Lin Li

The persistence of latent reservoirs remains the primary barrier to HIV-1 eradication. Although diverse latency-reversing agents (LRAs) have been designed to induce latent HIV-1 expression, their clinical utility is frequently limited by significant toxicity or insufficient potency. Our previous research confirmed that resveratrol reverses latent HIV-1 expression in vitro by regulating multiple signaling pathways. Based on the chemical structure of resveratrol, we designed and synthesized a small-molecule compound, XQ2 (5,7-dimethoxy-2-[5-(Ethoxymethyl)-2-furanyl]-4­(3H)-quinazolinone). Current data indicate that XQ2 efficiently promotes viral reactivation in latently infected cell models while maintaining low cytotoxicity and avoiding broad T-cell stimulation. Significantly, XQ2 demonstrates synergistic potential when administered alongside several typical LRAs. The mechanism driving XQ2-mediated reactivation appears to involve the release of positive transcription elongation factor b (P-TEFb) from bromodomain 4 (BRD4), facilitating Tat-dependent viral transcription. These results suggest that XQ2 is a promising, low-toxicity LRA candidate for advancing the “shock and kill” eradication strategy.

The latency of human immunodeficiency virus type 1 (HIV-1) is a major barrier to achieving an HIV-1 cure, as antiretroviral therapy does not target the latent virus. Virus-host interactions play an essential role in various stages of the HIV-1 lifecycle. Exploring the interaction between host factors and HIV-1 infection is critical for developing new HIV-1 treatment strategies. Yes-associated protein (YAP) is a key co-transcription factor in the Hippo signaling pathway, which regulates the occurrence and development of various diseases, including cellular metabolism, cancer, immunity, and viral infection. In this study, we first confirmed that YAP gene expression in patients with acquired immune deficiency syndrome (AIDS) was significantly lower than that in the healthy control group, as determined using the GEO2R online tool. Furthermore, YAP was identified as a negative regulator of HIV-1 transcription by mediating K33- and K48-linked ubiquitination and proteasomal degradation of Tat. Here, we further confirmed that the YAP TAD domain recruited ubiquitin-like with PHD and RING finger domain 1 (UHRF1) to mediate Tat’s ubiquitination and degradation by the screening of the BioGRID database combined with IP-MS analysis. The conserved lysine residues K28, K29, and K41 on Tat were critical acceptor sites for ubiquitination and proteasomal degradation. Our findings revealed that YAP promotes the suppression of HIV-1 transcription and the maintenance of HIV-1 latency, providing novel insights into virus-host interactions for regulating HIV-1 latency.

Ebola virus (EBOV) causes deadly Ebola virus disease (EVD), and EVD survivors are at high risk of developing blinding ocular complications, which associate with the breakdown of human retinal pigment epithelial (RPE) barrier. Here, we demonstrated EBOV glycoprotein (GP) could directly impair RPE barrier function. EBOV GP significantly decreased expression of tight junction (TJ) proteins in RPE monolayers, resulting in an increase of monolayer permeability. EBOV GP activated PI3K/Akt pathway and induced oxidative stress in RPE cells as evidenced by an increase in the production of reactive oxygen species (ROS), decreased expression of an antioxidant factor, nuclear factor erythroid 2-related factor 2 (Nrf2), and its downstream proteins heme oxygenase 1 (HO-1) and NAD(P)H dehydrogenase (quinone) 1 (NQO1). We found activating Nrf2 could counteract EBOV GP-induced RPE barrier injury. Furthermore, GP2 subunit is the key region in the GP that impairs RPE barrier function. Destruction of RPE barrier function by EBOV GP leads to translocation of bacteria and HIV-1. We confirmed EBOV GP-mediated impairment of RPE barrier function in mice. As an Nrf2 activator, resveratrol displays protective effects on the RPE barrier function. Collectively, our study demonstrates EBOV GP impairs the RPE barrier function through PI3K/Akt-Nrf2 pathway and resveratrol is a promising therapeutic agent for EVD-associated retinal complications.

The study shows SRT is an effective entry inhibitor against infection of SARS-CoV-2, which is currently prevalent globally. SRT targets the S protein of SARS-CoV-2 and is effective against a panel of SARS-CoV-2 variants.