Autophagy facilitates macrophage depots of sustained-release nanoformulated antiretroviral drugs

Divya Prakash Gnanadhas, Prasanta K. Dash, Brady Sillman, Aditya N. Bade, Zhiyi Lin, Diana L. Palandri, Nagsen Gautam, Yazen Alnouti, Harris A. Gelbard, JoEllyn M McMillan, R Lee Mosley, Benson J Edagwa, Howard Eliot Gendelman, Santhi Gorantla

Research output: Contribution to journalArticle

23 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)857-873
Number of pages17
JournalJournal of Clinical Investigation
Volume127
Issue number3
DOIs
StatePublished - Mar 1 2017

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Autophagy
Macrophages
Pharmaceutical Preparations
Nanoparticles
Integrase Inhibitors
HIV
Prodrugs
Standard of Care
Protease Inhibitors
HIV-1
Rodentia
Acquired Immunodeficiency Syndrome
Transcription Factors
URMC-099

ASJC Scopus subject areas

  • Medicine(all)

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Autophagy facilitates macrophage depots of sustained-release nanoformulated antiretroviral drugs. / 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 M; Mosley, R Lee; Edagwa, Benson J; Gendelman, Howard Eliot; Gorantla, Santhi.

In: Journal of Clinical Investigation, Vol. 127, No. 3, 01.03.2017, p. 857-873.

Research output: Contribution to journalArticle

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 M ; Mosley, R Lee ; Edagwa, Benson J ; Gendelman, Howard Eliot ; Gorantla, Santhi. / Autophagy facilitates macrophage depots of sustained-release nanoformulated antiretroviral drugs. In: Journal of Clinical Investigation. 2017 ; Vol. 127, No. 3. pp. 857-873.
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