title: Role of APOBEC3F Gene Variation in HIV-1 Disease Progression and Pneumocystis Pneumonia.
abstract: Human APOBEC3 cytidine deaminases are intrinsic resistance factors to HIV-1. However, HIV-1 encodes a viral infectivity factor (Vif) that degrades APOBEC3 proteins. In vitro APOBEC3F (A3F) anti-HIV-1 activity is weaker than A3G but is partially resistant to Vif degradation unlike A3G. It is unknown whether A3F protein affects HIV-1 disease in vivo. To assess the effect of A3F gene on host susceptibility to HIV- acquisition and disease progression, we performed a genetic association study in six well-characterized HIV-1 natural cohorts. A common six-Single Nucleotide Polymorphism (SNP) haplotype of A3F tagged by a codon-changing variant (p. I231V, with allele (V) frequency of 48% in European Americans) was associated with significantly lower set-point viral load and slower rate of progression to AIDS (Relative Hazards (RH) = 0.71, 95% CI: 0.56, 0.91) and delayed development of pneumocystis pneumonia (PCP) (RH = 0.53, 95% CI: 0.37-0.76). A validation study in the International Collaboration for the Genomics of HIV (ICGH) showed a consistent association with lower set-point viral load. An in vitro assay revealed that the A3F I231V variant may influence Vif mediated A3F degradation. Our results provide genetic epidemiological evidence that A3F modulates HIV-1/AIDS disease progression.
authors.affiliation: Basic Research Laboratory, Center for Cancer Research, National Cancer Institute, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland, United States of America.
authors.forename: Ping
authors.initials: P
authors.lastname: An
authors.affiliation: Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States of America.
authors.forename: Sudhir
authors.initials: S
authors.lastname: Penugonda
authors.affiliation: School of Life Sciences, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.|Swiss Institute of Bioinformatics, Lausanne, Switzerland.
authors.forename: Christian W
authors.initials: CW
authors.lastname: Thorball
authors.affiliation: School of Life Sciences, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.|Swiss Institute of Bioinformatics, Lausanne, Switzerland.
authors.forename: Istvan
authors.initials: I
authors.lastname: Bartha
authors.affiliation: Infections and Immunoepidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, United States of America.
authors.forename: James J
authors.initials: JJ
authors.lastname: Goedert
authors.affiliation: Rho, Inc., Chapel Hill, North Carolina, United States of America.
authors.forename: Sharyne
authors.initials: S
authors.lastname: Donfield
authors.affiliation: San Francisco Department of Public Health, San Francisco, California, United States of America.
authors.forename: Susan
authors.initials: S
authors.lastname: Buchbinder
authors.affiliation: Basic Research Laboratory, Center for Cancer Research, National Cancer Institute, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland, United States of America.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Binns-Roemer
authors.affiliation: Department of Epidemiology, Johns Hopkins School of Public Health, Baltimore, Maryland, United States of America.
authors.forename: Gregory D
authors.initials: GD
authors.lastname: Kirk
authors.affiliation: Institute of Virology and AIDS Research, First Hospital of Jilin University, Changchun, China.
authors.forename: Wenyan
authors.initials: W
authors.lastname: Zhang
authors.affiliation: School of Life Sciences, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.|Swiss Institute of Bioinformatics, Lausanne, Switzerland.
authors.forename: Jacques
authors.initials: J
authors.lastname: Fellay
authors.affiliation: Institute of Virology and AIDS Research, First Hospital of Jilin University, Changchun, China.|Department of Molecular Microbiology and Immunology, Johns Hopkins School of Public Health, Baltimore, Maryland, United States of America.
authors.forename: Xiao-Fang
authors.initials: XF
authors.lastname: Yu
authors.affiliation: Basic Research Laboratory, Center for Cancer Research, National Cancer Institute, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland, United States of America.
authors.forename: Cheryl A
authors.initials: CA
authors.lastname: Winkler
mesh_terms: D000595:Amino Acid Sequence; D043525:Cytosine Deaminase / Q000235:genetics* / Q000378:metabolism; D018450:Disease Progression; D015658:HIV Infections / Q000235:genetics* / Q000473:pathology / Q000821:virology; D015497:HIV-1 / Q000472:pathogenicity; D006239:Haplotypes; D006801:Humans; D011020:Pneumonia, Pneumocystis / Q000235:genetics* / Q000473:pathology / Q000821:virology; D020641:Polymorphism, Single Nucleotide; D011485:Protein Binding; D054320:vif Gene Products, Human Immunodeficiency Virus / Q000235:genetics* / Q000378:metabolism
chemical_list: D054320:vif Gene Products, Human Immunodeficiency Virus; C514847:vif protein, Human immunodeficiency virus 1; C492906:APOBEC3F protein, human; D043525:Cytosine Deaminase