Journal article
Metastable HIV‑1 Surface Protein Env Sensitizes Cell Membranes to Transformation and Poration by Dual-Acting Virucidal Entry Inhibitors
Biochemistry (Easton), v 59(6), pp 818-828
18 Feb 2020
PMID: 31942789
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Dual-acting virucidal entry inhibitors (DAVEIs) have previously been shown to cause irreversible inactivation of HIV-1 Env-presenting pseudovirus by lytic membrane transformation. This study examined whether this transformation could be generalized to include membranes of Env-presenting cells. Flow cytometry was used to analyze HEK293T cells transiently transfected with increasing amounts of DNA encoding JRFL Env, loaded with calcein dye, and treated with serial dilutions of microvirin (Q831K/M83R)-DAVEI. Comparing calcein retention against intact Env expression (via Ab 35O22) on individual cells revealed effects proportional to Env expression. “Low-Env” cells experienced transient poration and calcein leakage, while “high-Env” cells were killed. The cell-killing effect was confirmed with an independent mitochondrial activity-based cell viability assay, showing dose-dependent cytotoxicity in response to DAVEI treatment. Transfection with increasing quantities of Env DNA showed further shifts toward “High-Env” expression and cytotoxicity, further reinforcing the Env dependence of the observed effect. Controls with unlinked DAVEI components showed no effect on calcein leakage or cell viability, confirming a requirement for covalently linked DAVEI compounds to achieve Env transformation. These data demonstrate that the metastability of Env is an intrinsic property of the transmembrane protein complex and can be perturbed to cause membrane disruption in both virus and cell contexts.
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Details
- Title
- Metastable HIV‑1 Surface Protein Env Sensitizes Cell Membranes to Transformation and Poration by Dual-Acting Virucidal Entry Inhibitors
- Creators
- Charles G Ang - Drexel UniversityMd. Alamgir Hossain - Drexel UniversityMarg Rajpara - Drexel UniversityHarry Bach - Drexel UniversityKriti Acharya - Drexel UniversityAlexej Dick - Drexel UniversityAdel A Rashad - Drexel UniversityMichele Kutzler - Drexel UniversityCameron F Abrams - Drexel UniversityIrwin Chaiken - Drexel University
- Publication Details
- Biochemistry (Easton), v 59(6), pp 818-828
- Publisher
- American Chemical Society; Washington, DC
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Biochemistry and Molecular Biology; Infectious Diseases (and HIV Medicine); Chemical and Biological Engineering
- Web of Science ID
- WOS:000514759500012
- Scopus ID
- 2-s2.0-85080068101
- Other Identifier
- 991019168577604721
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- Web of Science research areas
- Biochemistry & Molecular Biology