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

Retrovirology

Howard E Gendelman²  JoEllyn McMillan¹  Pawel Ciborowski¹  Jayme Wiederin¹  Dongwei Guo²  Mariluz Araínga¹ 

[1] Departments of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, 985880 Nebraska Medical Center, Omaha 68198-5880, NE, USA;Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha 68198-5880, NE, USA

关键词: Rab proteins;    Endocytic pathways;    NanoART;    Proteomics;    HIV-1;    Macrophages;   

Others  :  1131918
DOI  :  10.1186/s12977-014-0133-5

 received in 2014-10-22, accepted in 2014-12-19,  发布年份 2015

【 摘 要 】

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.

【 授权许可】

   
2015 Araínga et al.; licensee BioMed Central.

【 图 表 】

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