Enhancing the Catalytic Deamination Activity of APOBEC3C Is Insufficient to Inhibit Vif-Deficient HIV-1.
The retroviral restriction factors of the APOBEC3 (A3) cytidine deaminase family catalyze the deamination of cytidines in single-stranded viral DNA. APOBEC3C (A3C) is a strong antiviral factor against viral infectivity factor (vif)-deficient simian immunodeficiency virus Δvif, which is, however, a weak inhibitor against human immunodeficiency virus (HIV)-1 for reasons unknown. The precise link between the antiretroviral effect of A3C and its catalytic activity is incompletely understood. Here, we show that the S61P mutation in human A3C (A3C.S61P) boosted hypermutation in the viral genomes of simian immunodeficiency virus Δvif and murine leukemia virus but not in human immunodeficiency virus HIV-1Δvif. The enhanced antiviral activity of A3C.S61P correlated with enhanced in vitro cytidine deamination. Furthermore, the S61P mutation did not change the substrate specificity of A3C, ribonucleoprotein complex formation, self-association, Zinc coordination, or viral incorporation features. We propose that local structural changes induced by the serine-to-proline substitution are responsible for the gain of catalytic activity of A3C.S61P. Our results are a first step toward an understanding of A3C's DNA binding capacity, deamination-dependent editing, and antiviral functions at the molecular level. We conclude that the enhanced enzymatic activity of A3C is insufficient to restrict HIV-1, indicating an unknown escape mechanism of HIV-1.
Clinic for Gastroenterology, Hepatology, and Infectiology, Medical Faculty, Heinrich-Heine-University Düsseldorf, Moorenstr. 5, 40225 Düsseldorf, Germany.
Ananda Ayyappan
AA
Jaguva Vasudevan
Clinic for Gastroenterology, Hepatology, and Infectiology, Medical Faculty, Heinrich-Heine-University Düsseldorf, Moorenstr. 5, 40225 Düsseldorf, Germany.
Henning
H
Hofmann
Institute of Complex Systems, Structural Biochemistry (ICS-6), Forschungszentrum Jülich, 52425 Jülich, Germany; Institut für Physikalische Biologie, Heinrich-Heine-University Düsseldorf, Universitätsstr. 1, 40225 Düsseldorf, Germany.
Dieter
D
Willbold
Clinic for Gastroenterology, Hepatology, and Infectiology, Medical Faculty, Heinrich-Heine-University Düsseldorf, Moorenstr. 5, 40225 Düsseldorf, Germany.
Dieter
D
Häussinger
Institute of Complex Systems, Structural Biochemistry (ICS-6), Forschungszentrum Jülich, 52425 Jülich, Germany; Institut für Physikalische Biologie, Heinrich-Heine-University Düsseldorf, Universitätsstr. 1, 40225 Düsseldorf, Germany.
Bernd W
BW
Koenig
Clinic for Gastroenterology, Hepatology, and Infectiology, Medical Faculty, Heinrich-Heine-University Düsseldorf, Moorenstr. 5, 40225 Düsseldorf, Germany. Electronic address: carsten.muenk@med.uni-duesseldorf.de.
Carsten
C
Münk
D019943:Amino Acid Substitution; D000818:Animals; D003564:Cytidine Deaminase / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D003596:Cytosine / Q000378:metabolism; D004277:DNA, Single-Stranded / Q000737:chemistry / Q000378:metabolism; D004279:DNA, Viral / Q000378:metabolism; D057809:HEK293 Cells / Q000821:virology; D015497:HIV-1 / Q000235:genetics / Q000472:pathogenicity*; D054884:Host-Pathogen Interactions; D006801:Humans; D009052:Leukemia Virus, Murine / Q000378:metabolism / Q000472:pathogenicity; D002679:Pan troglodytes; D011487:Protein Conformation; D015302:Simian Immunodeficiency Virus / Q000378:metabolism / Q000472:pathogenicity; D015032:Zinc / Q000378:metabolism; D054320:vif Gene Products, Human Immunodeficiency Virus / Q000235:genetics / Q000378:metabolism
D004277:DNA, Single-Stranded; D004279:DNA, Viral; D054320:vif Gene Products, Human Immunodeficiency Virus; C514847:vif protein, Human immunodeficiency virus 1; D003596:Cytosine; C495795:APOBEC3C protein, human; D003564:Cytidine Deaminase; D015032:Zinc
APOBEC3C; cytidine deaminase; deamination-dependent virus restriction; human immunodeficiency virus (HIV); retrovirus