Abstract
Entry of HIV-1 into host cells remains a compelling yet elusive target for developing agents to prevent infection. A peptide triazole (PT) class of entry inhibitor has previously been shown to bind to HIV-1 gp120, suppress interactions of the Env protein at host cell receptor binding sites, inhibit cell infection, and cause envelope spike protein breakdown, including gp120 shedding and, for some variants, virus membrane lysis. We found that gold nanoparticle-conjugated forms of peptide triazoles (AuNP-PT) exhibit substantially more potent antiviral effects against HIV-1 than corresponding peptide triazoles alone. Here, we sought to reveal the mechanism of potency enhancement underlying nanoparticle conjugate function. We found that altering the physical properties of the nanoparticle conjugate, by increasing the AuNP diameter and/or the density of PT conjugated on the AuNP surface, enhanced potency of infection inhibition to impressive picomolar levels. Further, compared with unconjugated PT, AuNP-PT was less susceptible to reduction of antiviral potency when the density of PT-competent Env spikes on the virus was reduced by incorporating a peptide-resistant mutant gp120. We conclude that potency enhancement of virolytic activity and corresponding irreversible HIV-1 inactivation of PTs upon AuNP conjugation derives from multivalent contact between the nanoconjugates and metastable Env spikes on the HIV-1 virus. The findings reveal that multispike engagement can exploit the metastability built into virus the envelope to irreversibly inactivate HIV-1 and provide a conceptual platform to design nanoparticle-based antiviral agents for HIV-1 specifically and putatively for metastable enveloped viruses generally.
Highlights
HIV-1 envelope spike protein remains a compelling but elusive target for preventing infection
We investigated the mechanism underlying the antiviral functions of AuNP-KR13 conjugates against HIV-1 and, in particular, the ability of the nanoconjugates to cause specific virus lytic inactivation
The physical characteristics of gold nanoparticle-peptide triazole conjugates were validated by dynamic light scattering (DLS), Transmission electron microscopy (TEM), and UV
Summary
HIV-1 envelope spike protein remains a compelling but elusive target for preventing infection. A peptide triazole (PT) class of entry inhibitor has previously been shown to bind to HIV-1 gp120, suppress interactions of the Env protein at host cell receptor binding sites, inhibit cell infection, and cause envelope spike protein breakdown, including gp120 shedding and, for some variants, virus membrane lysis. We showed that a family of entry inhibitors, peptide triazoles (29 –34) derived from the peptide 12p1 [35, 36], bind and with high affinity to HIV-1 Env gp120, antagonize the interactions of Env binding sites for both host cell receptors CD4 and CCR5/CXCR4, and cause gp120 shedding from the virus surface, leading to HIV-1 inactivation before host cell encounter [37, 38]. The investigation demonstrates that the multivalent physical contact approach can be used as a general strategy for antagonizing HIV-1 transmission and proliferation
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