Cardiac glycoside/aglycones inhibit HIV-1 gene expression by a mechanism requiring MEK1/2-ERK1/2 signaling

Abstract

The capacity of HIV-1 to develop resistance to current drugs calls for innovative strategies to control this infection. We aimed at developing novel inhibitors of HIV-1 replication by targeting viral RNA processing—a stage dependent on conserved host processes. We previously reported that digoxin is a potent inhibitor of this stage. Herein, we identify 12 other cardiac glycoside/aglycones or cardiotonic steroids (CSs) that impede HIV growth in HIV-infected T cells from clinical patients at IC50s (1.1–1.3 nM) that are 2–26 times below concentrations used in patients with heart conditions. We subsequently demonstrate that CSs inhibit HIV-1 gene expression in part through modulation of MEK1/2-ERK1/2 signaling via interaction with the Na+/K+-ATPase, independent of alterations in intracellular Ca2+. Supporting this hypothesis, depletion of the Na+/K+-ATPase or addition of a MEK1/2-ERK1/2 activator also impairs HIV-1 gene expression. Similar to digoxin, all CSs tested induce oversplicing of HIV-1 RNAs, reducing unspliced (Gag) and singly spliced RNAs (Env/p14-Tat) encoding essential HIV-1 structural/regulatory proteins. Furthermore, all CSs cause nuclear retention of genomic/unspliced RNAs, supporting viral RNA processing as the underlying mechanism for their disruption of HIV-1 replication. These findings call for further in vivo validation and supports the targeting of cellular processes to control HIV-1 infection.

Strophanthidin Attenuates MAPK, PI3K/AKT/mTOR, and Wnt/β-Catenin Signaling Pathways in Human Cancers

“…The activation of p38 MAPK depends on the upstream events such as caspase activations (50), which are also identified in the present study. Taken together, our findings are consistent with the literature that states that CGs inhibit the expression of MEK1/2 and ERK1/2 signaling to inhibit cancer cell proliferation and also inhibit the HIV-1 gene in HIV infections (51,52).…”

An activator of G protein-coupled receptor and MEK1/2-ERK1/2 signaling inhibits HIV-1 replication by altering viral RNA processing

“…Our work determined that cardiotonic steroids (CSs) alter HIV-1 RNA processing to suppress HIV-1 Gag, Env, and Rev expression, an effect correlated with hyperphosphorylation of SRSF3 [27]. Inhibition of HIV-1 gene expression by CSs requires, in part, activation of mitogen-activated protein (MAP) kinase (MAPK)/extracellular signal-regulated kinase (ERK) kinase (MEK) 1/2-ERK1/2 by a mechanism that is independent of the toxic/arrhythmogenic properties of this family of drugs [28]. However, the narrow therapeutic index of CSs makes this family of drugs unattractive candidates to repurpose as ARTs [27][28][29].…”

“…Inhibition of HIV-1 gene expression by CSs requires, in part, activation of mitogen-activated protein (MAP) kinase (MAPK)/extracellular signal-regulated kinase (ERK) kinase (MEK) 1/2-ERK1/2 by a mechanism that is independent of the toxic/arrhythmogenic properties of this family of drugs [28]. However, the narrow therapeutic index of CSs makes this family of drugs unattractive candidates to repurpose as ARTs [27][28][29]. Thus, while MEK1/2-ERK1/2 signaling may play a supportive role during early stages proteomecentral.proteomexchange.org) via the PRIDE partner repository with dataset identifiers: PXD011079 and DOI 10.6019/PXD011079.…”

Elucidation of the mechanism of anti-herpes action of two novel semisynthetic cardenolide derivatives

“…The mechanism by which cardenolides affect several steps of HSV replication could be related to the inhibition of Na + / K + -ATPase in host cells. Many studies have demonstrated the modulation of Na + /K + -ATPase functions in host cells by DNA viruses (adenoviruses [18], cytomegalovirus [23,[70][71][72], and HSV [27,28]), and RNA viruses (chikungunya virus [19,73], coronaviruses [20,74,75], respiratory syncytial virus [76,77], Ebola virus [78,79], influenza virus [33,80,81], and HIV [30,31,82]). By activating signaling cascades or by altering the concentration of intracellular ions, the binding of cardenolides to Na + /K + -ATPase seems to create an unfavorable environment for viral replication.…”

“…Among them, their cytotoxic and antitumor effects recently reviewed by Cerella et al [10], De et al [11], Diederich et al [12], Schneider et al [13] and El-Seedi et al [14], as well as their anti-inflammatory [15], antiprotozoal [16], anti-oxidant and anti-aging [17] activities can be cited. Another suggested possibility is their potential antiviral action, as reported by several authors against adenovirus [18], chikungunya virus [19], coronavirus [20,21], cytomegalovirus [22][23][24], dengue virus [25], herpes virus [26][27][28], HIV [29][30][31], human papillomarivus (HPV) [32], influenza virus [33][34][35], and respiratory syncytial virus [36] replication. The effects of six well-known cardiac glycosides (digoxin, digitoxin, ouabain, convallatoxin, G-strophanthin and lanatoside C) on viral biology and the mechanisms by which they impair the replication of different RNA and DNA viruses were recently compiled [37].…”