Procyanidin Trimer C1 Derived from Theobroma cacao Reactivates Latent Human Immunodeficiency Virus Type 1 Provirus (original) (raw)
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39 Novel activators and suppressors of latent HIV-1 from natural products
Journal of Virus Eradication, 2016
Lats by flow cytometry or stimulation using PMA/ionomycin or co-culture with peptide-pulsed target cells for 6 h. NFAT signaling was measured by luminescence. Cell viability (Annexin-V/7-AAD), Gag-p24 expression, and intracellular cytokines (IL-2 and IFNγ) were measured by flow cytometry. TNFα was used as positive control for reactivation and negative control for activation. Results: Significant toxicity was observed with HDACi; a 50% cytotoxicity dose (CC50) was calculated. In Jurkats treated with HDACi at doses below or near the CC50 prior to stimulation with PMA/ ionomycin, NFAT signaling was enhanced 15-to 25-fold and cytokine producing cells increased 14-31% (for IL-2) and~5% (for IFNγ). Similar results were seen for J-Lats stimulated with PMA/ionomycin and Jurkats stimulated via TCR. In contrast, doses of HDACi above the CC50 were required to reactivate HIV in J-Lats. Conclusions: Results suggest that distinct mechanisms contribute to the ability of HDACi to stimulate gene expression versus activity to reverse latency. HDACi doses below the CC50 enhanced measures of T cell activation, while doses above the CC50 were necessary to reactivate HIV. The concentration of HDACi used for studies must balance immune stimulation and toxicity with viral reactivation efficiency to enhance shock and kill strategies.
Naturally Occurring Compounds Elicit HIV-1 Replication in Chronically Infected Promonocytic Cells
BioMed Research International, 2014
Since antiretroviral therapy suppresses but does not eradicate HIV-1 infection, methods to purge viral reservoirs are required. Many strategies involve the reactivation of chronically HIV infected cells to induce the expression of integrated viral genome. In this study, five bioactive compounds, the plant derivatives 1-cinnamoyl-3,11-dihydroxymeliacarpin (CDM), nordihydroguaiaretic acid (NDGA), and curcumin (Cur) and the synthetic stigmasterol analogs (22S,23S)-22,23-dihydroxystigmast-4-en-3-one (compound 1) and (22S,23S)-3 -bromo-5 ,22,23-trihydroxystigmastan-6-one (compound 2), were evaluated for their ability to elicit HIV replication in promonocytic (U1) and lymphocytic (H9+) HIV-1 chronically infected cells. The results revealed that natural compounds CDM, NDGA, and Cur were able to increase HIV-1 p24 antigen, determined by ELISA, only in latently infected promonocytic cells. CDM would reactivate HIV from latency by modulating the release of IL-6 and TNF-, since the amount of both cytokines measured through ELISA significantly increased in U1 treated cells. Besides, NDGA increased ROS production, which might be related to the increase on p24 level observed in NDGA treated U1. These findings suggest that CDM, NDGA, and Cur might be candidates for further studies on latency-reversing therapeutics to eliminate latently HIV-1 reservoirs.
Amongst the many strategies aiming at inhibiting HIV-1 infection, blocking viral entry has been recently recognized as a very promising approach. Using diverse in vitro models and a broad range of HIV-1 primary patient isolates, we report here that IND02, a type A procya-nidin polyphenol extracted from cinnamon, that features trimeric and pentameric forms displays an anti-HIV-1 activity against CXCR4 and CCR5 viruses with 1–7 μM ED 50 for the trimer. Competition experiments, using a surface plasmon resonance-based binding assay, revealed that IND02 inhibited envelope binding to CD4 and heparan sulphate (HS) as well as to an antibody (mAb 17b) directed against the gp120 co-receptor binding site with an IC 50 in the low μM range. IND02 has thus the remarkable property of simultaneously blocking gp120 binding to its major host cell surface counterparts. Additionally, the IND02-trimer impeded up-regulation of the inhibitory receptors Tim-3 and PD-1 on CD4 + and CD8 + cells, thereby demonstrating its beneficial effect by limiting T cell exhaustion. Among naturally derived products significantly inhibiting HIV-1, the IND02-trimer is the first component demonstrating an entry inhibition property through binding to the viral envelope glycopro-tein. These data suggest that cinnamon, a widely consumed spice, could represent a novel and promising candidate for a cost-effective, natural entry inhibitor for HIV-1 which can also down-modulate T cell exhaustion markers Tim-3 and PD-1.
