Bryostatin modulates latent HIV-1 infection via PKC and AMPK signaling but inhibits acute infection in a receptor independent manner.
HIV's ability to establish long-lived latent infection is mainly due to transcriptional silencing in resting memory T lymphocytes and other non dividing cells including monocytes. Despite an undetectable viral load in patients treated with potent antiretrovirals, current therapy is unable to purge the virus from these latent reservoirs. In order to broaden the inhibitory range and effectiveness of current antiretrovirals, the potential of bryostatin was investigated as an HIV inhibitor and latent activator. Bryostatin revealed antiviral activity against R5- and X4-tropic viruses in receptor independent and partly via transient decrease in CD4/CXCR4 expression. Further, bryostatin at low nanomolar concentrations robustly reactivated latent viral infection in monocytic and lymphocytic cells via activation of Protein Kinase C (PKC) -alpha and -delta, because PKC inhibitors rottlerin and GF109203X abrogated the bryostatin effect. Bryostatin specifically modulated novel PKC (nPKC) involving stress induced AMP Kinase (AMPK) inasmuch as an inhibitor of AMPK, compound C partially ablated the viral reactivation effect. Above all, bryostatin was non-toxic in vitro and was unable to provoke T-cell activation. The dual role of bryostatin on HIV life cycle may be a beneficial adjunct to the treatment of HIV especially by purging latent virus from different cellular reservoirs such as brain and lymphoid organs.
Mehla
Rajeev
R
Department of Pathology, Microbiology and Immunology, University of South Carolina School of Medicine, Columbia, South Carolina, United States of America.
Bivalkar-Mehla
Shalmali
S
Zhang
Ruonan
R
Handy
Indhira
I
Albrecht
Helmut
H
Giri
Shailendra
S
Nagarkatti
Prakash
P
Nagarkatti
Mitzi
M
Chauhan
Ashok
A
D000263:Adenylate Kinase / Q000378:metabolism*; D054713:Bryostatins / Q000494:pharmacology*; D002478:Cells, Cultured; D015658:HIV Infections / Q000517:prevention & control*; D015497:HIV-1 / Q000502:physiology; D006801:Humans; D011493:Protein Kinase C / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D015398:Signal Transduction; D017735:Virus Latency
D054713:Bryostatins; D047428:Protein Kinase Inhibitors; C046785:bryostatin 1; D011493:Protein Kinase C; D000263:Adenylate Kinase