title: Codon pairs of the HIV-1 vif gene correlate with CD4+ T cell count.
abstract: BACKGROUND
  The human APOBEC3G (A3G) protein activity is associated with innate immunity against HIV-1 by inducing high rates of guanosines to adenosines (G-to-A) mutations (viz., hypermutation) in the viral DNA. If hypermutation is not enough to disrupt the reading frames of viral genes, it may likely increase the HIV-1 diversity. To counteract host innate immunity HIV-1 encodes the Vif protein that binds A3G protein and form complexes to be degraded by cellular proteolysis.
  
  
  METHODS
  Here we studied the pattern of substitutions in the vif gene and its association with clinical status of HIV-1 infected individuals. To perform the study, unique vif gene sequences were generated from 400 antiretroviral-naïve individuals.
  
  
  RESULTS
  The codon pairs: 78-154, 85-154, 101-157, 105-157, and 105-176 of vif gene were associated with CD4+ T cell count lower than 500 cells per mm(3). Some of these codons were located in the (81)LGQGVSIEW(89) region and within the BC-Box. We also identified codons under positive selection clustered in the N-terminal region of Vif protein, between (21)WKSLVK(26) and (40)YRHHY(44) regions (i.e., 31, 33, 37, 39), within the BC-Box (i.e., 155, 159) and the Cullin5-Box (i.e., 168) of vif gene. All these regions are involved in the Vif-induced degradation of A3G/F complexes and the N-terminal of Vif protein binds to viral and cellular RNA.
  
  
  CONCLUSIONS
  Adaptive evolution of vif gene was mostly to optimize viral RNA binding and A3G/F recognition. Additionally, since there is not a fully resolved structure of the Vif protein, codon pairs associated with CD4+ T cell count may elucidate key regions that interact with host cell factors. Here we identified and discriminated codons under positive selection and codons under functional constraint in the vif gene of HIV-1.
authors.affiliation: Department of Medicine, Federal University of São Paulo, São Paulo, Brazil.
authors.forename: Maria Clara
authors.initials: MC
authors.lastname: Bizinoto
authors.forename: Shiori
authors.initials: S
authors.lastname: Yabe
authors.forename: Élcio
authors.initials: É
authors.lastname: Leal
authors.forename: Hirohisa
authors.initials: H
authors.lastname: Kishino
authors.forename: Leonardo de Oliveira
authors.initials: Lde O
authors.lastname: Martins
authors.forename: Mariana Leão
authors.initials: ML
authors.lastname: de Lima
authors.forename: Edsel Renata
authors.initials: ER
authors.lastname: Morais
authors.forename: Ricardo Sobhie
authors.initials: RS
authors.lastname: Diaz
authors.forename: Luiz Mário
authors.initials: LM
authors.lastname: Janini
mesh_terms: D000071480:APOBEC-3G Deaminase; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D018791:CD4 Lymphocyte Count; D015496:CD4-Positive T-Lymphocytes / Q000821:virology*; D003564:Cytidine Deaminase / Q000378:metabolism; D043525:Cytosine Deaminase / Q000378:metabolism; D005260:Female; D015658:HIV Infections / Q000276:immunology* / Q000821:virology*; D015497:HIV-1 / Q000235:genetics*; D006801:Humans; D008297:Male; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011485:Protein Binding; D011487:Protein Conformation; D012367:RNA, Viral / Q000378:metabolism; D054320:vif Gene Products, Human Immunodeficiency Virus / Q000235:genetics*
chemical_list: D012367:RNA, Viral; D054320:vif Gene Products, Human Immunodeficiency Virus; C514847:vif protein, Human immunodeficiency virus 1; C492906:APOBEC3F protein, human; D043525:Cytosine Deaminase; D000071480:APOBEC-3G Deaminase; C464924:APOBEC3G protein, human; D003564:Cytidine Deaminase