Nf-κb-Dependent Inhibition of HIV-1 Transcription by Withaferin A

Abstract

Despite the remarkable progress made in suppressing HIV-1 infection, antiretroviral drugs are still often inaccessible in developing countries, and there is an urgent need for cheaper and alternative drugs. HIV-1 replication is triggered by the activation of the long terminal repeat (LTR) promoter, which contains two binding sites for the transcription factor nuclear factor κB (NF-κB). Withaferin A (WA), a steroidal lactone isolated from the Indian medicinal plant Withania somnifera, has been found to have significant pharmacological effects on the regulation of immune response. Recent studies have demonstrated that the anti-inflammatory properties of WA are mainly due to its inhibition of the NF-κB pathway. In the present study, we demonstrate that WA represses HIV-1 LTR transcription and viral replication through NF-κB inhibition.The human lymphocyte T cell line Jurkat E6.1 was treated with WA and infected with wild-type pseudotyped HIV-1 particles or mutant viruses containing inactive κB sites. Then, the effect of WA on HIV-1 replication was evaluated by the measurement of reporter activity. Electrophoretic mobility shift assays and Western blots analysis were also performed to study the impact of WA on NF-κB. We found that WA inhibited the transcription of wild-type pseudotyped viruses in single-round infection assays, whereas mutant viruses containing inactive κB sites showed a reduced response to WA. Moreover, we found that WA directly or indirectly inhibits NF-κB nuclear translocation, including RelA and p50 subunits. However, the degradation of inhibitory protein IκB-α was not prevented by WA. Taken together, our results suggest that WA inhibits HIV-1 transcription in human Jurkat E6.1 lymphocyte T cells through the NF-κB pathway.

Molecular mechanism of anti-SARS-CoV2 activity of Ashwagandha-derived withanolides

“…Ashwagandha ( Withania somnifera ), an Indian Ayurvedic herb, is known for its therapeutic activities and potential to boost the body immunity. Withaferin-A (Wi-A), a bioactive steroidal lactone from Ashwagandha, has been shown to be capable of inhibiting herpes simplex virus and suppress HIV-1 LTR transcription and viral replication [33] , [34] . Wi-A has also been predicted to target the neuraminidase of H1N1 influenza virus [35] .…”

COVID19-inhibitory activity of withanolides involves targeting of the host cell surface receptor ACE2: insights from computational and biochemical assays

“…Multiple reports previously have underlined potential of Ashwagandha for inducing tumor-suppressor activity and anti-inflammatory activities (Bhargava et al., 2019 ; Chaudhary et al., 2017 ; Gao et al., 2014 ; Grover, Priyandoko, et al., 2012 ; Grover, Singh, et al., 2012 ; Sundar et al., 2019 ; Widodo et al., 2007, 2010 ; Yu et al., 2017 ). Ashwagandha withanolides were also studied for their anti-viral effects, wherein Withaferin-A was shown to be effective against herpes simplex virus, HIV and H1N1 influenza virus (Cai et al., 2015 ; Grover et al., 2011 ; Shi et al., 2017 ). Aqueous extracts of Ashwagandha leaf and stem provide affordable and readily accessible withanolides-rich alternative of purified withanolides, which made it a promising resource for usage for a variety of health benefits facilitated by its multimodal action.…”

“…These withanolides have also been studied for their anti-viral effects. Withaferin-A has been previously reported to be effective against herpes simplex virus, HIV and H1N1 influenza virus (Cai et al., 2015 ; Grover et al., 2011 ; Shi et al., 2017 ). We have earlier demonstrated the effect of Withaferin-A and Withanone on TMPRSS2 (required for SARS-CoV-2 entry into the host cells) (Kumar, Dhanjal, Bhargava, et al., 2020 ).…”

Unmapped exome reads implicate a role for Anelloviridae in childhood HIV-1 long-term non-progression

“…In addition, TTV has two main open reading frames (ORFs), ORF1 and ORF2, of which ORF2 suppresses the NF-κB pathways via interaction with IκB kinases 73 . Because the NF-κB signalling pathway is central to HIV-1 gene expression 74 , suppression of NF-κB activity could slow the rate of HIV-1 replication 75 , 76 . ORF2-mediated suppression of NF-κB activity could also lead to fewer activated CD4 T cells 77 , 78 , resulting in LTNP 16 , 79 , or may result in reduced pro-inflammatory cytokines such as TNFα slowing the disease progression 80 .…”