Autophagy facilitates macrophage depots of sustained-release nanoformulated antiretroviral drugs

• Published in: The Journal of clinical investigation Vol. 127; no. 3; pp. 857 - 873
• Main Authors: Gnanadhas, Divya Prakash, Dash, Prasanta K, Sillman, Brady, Bade, Aditya N, Lin, Zhiyi, Palandri, Diana L, Gautam, Nagsen, Alnouti, Yazen, Gelbard, Harris A, McMillan, JoEllyn, Mosley, R Lee, Edagwa, Benson, Gendelman, Howard E, Gorantla, Santhi
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 01.03.2017
• Subjects: Acquired Immunodeficiency Syndrome - drug therapy; Acquired Immunodeficiency Syndrome - metabolism; Animals; Anti-Retroviral Agents - pharmacology; Antiretroviral agents; Atazanavir Sulfate - pharmacology; Autophagy; Autophagy - drug effects; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors - metabolism; Biomedical research; Colleges & universities; Drug dosages; Female; Heterocyclic Compounds, 3-Ring - pharmacology; HIV; HIV-1 - metabolism; Human immunodeficiency virus; Humans; Immunoglobulins; Infections; Laboratory animals; Lentivirus; Localization; Macrophages; Macrophages - metabolism; Male; Mice; Nanoparticles; Oxazines; Phosphorylation; Piperazines; Product development; Protease inhibitors; Pyridines - pharmacology; Pyridones; Pyrroles - pharmacology; Retroviridae; Substance abuse treatment; Transcription factors; Viral infections
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/JCI90025

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.