A Flavonoid, Luteolin, Cripples HIV-1 by Abrogation of Tat Function

Abstract

Despite the effectiveness of combination antiretroviral treatment (cART) against HIV-1, evidence indicates that residual infection persists in different cell types. Intensification of cART does not decrease the residual viral load or immune activation. cART restricts the synthesis of infectious virus but does not curtail HIV-1 transcription and translation from either the integrated or unintegrated viral genomes in infected cells. All treated patients with full viral suppression actually have low-level viremia. More than 60% of treated individuals also develop minor HIV-1 –associated neurocognitive deficits (HAND) due to residual virus and immune activation. Thus, new therapeutic agents are needed to curtail HIV-1 transcription and residual virus. In this study, luteolin, a dietary supplement, profoundly reduced HIV-1 infection in reporter cells and primary lymphocytes. HIV-1inhibition by luteolin was independent of viral entry, as shown by the fact that wild-type and VSV–pseudotyped HIV-1 infections were similarly inhibited. Luteolin was unable to inhibit viral reverse transcription. Luteolin had antiviral activity in a latent HIV-1 reactivation model and effectively ablated both clade-B- and -C -Tat-driven LTR transactivation in reporter assays but had no effect on Tat expression and its sub-cellular localization. We conclude that luteolin confers anti–HIV-1 activity at the Tat functional level. Given its biosafety profile and ability to cross the blood-brain barrier, luteolin may serve as a base flavonoid to develop potent anti–HIV-1 derivatives to complement cART.

Endocytosis-mediated HIV-1 entry and its significance in the elusive behavior of the virus in astrocytes

“…RT-PCR for CXCR4, CCR5, CD4 and CD11a transcripts were done as described earlier (Chauhan et al, 2007; Mehla et al, 2011; Mehla et al, 2010) with primer sequnecs (Table S6). In each case, total RNA was extracted from 3–4 × 10 6 cells by Trizol reagent (Invitrogen).…”

“…Viral integration in HIV-1-infected astrocytes was monitored by Alu-HIV LTR PCR, as described (Mehla et al, 2011; Vijaykumar et al, 2008). Total DNA was extracted using DNAzol reagent (Invitrogen) and amplified by nested PCR using 1.25 units of platinum Taq polymerase, 0.1 mM dNTP mix, 30 pico-moles of each primer with 1.2 mM Mg 2+ in a 50 μl reaction.…”

Extracts of Moringa oleifera Lam. showing inhibitory activity against early steps in the infectivity of HIV-1 lentiviral particles in a viral vector-based screening

“…Similarly, flavonoids have been shown to show inhibitory effects against viruses including HIV and respiratory syncytial virus (Li et al, 2000). Plant-derived flavonoids have been reported to inhibit critical steps in the life cycle of HIV infectivity such as viral entry (Liu et al, 2011), reverse transcriptase (Li et al, 2011), integrase (Lee et al, 2003;Tewtrakul et al, 2003), viral transcriptional activities of HIV tat (Mehla et al, 2011) and protease inhibitory activities (Lee et al, 2009) and other activities. M. oleifera is also rich in saponins which have been reported to inhibit HIV infectivity, in vitro (Konoshima et al, 1995;Yang et al, 1999;Li et al, 2012).…”

Flavonoids: promising natural compounds against viral infections

“…For baicalin, computational studies also showed a high binding affinity (-9.8 kcal/mol) against chikungunya virus (CHIKV) nsP3 protein, suggesting that baicalin can potentially interfere with CHIKV infection [114]. It was found that luteolin has antiviral effect on HIV-1 reactivation by blocking both clade B-and C-Tat-driven LTR transactivation [87]. Luteolin also showed significant inhibition of Epstein-Barr virus (EBV) reactivation in cells [133]; it suppressed the activities of the immediate-early genes Zta and Rta by deregulating transcription factor Sp1 binding.…”