Procyanidin trimer C1 derived from Theobroma cacao reactivates latent human immunodeficiency virus type 1 provirus

Abstract

Despite remarkable advances in combination antiretroviral therapy (cART), human immunodeficiency virus type 1 (HIV-1) infection remains incurable due to the incomplete elimination of the replication-competent virus, which persists in latent reservoirs. Strategies for targeting HIV reservoirs for eradication that involves reactivation of latent proviruses while protecting uninfected cells by cART are urgently needed for cure of HIV infection. We screened medicinal plant extracts for compounds that could reactivate the latent HIV-1 provirus and identified a procyanidin trimer C1 derived from Theobroma cacao as a potent activator of the provirus in human T cells latently infected with HIV-1. This reactivation largely depends on the NF-κB and MAPK signaling pathways because either overexpression of a super-repressor form of IκBα or pretreatment with a MEK inhibitor U0126 diminished provirus reactivation by C1. A pan-PKC inhibitor significantly blocked the phorbol ester-induced but not the C1-induced HIV-1 reactivation. Although C1-induced viral gene expression persisted for as long as 48 h post-stimulation, NF-κB-dependent transcription peaked at 12 h post-stimulation and then quickly declined, suggesting Tat-mediated self-sustainment of HIV-1 expression. These results suggest that procyanidin C1 trimer is a potential compound for reactivation of latent HIV-1 reservoirs.

Reactivation of HIV-1 from Latency by an Ingenol Derivative from Euphorbia Kansui

“…The discovery of artemisinin, an anti-malarial compound extracted from the traditional Chinese medicinal herb Artemisia annua was awarded the 2015 Nobel Prize in Physiology or Medicine 50 . Two procyanidin compounds isolated from the traditional medicinal plants Theobroma cacao 51 and Polygonum cuspidatum 52 have also been reported recently to reactivate latent HIV-1 in cell line models. Given this context, we attempted to examine active compounds from traditional Chinese medicinal herbs that may display HIV-1 latency-reversing activity.…”

Euphorbia Kansui Reactivates Latent HIV

“…Theobroma cacao , the plant source of cocoa, has cardiovascular and metabolic health benefits as well as potential anti-inflammatory and anti-cancer properties. Procyanidin from cacao reactivates latent HIV via the MAPK pathway, and shows synergistic activation when added in combination with PMA [12]. A second procyanidin compound isolated from Polygonum cuspidatum Sieb .…”

“…HIV uses host transcription machinery for its own replication, and factors which activate CD4+ T cells, such as protein kinase C (PKC) and mitogen-activated protein kinase (MAPK) agonists, also reactivate latent HIV [9–12]. The HIV long terminal repeat (LTR), which acts as the HIV promoter, is highly dependent on positive transcription elongation factor b (P-TEFb) for its activation [13].…”

Molecular mechanisms of HIV latency

“…Because amounts of transcriptional CDKs are low in resting cells, they must be increased for HIV gene expression (58). PKC agonists, including phorbol esters, prostratin, bryostatin, and ingenol, can accomplish this task (74,(83)(84)(85)(86)(87)(88). These compounds have appreciable toxicity, and most of them cannot be administered orally.…”