Phytochemicals May Arrest HIV-1 Progression
Journal of Clinical Research in HIV AIDS and Prevention, 2014
The application of current antiretroviral chemotherapeutics such as antiHIV-1 RT drugs (nucleoside, nucleotide and non-nucleotide reverse transcriptase inhibitors) as well as antiproteases including those used in combinatorial therapy such as highly active antiretroviral; (HAART) has caused significant reduction in the rate of mortality of HIV-1 infected individuals. It has allowed sufficient rise in CD4+ve lymphocyte counts into the HIV-1 infected individuals and imparted relatively longer and healthier lives. Recent reports, however, have indicated that application of plant based principles may prove to be highly useful, affordable and efficient in order to arrest the HIV-1 progression. It may be accelerative in transition from development to usage. Also, the toxicity issues may be easily managed while treating AIDS patients with herbal preparations as these plantingredients are suitably metabolized and excreted out of body without much accumulation in human organs. Certain plant extracts such as green tea containing ((-)-Epigallocatechin-3-gallate (EGCG)), Brazil nut and Caocao containing immunopotentiators, grapes and red wine containing plenty of antioxidants which mimic oxidative stress induced by intake of antiHIV-1 regimen, Punica granatum (pomegranate) and several others have been recently shown to possess properties of intervention in HIV-1 proliferation [1].
In-vitro Assays for Determining Anti-HIV Potential of Phytochemicals
Phytochemistry: An in-silico and in-vitro Update, 2019
The HIV epidemic continues to affect people worldwide. According to the UNAIDS fact sheet of 2018, approximately 36.9 million people were living with HIV in 2017 and since the start of the epidemic, approximately 35.4 million people had died from AIDS related illnesses (UNAIDS 2018). Antiviral treatment currently involves the use of combination antiretroviral therapy abbreviated as cART (Cihlar and Fordyce 2016). cART usually consists of two nucleotide or nucleoside reverse transcriptase inhibitors and a third drug from another class (Cihlar and Fordyce 2016). Such a combination is known to significantly suppress virus replication leading to substantial improvement in the clinical management of HIV infection by delaying disease progression, prolonging survival and improving the overall quality of life (Cihlar and Fordyce 2016). A total of 25 anti-HIV drugs from 6 different mechanistic classes have reportedly been developed for use since the approval of zidovudine (AZT) in 1987 (Cihlar and Fordyce 2016). Limitations of existing treatment such as toxicity to the host, development of drug resistant viruses together with the persistence of latent pools of the virus makes lifelong treatment a necessity (Tang and Shafer 2012). AZT and other HIV-drugs originated from anti-cancer investigations of phytochemicals, the latter known for
Molecules, 2022
Since the efficiency in the transcription of the HIV genome contributes to the success of viral replication and infectivity, we investigated the downregulating effects of the spirobisindole alkaloids globospiramine (1), deoxyvobtusine (2), and vobtusine lactone (3) from the endemic Philippine medicinal plant, Voacanga globosa, during HIV gene transcription. Alkaloids 1–3 were explored for their inhibitory activity on TNF-α-induced viral replication in two latently HIV-infected cell lines, OM10.1 and J-Lat. The induction of HIV replication from OM10.1 and J-Lat cells elicited by TNF-α was blocked by globospiramine (1) within noncytotoxic concentrations. Furthermore, globospiramine (1) was found to target the NF-ĸB activation cascade in a dose-dependent manner when the transcriptional step at which inhibitory activity is exerted was examined in TNF-α-induced 293 human cells using transient reporter (luciferase) gene expression systems (HIV LTR-luc, ĸB-luc, and mutant ĸB-luc). Interrog...
Since the discovery of the human immunodeficiency virus as the causative agent of AIDS New chemical entities with such activity may be identified through a variety of approaches, one of them being the screening of natural products. Plant substances are especially explored due to their amazing structural diversity and their broad range of biological activities. Several plant extracts have been shown to possess activity against HIV by inhibiting various viral enzymes (Vermani and Garg, 2002). Various resource-poor settings, government-sponsored ART programmes discourage the use of traditional medicines, fearing that the efficacy of antiretroviral drugs may be inhibited by such natural products, or that their pharmacological interactions could lead to toxicity (Chinsembu, 2009). Medicinal plants like Osimum sanctum (Anuya et al., 2010), Phyllanthus myrtifolium (Chang et al., 1995), Linocera japonica (Joshi, 2002), Rhus chinensis (Rui-Rui wang et al., 2008) and Jatropha curcas (Kazhila et al., 2010) as potential sources of new active agents not only combine the advantage of being relatively non-toxic and hence more tolerable than rationally designed drugs, but also represent an affordable and valuable source of pharmacologically active substances that can be made sufficiently available through cultivation. With the rapid explosion of new molecular targets available for drug discovery and advances in high put screening technology, there has been a dramatic increase in interest from the pharmaceutical and biotechnology industries in the huge molecular diversity present in plant sources. In this study the medicinal plant extracts used in tribal areas of Warangal districts is exhibits significant potency against various bacterial and fungal pathogens, as well as potent antioxidant activity. It was therefore decided to analyse the anti-HIV activity of these potential medicinal plant and also evaluate its cytotoxicity in PBMC cell cultures.