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Autophagy facilitates macrophage depots of sustained-release nanoformulated antiretroviral drugs.
- Source :
-
The Journal of clinical investigation [J Clin Invest] 2017 Mar 01; Vol. 127 (3), pp. 857-873. Date of Electronic Publication: 2017 Jan 30. - Publication Year :
- 2017
-
Abstract
- Long-acting anti-HIV products can substantively change the standard of care for patients with HIV/AIDS. To this end, hydrophobic antiretroviral drugs (ARVs) were recently developed for parenteral administration at monthly or longer intervals. While shorter-acting hydrophilic drugs can be made into nanocarrier-encased prodrugs, the nanocarrier encasement must be boosted to establish long-acting ARV depots. The mixed-lineage kinase 3 (MLK-3) inhibitor URMC-099 provides this function by affecting autophagy. Here, we have shown that URMC-099 facilitates ARV sequestration and its antiretroviral responses by promoting the nuclear translocation of the transcription factor EB (TFEB). In monocyte-derived macrophages, URMC-099 induction of autophagy led to retention of nanoparticles containing the antiretroviral protease inhibitor atazanavir. These nanoparticles were localized within macrophage autophagosomes, leading to a 4-fold enhancement of mitochondrial and cell vitality. In rodents, URMC-099 activation of autophagy led to 50-fold increases in the plasma drug concentration of the viral integrase inhibitor dolutegravir. These data paralleled URMC-099-mediated induction of autophagy and the previously reported antiretroviral responses in HIV-1-infected humanized mice. We conclude that pharmacologic induction of autophagy provides a means to extend the action of a long-acting, slow, effective release of antiretroviral therapy.
- Subjects :
- Acquired Immunodeficiency Syndrome metabolism
Animals
Atazanavir Sulfate pharmacology
Basic Helix-Loop-Helix Leucine Zipper Transcription Factors metabolism
Female
Heterocyclic Compounds, 3-Ring pharmacology
Humans
Male
Mice
Oxazines
Piperazines
Pyridines pharmacology
Pyridones
Pyrroles pharmacology
Acquired Immunodeficiency Syndrome drug therapy
Anti-Retroviral Agents pharmacology
Autophagy drug effects
HIV-1 metabolism
Macrophages metabolism
Nanoparticles
Subjects
Details
- Language :
- English
- ISSN :
- 1558-8238
- Volume :
- 127
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- The Journal of clinical investigation
- Publication Type :
- Academic Journal
- Accession number :
- 28134625
- Full Text :
- https://doi.org/10.1172/JCI90025