Interactions of peptide triazole thiols with Env gp120 induce irreversible breakdown and inactivation of HIV-1 virions

Arangassery Rosemary Bastian,Lauren D Bailey,Rachna Aneja,Mark Contarino,Diogo Rodrigo Magalhaes Moreira,James A Hoxie,Jeffrey M Jacobson,Irwin Chaiken,George Leslie,Caitlin Duffy,Karyn Mcfadden,Kevin Freedman,Ali Emileh

doi:10.1186/1742-4690-10-153

Arangassery Rosemary Bastian, Lauren D Bailey + Show 11 more

Open Access

https://doi.org/10.1186/1742-4690-10-153

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Abstract

BackgroundWe examined the underlying mechanism of action of the peptide triazole thiol, KR13 that has been shown previously to specifically bind gp120, block cell receptor site interactions and potently inhibit HIV-1 infectivity.ResultsKR13, the sulfhydryl blocked KR13b and its parent non-sulfhydryl peptide triazole, HNG156, induced gp120 shedding but only KR13 induced p24 capsid protein release. The resulting virion post virolysis had an altered morphology, contained no gp120, but retained gp41 that bound to neutralizing gp41 antibodies. Remarkably, HIV-1 p24 release by KR13 was inhibited by enfuvirtide, which blocks formation of the gp41 6-helix bundle during membrane fusion, while no inhibition of p24 release occurred for enfuvirtide-resistant virus. KR13 thus appears to induce structural changes in gp41 normally associated with membrane fusion and cell entry. The HIV-1 p24 release induced by KR13 was observed in several clades of HIV-1 as well as in fully infectious HIV-1 virions.ConclusionsThe antiviral activity of KR13 and its ability to inactivate virions prior to target cell engagement suggest that peptide triazole thiols could be highly effective in inhibiting HIV transmission across mucosal barriers and provide a novel probe to understand biochemical signals within envelope that are involved in membrane fusion.

Highlights

We examined the underlying mechanism of action of the peptide triazole thiol, KR13 that has been shown previously to bind gp120, block cell receptor site interactions and potently inhibit HIV-1 infectivity
The proteins involved in HIV-1 entry include gp120 and gp41 organized as a trimer on the viral envelope spike, and both CD4 and a chemokine receptor, either CCR5 or CXCR4, on the cell surface
Our findings strongly suggest that the novel virolytic effect induced by KR13 is related to physiological triggering of fusion machinery on the envelope glycoprotein trimer, which in the absence of CD4 or coreceptor engagement leads to disruption of the viral membrane and potent, irreversible viral inhibition

Summary

Introduction

We examined the underlying mechanism of action of the peptide triazole thiol, KR13 that has been shown previously to bind gp120, block cell receptor site interactions and potently inhibit HIV-1 infectivity. Most of the currently approved HIV drugs target viral enzymes, in particular reverse transcriptase, protease and integrase [1,2,3,4]. The number of anti-HIV drugs targeting the entry process is more limited. The proteins involved in HIV-1 entry include gp120 and gp organized as a trimer on the viral envelope spike, and both CD4 and a chemokine receptor, either CCR5 or CXCR4, on the cell surface. The fusion inhibitor enfuvirtide (T20) [5] and the CCR5 inhibitor maraviroc [6] are the only currently approved HIV entry drugs for both first-line and salvage therapy [7,8,9]. T20 targets the N-terminal heptad repeat region of gp, blocking gp conformational changes

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