Induction of autophagy by PI3K/MTOR and PI3K/MTOR/BRD4 inhibitors suppresses HIV-1 replication

Grant R. Campbell, Rachel S. Bruckman, Shayna D. Herns, Shweta Joshi, Donald L. Durden, Stephen A. Spector

Research output: Contribution to journalArticle

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Abstract

In this study, we investigated the effects of the dual phosphatidylinositol 3-kinase/mechanistic target of rapamycin (PI3K/ MTOR) inhibitor dactolisib (NVP-BEZ235), the PI3K/MTOR/ bromodomain-containing protein 4 (BRD4) inhibitor SF2523, and the bromodomain and extra terminal domain inhibitor JQ1 on the productive infection of primary macrophages with human immunodeficiency type-1 (HIV). These inhibitors did not alter the initial susceptibility of macrophages to HIV infection. However, dactolisib, JQ1, and SF2523 all decreased HIV replication in macrophages in a dose-dependent manner via degradation of intracellular HIV through autophagy. Macrophages treated with dactolisib, JQ1, or SF2523 displayed an increase in LC3B lipidation combined with SQSTM1 degradation without inducing increased cell death. LC3B-II levels were further increased in the presence of pepstatin A suggesting that these inhibitors induce autophagic flux. RNA interference for ATG5 and ATG7 and pharmacological inhibitors of autophagosome-lysosome fusion and of lysosomal hydrolases all blocked the inhibition of HIV. Thus, we demonstrate that the mechanism of PI3K/MTOR and PI3K/MTOR/BRD4 inhibitor suppression of HIV requires the formation of autophagosomes, as well as their subsequent maturation into autolysosomes. These data provide further evidence in support of a role for autophagy in the control of HIV infection and open new avenues for the use of this class of drugs in HIV therapy.

Original languageEnglish (US)
Pages (from-to)5808-5820
Number of pages13
JournalJournal of Biological Chemistry
Volume293
Issue number16
DOIs
StatePublished - Jan 1 2018

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Macrophages
Autophagy
Phosphatidylinositol 3-Kinases
HIV-1
HIV
Proteins
Phosphatidylinositol 3-Kinase
Degradation
HIV Infections
Hydrolases
Cell death
Sirolimus
Fusion reactions
RNA
Fluxes
RNA Interference
Lysosomes
dactolisib
Cell Death
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Campbell, G. R., Bruckman, R. S., Herns, S. D., Joshi, S., Durden, D. L., & Spector, S. A. (2018). Induction of autophagy by PI3K/MTOR and PI3K/MTOR/BRD4 inhibitors suppresses HIV-1 replication. Journal of Biological Chemistry, 293(16), 5808-5820. https://doi.org/10.1074/jbc.RA118.002353

Induction of autophagy by PI3K/MTOR and PI3K/MTOR/BRD4 inhibitors suppresses HIV-1 replication. / Campbell, Grant R.; Bruckman, Rachel S.; Herns, Shayna D.; Joshi, Shweta; Durden, Donald L.; Spector, Stephen A.

In: Journal of Biological Chemistry, Vol. 293, No. 16, 01.01.2018, p. 5808-5820.

Research output: Contribution to journalArticle

Campbell, GR, Bruckman, RS, Herns, SD, Joshi, S, Durden, DL & Spector, SA 2018, 'Induction of autophagy by PI3K/MTOR and PI3K/MTOR/BRD4 inhibitors suppresses HIV-1 replication', Journal of Biological Chemistry, vol. 293, no. 16, pp. 5808-5820. https://doi.org/10.1074/jbc.RA118.002353
Campbell, Grant R. ; Bruckman, Rachel S. ; Herns, Shayna D. ; Joshi, Shweta ; Durden, Donald L. ; Spector, Stephen A. / Induction of autophagy by PI3K/MTOR and PI3K/MTOR/BRD4 inhibitors suppresses HIV-1 replication. In: Journal of Biological Chemistry. 2018 ; Vol. 293, No. 16. pp. 5808-5820.
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