title: Opposing regulation of endolysosomal pathways by long-acting nanoformulated antiretroviral therapy and HIV-1 in human macrophages.
abstract: BACKGROUND
  Long-acting nanoformulated antiretroviral therapy (nanoART) is designed to improve patient regimen adherence, reduce systemic drug toxicities, and facilitate clearance of human immunodeficiency virus type one (HIV-1) infection. While nanoART establishes drug depots within recycling and late monocyte-macrophage endosomes, whether or not this provides a strategic advantage towards viral elimination has not been elucidated.
  
  
  RESULTS
  We applied quantitative SWATH-MS proteomics and cell profiling to nanoparticle atazanavir (nanoATV)-treated and HIV-1 infected human monocyte-derived macrophages (MDM). Native ATV and uninfected cells served as controls. Both HIV-1 and nanoATV engaged endolysosomal trafficking for assembly and depot formation, respectively. Notably, the pathways were deregulated in opposing manners by the virus and the nanoATV, likely by viral clearance. Paired-sample z-scores, of the proteomic data sets, showed up- and down- regulation of Rab-linked endolysosomal proteins. NanoART and native ATV treated uninfected cells showed limited effects. The data was confirmed by Western blot. DAVID and KEGG bioinformatics analyses of proteomic data showed relationships between secretory, mobility and phagocytic cell functions and virus and particle trafficking.
  
  
  CONCLUSIONS
  We posit that modulation of endolysosomal pathways by antiretroviral nanoparticles provides a strategic path to combat HIV infection.
authors.forename: Mariluz
authors.initials: M
authors.lastname: Araínga
authors.forename: Dongwei
authors.initials: D
authors.lastname: Guo
authors.forename: Jayme
authors.initials: J
authors.lastname: Wiederin
authors.forename: Pawel
authors.initials: P
authors.lastname: Ciborowski
authors.forename: JoEllyn
authors.initials: J
authors.lastname: McMillan
authors.affiliation: Departments of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, 985880 Nebraska Medical Center, Omaha 68198-5880, NE, USA. hegendel@unmc.edu.
authors.forename: Howard E
authors.initials: HE
authors.lastname: Gendelman
mesh_terms: D019380:Anti-HIV Agents / Q000008:administration & dosage* / Q000494:pharmacology; D000069446:Atazanavir Sulfate; D015153:Blotting, Western; D002478:Cells, Cultured; D019295:Computational Biology; D003692:Delayed-Action Preparations; D005786:Gene Expression Regulation; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D051907:Lysosomal Membrane Proteins / Q000235:genetics; D008247:Lysosomes / Q000187:drug effects* / Q000502:physiology*; D008264:Macrophages / Q000821:virology*; D013058:Mass Spectrometry; D053758:Nanoparticles; D009842:Oligopeptides / Q000008:administration & dosage* / Q000494:pharmacology; D060066:Protein Interaction Maps; D040901:Proteomics; D011725:Pyridines / Q000008:administration & dosage* / Q000494:pharmacology; D020691:rab GTP-Binding Proteins / Q000235:genetics; D020696:rab5 GTP-Binding Proteins / Q000235:genetics; D000090802:rab7 GTP-Binding Proteins; D000099193:rab11 GTP-Binding Proteins; D052118:Lysosomal-Associated Membrane Protein 1
chemical_list: D019380:Anti-HIV Agents; D000069446:Atazanavir Sulfate; D003692:Delayed-Action Preparations; D051907:Lysosomal Membrane Proteins; D009842:Oligopeptides; D011725:Pyridines; D020691:rab GTP-Binding Proteins; D020696:rab5 GTP-Binding Proteins; D000090802:rab7 GTP-Binding Proteins; D000099193:rab11 GTP-Binding Proteins; C489116:LAMP1 protein, human; D052118:Lysosomal-Associated Membrane Protein 1; C427755:RAB5C protein, human