evidence suggested that A3G is expressed in H9 and other nonpermissive cells that contain this antiviral defense but not in several permissive cells, and that overexpression of A3G or A3F makes permissive cells nonpermissive. Using a broader panel of cell lines, we confirmed a correlation between A3G and cellular abilities to inactivate HIV-1(Deltavif). However, there was a quantitative discrepancy because several cells with weak antiviral activities had similar amounts of wild-type A3G mRNA and protein compared to H9 cells. Antiviral activity of H9 cells was also attenuated in some conditions. These quantitative discrepancies could not be explained by the presence of A3F or other A3G paralogs in some of the cell lines. Thus, A3A, A3B, and A3C had weak but significant anti-HIV-1 activities and did not dominantly interfere with A3G or A3F antiviral functions. Control of A3G synthesis by the protein kinase C/mitogen-activated protein kinase kinase/extracellular signal-regulated kinase pathway was also similar in permissive and nonpermissive cells. A3G in highly permissive cells is degraded by Vif, suggesting that it is not in a sequestered site, and is specifically incorporated in low amounts into HIV-1(Deltavif). Although A3G and/or A3F inactivate HIV-1(Deltavif) and are neutralized by Vif, the antiviral properties of cell lines are also influenced by other cellular and viral factors.
Rose
Kristine M
KM
Department of Biochemistry and Molecular Biology, Oregon Health and Science University, Portland, Oregon 97239-3098, USA.
Marin
Mariana
M
Kozak
Susan L
SL
Kabat
David
D
D000071480:APOBEC-3G Deaminase; D000998:Antiviral Agents; D001483:Base Sequence; D015152:Blotting, Northern; D003564:Cytidine Deaminase / Q000096:biosynthesis* / Q000502:physiology; D043525:Cytosine Deaminase / Q000096:biosynthesis* / Q000502:physiology; D017931:DNA Primers; D016346:Gene Products, vif / Q000502:physiology; D006367:HeLa Cells; D006801:Humans; D015778:Minor Histocompatibility Antigens; D008969:Molecular Sequence Data; D009700:Nucleoside Deaminases / Q000378:metabolism* / Q000502:physiology; D012097:Repressor Proteins / Q000378:metabolism* / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction
D000998:Antiviral Agents; D017931:DNA Primers; D016346:Gene Products, vif; D015778:Minor Histocompatibility Antigens; D012097:Repressor Proteins; D009700:Nucleoside Deaminases; C492906:APOBEC3F protein, human; D043525:Cytosine Deaminase; D000071480:APOBEC-3G Deaminase; C495794:APOBEC3B protein, human; C464924:APOBEC3G protein, human; D003564:Cytidine Deaminase