Advertisement

 

 

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

Induction of autophagy by PI3K/MTOR and PI3K/MTOR/BRD4 inhibitors suppresses HIV-1 replication.
Author Information (click to view)

Campbell GR, Bruckman RS, Herns SD, Joshi S, Durden D, Spector SA,


Campbell GR, Bruckman RS, Herns SD, Joshi S, Durden D, Spector SA, (click to view)

Campbell GR, Bruckman RS, Herns SD, Joshi S, Durden D, Spector SA,

Advertisement

The Journal of biological chemistry 2018 02 23() pii jbc.RA118.002353
Abstract

In this study, we investigated the effect 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 BET 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 forand, 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.

Submit a Comment

Your email address will not be published. Required fields are marked *

eighteen − 13 =

[ HIDE/SHOW ]