title: Exome analysis of HIV patients submitted to dendritic cells therapeutic vaccine reveals an association of CNOT1 gene with response to the treatment.
abstract: BACKGROUND
  With the aim of searching genetic factors associated with the response to an immune treatment based on autologous monocyte-derived dendritic cells pulsed with autologous inactivated HIV, we performed exome analysis by screening more than 240,000 putative functional exonic variants in 18 HIV-positive Brazilian patients that underwent the immune treatment.
  
  
  METHODS
  Exome analysis has been performed using the ILLUMINA Infinium HumanExome BeadChip. zCall algorithm allowed us to recall rare variants. Quality control and SNP-centred analysis were done with GenABEL R package. An in-house implementation of the Wang method permitted gene-centred analysis.
  
  
  RESULTS
  CCR4-NOT transcription complex, subunit 1 (CNOT1) gene (16q21), showed the strongest association with the modification of the response to the therapeutic vaccine (p=0.00075). CNOT1 SNP rs7188697 A/G was significantly associated with DC treatment response. The presence of a G allele indicated poor response to the therapeutic vaccine (p=0.0031; OR=33.00; CI=1.74-624.66), and the SNP behaved in a dominant model (A/A vs. A/G+G/G p=0.0009; OR=107.66; 95% CI=3.85-3013.31), being the A/G genotype present only in weak/transient responders, conferring susceptibility to poor response to the immune treatment.
  
  
  CONCLUSIONS
  CNOT1 is known to be involved in the control of mRNA deadenylation and mRNA decay. Moreover, CNOT1 has been recently described as being involved in the regulation of inflammatory processes mediated by tristetraprolin (TTP). The TTP-CCR4-NOT complex (CNOT1 in the CCR4-NOT complex is the binding site for TTP) has been reported as interfering with HIV replication, through post-transcriptional control. Therefore, we can hypothesize that genetic variation occurring in the CNOT1 gene could impair the TTP-CCR4-NOT complex, thus interfering with HIV replication and/or host immune response.
  
  
  CONCLUSIONS
  Being aware that our findings are exclusive to the 18 patients studied with a need for replication, and that the genetic variant of CNOT1 gene, localized at intron 3, has no known functional effect, we propose a novel potential candidate locus for the modulation of the response to the immune treatment, and open a discussion on the necessity to consider the host genome as another potential variant to be evaluated when designing an immune therapy study.
authors.affiliation: Department of Genetics, Federal University of Pernambuco, Recife, Brazil;
authors.forename: Ronald
authors.initials: R
authors.lastname: Moura
authors.affiliation: Department of Immunology, Institute of Biomedical Sciences, University of San Paolo, Brazil.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Pontillo
authors.affiliation: Department of Reproductive Sciences and Development, IRCCS-Burlo Garofolo, University of Trieste, Trieste, Italy.
authors.forename: Pio
authors.initials: P
authors.lastname: D'Adamo
authors.affiliation: Department of Reproductive Sciences and Development, IRCCS-Burlo Garofolo, University of Trieste, Trieste, Italy.
authors.forename: Nicola
authors.initials: N
authors.lastname: Pirastu
authors.affiliation: Department of Genetics, Federal University of Pernambuco, Recife, Brazil;
authors.forename: Antonio
authors.initials: A
authors.lastname: Campos Coelho
authors.affiliation: Department of Reproductive Sciences and Development, IRCCS-Burlo Garofolo, University of Trieste, Trieste, Italy; crovella@burlo.trieste.it.
authors.forename: Sergio
authors.initials: S
authors.lastname: Crovella
mesh_terms: D016915:AIDS Vaccines / Q000627:therapeutic use*; D003713:Dendritic Cells / Q000276:immunology*; D059472:Exome / Q000235:genetics*; D015658:HIV Infections / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D006801:Humans; D056724:Immunity, Humoral / Q000235:genetics / Q000276:immunology; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D020641:Polymorphism, Single Nucleotide / Q000235:genetics / Q000276:immunology; D014157:Transcription Factors / Q000235:genetics*; D016896:Treatment Outcome
chemical_list: D016915:AIDS Vaccines; C528690:CNOT1 protein, human; D014157:Transcription Factors
keywords: CNOT1; DC immunotherapy; HIV; TTP; exome analysis