Products Cited in Publications Worldwide Conformational activation and disulfide exchange in HIV-1 Env induce cell-free lytic/fusogenic transformation and enhance infection

Conformational activation and disulfide exchange in HIV-1 Env induce cell-free lytic/fusogenic transformation and enhance infection

Ang, Charles G; Hyatt, Nadia L; Le Minh, Giang; Gupta, Monisha; Kadam, Manali; Hogg, Philip J; Smith III, Amos B; Chaiken, Irwin M

DOI: PMID:

Abstract

Disulfide exchange is underexplored as a mechanism influencing HIV-1 entry. Prior studies demonstrated that redox enzyme inhibition can prevent HIV-1 infection but with limited mechanistic explanation. We hypothesize that ligand-driven rearrangement (“conformational activation”) enables enzyme-mediated disulfide exchange in Env residues (“disulfide trigger”) that promotes fusion transformations, enhancing virus entry. We tested soluble CD4 and CD4-binding site entry inhibitors as conformational activators and the ubiquitous redox enzyme thioredoxin-1 (Trx1) as disulfide trigger. We found that combination treatment caused fusion-like Env transformation and pseudovirus lysis, independent of cells. Notably, only compounds associated with gp120 shedding caused lysis when paired with Trx1. In each case, lysis was prevented by adding the fusion inhibitor T20, demonstrating that six-helix bundle formation is required as in virus-cell fusion. In contrast to conformationally activating ligands, neither the ground state stabilizer BMS-806 with Trx1 nor Trx1 alone caused lysis. Order of addition experiments reinforced conformational activation/disulfide trigger as a sequential process, with virus/activator preincubation transiently enhancing lysis and virus/Trx1 preincubation reducing lysis. Lastly, addition of exogenous Trx1 to typical pseudovirus infections exhibited dose-dependent enhancement of infection. Altogether, these data support conformational activation and disulfide triggering as a mechanism that can induce and enhance the fusogenic transformation of Env.

Keywords

HIV-1 ; Env ; thioredoxins ; allosteric disulfides ; virus entry ; entry inhibitors ; thiols ; disulfide exchange

Purchased from AmBeed

A3812617787-70-499.5%

Copper(I) bromide

25.0/100g

Detail
L-Ascorbic acid sodium salt

A587658134-03-298%

L-Ascorbic acid sodium salt

48.0/1kg

Detail