title: Autophagy facilitates macrophage depots of sustained-release nanoformulated antiretroviral drugs.
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.
authors.forename: Divya Prakash
authors.initials: DP
authors.lastname: Gnanadhas
authors.forename: Prasanta K
authors.initials: PK
authors.lastname: Dash
authors.forename: Brady
authors.initials: B
authors.lastname: Sillman
authors.forename: Aditya N
authors.initials: AN
authors.lastname: Bade
authors.forename: Zhiyi
authors.initials: Z
authors.lastname: Lin
authors.forename: Diana L
authors.initials: DL
authors.lastname: Palandri
authors.forename: Nagsen
authors.initials: N
authors.lastname: Gautam
authors.forename: Yazen
authors.initials: Y
authors.lastname: Alnouti
authors.forename: Harris A
authors.initials: HA
authors.lastname: Gelbard
authors.forename: JoEllyn
authors.initials: J
authors.lastname: McMillan
authors.forename: R Lee
authors.initials: RL
authors.lastname: Mosley
authors.forename: Benson
authors.initials: B
authors.lastname: Edagwa
authors.forename: Howard E
authors.initials: HE
authors.lastname: Gendelman
authors.forename: Santhi
authors.initials: S
authors.lastname: Gorantla
mesh_terms: D000163:Acquired Immunodeficiency Syndrome / Q000188:drug therapy* / Q000378:metabolism; D000818:Animals; D044966:Anti-Retroviral Agents / Q000494:pharmacology*; D000069446:Atazanavir Sulfate / Q000494:pharmacology; D001343:Autophagy / Q000187:drug effects*; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000378:metabolism; D005260:Female; D015497:HIV-1 / Q000378:metabolism*; D006575:Heterocyclic Compounds, 3-Ring / Q000494:pharmacology; D006801:Humans; D008264:Macrophages / Q000378:metabolism*; D008297:Male; D051379:Mice; D053758:Nanoparticles; D010078:Oxazines; D010879:Piperazines; D011725:Pyridines / Q000494:pharmacology; D011728:Pyridones; D011758:Pyrroles / Q000494:pharmacology; D000099226:Dolutegravir
chemical_list: D044966:Anti-Retroviral Agents; D000069446:Atazanavir Sulfate; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D006575:Heterocyclic Compounds, 3-Ring; D010078:Oxazines; D010879:Piperazines; D011725:Pyridines; D011728:Pyridones; D011758:Pyrroles; D000099226:Dolutegravir; C064972:TFEB protein, human; C583037:URMC-099