Procyanidin trimer C1 reactivates latent HIV as a triple combination therapy with kansui and JQ1

Abstract

Although anti-retroviral therapies have greatly extended the lives of HIV infected individuals, current treatments are unable to completely eliminate virally infected cells. A number of latency reversing agents have been proposed for use in a “shock and kill” strategy to reactivate latent HIV, thus making it vulnerable to killing mechanisms. Procyanidin trimer C1 (PC1) is a flavonoid found in multiple plant sources including grape, apple, and cacao, which has antioxidant and anti-inflammatory properties. We determined that PC1 reactivates latent HIV in cell line and primary cell models of HIV, through activation of the MAPK pathway. Notably, PC1 reactivates latent HIV without increasing surface markers of T cell activation. Combining several therapeutics, which activate HIV transcription through different mechanisms, is the most efficient approach to clinically reactivate latent reservoirs. We utilized PC1 (MAPK agonist), kansui (PKC agonist), and JQ1 (BET bromodomain inhibitor) in a triple combination approach to reactivate latent HIV in cell line and primary cell models of HIV latency. When used in combination, low concentrations which fail to reactivate HIV as single treatments, are effective. Thus, several mechanisms, using distinct activation pathways, act together to reactivate latent HIV.

Broad‐spectrum antiviral activity of Spatholobus suberectus Dunn against SARS‐CoV‐2, SARS‐CoV‐1, H5N1, and other enveloped viruses

“…Zhang et al ( 2018 ) have also reported that PACs A2 could inhibit the replication of porcine reproductive and respiratory syndrome virus in vitro . Procyanidin trimer C1 is reported to have synergistic anti‐HIV effects when combined with kansui and JQ1 by activating latent HIV (Cary & Peterlin, 2018b ). Overall, designing antiviral derivatives from the inspiration of proanthocyanidin compounds are highly promising.…”

Experimental Systems for Measuring HIV Latency and Reactivation

“…Most LRAs aim to increase initial HIV transcription [ 19 , 94 ]. To date, there are several categories of LRAs being tested preclinically and clinically: (1) P-TEFb releaser/activators [ 42 ], (2) protein kinase c (PKC) agonist/canonical NFκB inducers [ 95 ], (3) non-canonical NFκB inducers, (4) Toll-like receptor agonists [ 19 ], (5) epigenetic modulators [ 96 ], (6) mTOR inhibitors [ 20 ], (7) protease inhibitors (PIs), (8) MAPK agonists [ 97 ], etc. Examples of LRAs are presented in Table 1 .…”

“…A main mechanism of latency in 2D10 is attenuated Tat activity, which is less capable of releasing RNAPII paused at the viral 5’ LTR by cellular NELF, although epigenetic silencing also occurs in these cells [ 30 , 183 ]. Although less than 1% of 2D10 cells express detectable GFP, as a surrogate marker for HIV gene expression in unstimulated culture condition, these cells respond to many LRAs robustly [ 97 , 98 , 183 ].…”

HIV-1 Latency and Viral Reservoirs: Existing Reversal Approaches and Potential Technologies, Targets, and Pathways Involved in HIV Latency Studies

“…Not only cell types but also different mechanisms come to play in affecting the degree of latency reversion. In both Jurkat cell line (2D10) and in the primary CD4 T cellular model of HIV latency, a triple combination of three agents, procyanidin trimer C1 (a MAPK agonist), kansui (a PKC agonist), and JQ1 (a BET bromodomain inhibitor and pTEFb activator) successfully reactivated latency, which failed when they were used in similar concentrations individually [ 68 ]. Notably, procyanidin trimer C1 and kansui are plant derivatives [ 68 ].…”

“…In both Jurkat cell line (2D10) and in the primary CD4 T cellular model of HIV latency, a triple combination of three agents, procyanidin trimer C1 (a MAPK agonist), kansui (a PKC agonist), and JQ1 (a BET bromodomain inhibitor and pTEFb activator) successfully reactivated latency, which failed when they were used in similar concentrations individually [ 68 ]. Notably, procyanidin trimer C1 and kansui are plant derivatives [ 68 ]. Other approaches to reverse HIV latency include using CpG oligodeoxynucleotides, which activate toll-like receptor 9 (TLR-9), or long noncoding RNA (lncRNA) uc002yug.2, which affects Runt-related transcription factors RUNX1b/c and viral Tat gene expressions [ 69 , 70 ].…”