DigitalCommons@UNMC

Title

Opposing regulation of endolysosomal pathways by long-acting nanoformulated antiretroviral therapy and HIV-1 in human macrophages.

Authors

Mariluz Araínga, University of Nebraska Medical CenterFollow
Dongwei Guo, University of Nebraska Medical CenterFollow
Jayme Wiederin, University of Nebraska Medical Center - OmahaFollow
Pawel Ciborowski, University of Nebraska Medical CenterFollow
JoEllyn McMillan, University of Nebraska Medical Center, OmahaFollow
Howard Gendelman, University of Nebraska Medical Center & Nebraska Center for VirologyFollow

Document Type

Article

Journal Title

Retrovirology

Publication Date

1-22-2015

Volume

12

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.

MeSH Headings

Anti-HIV Agents, Atazanavir Sulfate, Blotting, Western, Cells, Cultured, Computational Biology, Delayed-Action Preparations, Gene Expression Regulation, HIV-1, Humans, Lysosome-Associated Membrane Glycoproteins, Lysosomes, Macrophages, Mass Spectrometry, Nanoparticles, Oligopeptides, Protein Interaction Maps, Proteomics, Pyridines, rab GTP-Binding Proteins, rab5 GTP-Binding Proteins

DOI Link

10.1186/s12977-014-0133-5

ISSN

1742-4690

Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 International License.

Recommended Citation

Araínga, Mariluz; Guo, Dongwei; Wiederin, Jayme; Ciborowski, Pawel; McMillan, JoEllyn; and Gendelman, Howard, "Opposing regulation of endolysosomal pathways by long-acting nanoformulated antiretroviral therapy and HIV-1 in human macrophages." (2015). Journal Articles: Pharmacology & Experimental Neuroscience. 26.
https://digitalcommons.unmc.edu/com_pen_articles/26