Bryostatin Modulates Latent HIV-1 Infection via PKC and AMPK Signaling but Inhibits Acute Infection in a Receptor Independent Manner

Abstract

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) -α and -δ, 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.

Predicting the outcomes of treatment to eradicate the latent reservoir for HIV-1

“…Collectively called latencyreversing agents (LRAs), these drugs include histone deacetylase inhibitors (12)(13)(14), PKC activators (15)(16)(17)(18), and the bromodomain inhibitor JQ1 (19)(20)(21). Although LRAs are the subject of intense research, it is unclear how much the LR must be reduced to enable patients to safely discontinue ART.…”

Post-transcriptional gene silencing, transcriptional gene silencing and human immunodeficiency virus

“…Provirus refers to the viral form that has been integrated into the cell's genome and is inherited through each cell division. Latent means it is transcriptionally inactive, but is able to re-activate after stimulation [16][17][18][19] and is capable of causing substantial viremia when therapy ceases [20,21] . The viral reservoir, a term used to refer to the latently infected cells as a whole, is maintained throughout the life span of an infected individual.…”

Marine natural products: Bryostatins in preclinical and clinical studies

“…Bryostatin was also investigated as a potential HIV inhibitor. Mehla et al (2010) found that bryostatin revealed receptor independent antiviral activity against R5-and X4-tropic viruses and partly via transient decrease in CD4/ CXCR4 expression. Bryostatin, applied at low nanomolar concentrations, also strongly reactivated latent viral infection in monocytic and lymphocytic cells via activation of PKC-a and -d (PKC inhibitors such as rottlerin and GF109203X abrogated the bryostatin effect).…”

“…Nevertheless, interestingly, based on striking positive results produced by bryostatin in central nervous system models in rodents, a human Alzheimer's disease phase II clinical trial has been initiated with bryostatin-1 (Trindade-Silva et al, 2010). Most recently, bryostatin has been proposed as a possible therapy for human immunodeficiency virus (HIV) (Mehla et al, 2010). Although current antiviral therapy is effective against HIV, the disease cannot be cured because of latent viruses persisting in resting cells.…”