title: HIV infection and antiretroviral therapy lead to unfolded protein response activation.
abstract: BACKGROUND
  The unfolded protein response (UPR) is one of the pathways triggered to ensure quality control of the proteins assembled in the endoplasmic reticulum (ER) when cell homeostasis is compromised. This mechanism is primarily composed of three transmembrane proteins serving as stress sensors: PKR-like ER kinase (PERK), activating transcription factor 6 (ATF6), and inositol-requiring enzyme 1 (IRE1). These three proteins' synergic action elicits translation and transcriptional downstream pathways, leading to less protein production and activating genes that encode important proteins in folding processes, including chaperones. Previous reports showed that viruses have evolved mechanisms to curtail or customize this UPR signaling for their own benefit. However, HIV infection's effect on the UPR has scarcely been investigated.
  
  
  METHODS
  This work investigated UPR modulation by HIV infection by assessing UPR-related protein expression under in vitro and in vivo conditions via Western blotting. Antiretroviral (ARV) drugs' influence on this stress response was also considered.
  
  
  RESULTS
  In in vitro and in vivo analyses, our results confirm that HIV infection activates stress-response components and that ARV therapy contributes to changes in the UPR's activation profile.
  
  
  CONCLUSIONS
  This is the first report showing UPR-related protein expression in HIV target cells derived directly from HIV-infected patients receiving different ARV therapies. Thus, two mechanisms may occur simultaneously: interference by HIV itself and the ARV drugs' pharmacological effects as UPR activators. New evidence of how HIV modulates the UPR to enhance its own replication and secure infection success is also presented.
authors.affiliation: Laboratório de Imunologia Aplicada, Departamento de Microbiologia, Imunologia e Parasitologia, Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil. nanaborsa@gmail.com.
authors.forename: Mariana
authors.initials: M
authors.lastname: Borsa
authors.affiliation: Laboratório de Pesquisas sobre o Timo, Instituto Oswaldo Cruz, Rio de Janeiro, RJ, Brazil. ferreirapedrolc@gmail.com.
authors.forename: Pedro L C
authors.initials: PL
authors.lastname: Ferreira
authors.affiliation: Centro de Hematologia e Hemoterapia de Santa Catarina, Florianópolis, SC, Brazil. deapetry@yahoo.com.br.
authors.forename: Andrea
authors.initials: A
authors.lastname: Petry
authors.affiliation: Hospital Regional Homero de Miranda Gomes, São José, SC, Brazil. luizescada@hotmail.com.
authors.forename: Luiz G E
authors.initials: LG
authors.lastname: Ferreira
authors.affiliation: Departamento de Imunologia, Instituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo, SP, Brazil. mmcamar@usp.br.
authors.forename: Maristela M
authors.initials: MM
authors.lastname: Camargo
authors.affiliation: Laboratório de Pesquisas sobre o Timo, Instituto Oswaldo Cruz, Rio de Janeiro, RJ, Brazil. dumith@ioc.fiocruz.br.
authors.forename: Dumith Chequer
authors.initials: DC
authors.lastname: Bou-Habib
authors.affiliation: Laboratório de Imunologia Aplicada, Departamento de Microbiologia, Imunologia e Parasitologia, Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil. aguinaldo.pinto@ufsc.br.
authors.forename: Aguinaldo R
authors.initials: AR
authors.lastname: Pinto
mesh_terms: D051702:Activating Transcription Factor 6 / Q000032:analysis*; D000328:Adult; D044966:Anti-Retroviral Agents / Q000627:therapeutic use*; D023241:Antiretroviral Therapy, Highly Active / Q000379:methods*; D015153:Blotting, Western; D004722:Endoribonucleases / Q000032:analysis*; D005260:Female; D015658:HIV Infections / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D008297:Male; D008875:Middle Aged; D017346:Protein Serine-Threonine Kinases / Q000032:analysis*; D056811:Unfolded Protein Response; D055815:Young Adult; D019892:eIF-2 Kinase / Q000032:analysis*
chemical_list: C497111:ATF6 protein, human; D051702:Activating Transcription Factor 6; D044966:Anti-Retroviral Agents; C460640:EIF2AK3 protein, human; C528229:ERN1 protein, human; D017346:Protein Serine-Threonine Kinases; D019892:eIF-2 Kinase; D004722:Endoribonucleases