Hydrophobic Nanoparticles Reduce the β-Sheet Content of SEVI Amyloid Fibrils and Inhibit SEVI-Enhanced HIV Infectivity

Amyloid fibrils are linear polypeptide aggregates with a cross-β structure. These fibrils are best known for their association with neurodegenerative diseases, such as Alzheimer's or Parkinson's, but they may also be used by living organisms as functional units, e.g. in the synthesis of melanin or in the formation of bacterial biofilms. About a decade ago, in a search for semen factors that modulate infection by HIV-1 (a sexually transmitted virus and the causative agent of the acquired immune deficiency syndrome (AIDS)), it was demonstrated that semen harbors amyloid fibrils capable of markedly increasing HIV infection rates. This discovery not only created novel opportunities to prevent sexual HIV-1 transmission but also stimulated research to unravel the natural role of these factors. We discuss here the identification of these intriguing structures, their molecular properties, and their effects on both sexually transmitted diseases and reproductive health. Moreover, we review strategies to antagonize semen amyloid to prevent sexual transmission of viruses.

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“…99 . A nanoparticle formulation of this hydrophobic polymer reduced SEVI-mediated enhancement of HIV infection in cell culture experiments.…”

Section: Semen Amyloid Antagonistsmentioning

confidence: 99%

Structure, function and antagonism of semen amyloids

et al. 2018

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“…The high-level association β-sheet secondary structure in proteins has been confirmed to be a distinguishing feature in the formation of the protein aggregates and amyloid fibrils in many diseases ( Nabers et al, 2016 ). A highly stable cross-β-sheet secondary structure of amyloid fibrils is usually identified by CD spectra assay ( Sheik et al, 2017 ). However, PAP248-286 monomer lacks a significant proportion of ordered cross-β-sheet structure ( Figure 2D ).…”

Section: Discussionmentioning

confidence: 99%

3-Hydroxyphthalic Anhydride- Modified Rabbit Anti-PAP IgG as a Potential Bifunctional HIV-1 Entry Inhibitor

Zhang

Chen

et al. 2018

Front. Microbiol.

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Several studies have reported that amyloid fibrils in human semen formed from a naturally occurring peptide fragment of prostatic acidic phosphatase (PAP248-286), known as semen-derived enhancer of viral infection (SEVI), could dramatically enhance human immunodeficiency virus type 1 (HIV-1) infection. Accordingly, SEVI might serve as a novel target for new antiviral drugs or microbicide candidates for the prevention of sexually transmitted HIV. Theoretically, a special anti-PAP or anti-SEVI antibody could reduce the enhancement of viral infection by blocking the binding of HIV and SEVI fibrils. Here, 3-hydroxyphthalic anhydride modified anti-PAP248-286 antibody, named HP-API, exhibited broad-spectrum and highly effective anti-HIV-1 activities on different subtypes and tropism. By using time-of-addition, cell–cell fusion and a single-cycle HIV-1 infection assays, we demonstrated that HP-API is an HIV-1 entry/fusion inhibitor. Mechanism studies suggest that HP-API inhibited HIV-1 entry/fusion by targeting both HIV-1 gp120 envelop and CD4 receptor on the host cell specifically. It is noteworthy that HP-API abrogated the formation of SEVI fibrils and partially interfered with SEVI-mediated enhancement of HIV-1 infection. Based on these findings, HP-API could be considered a bifunctional HIV-1 entry/fusion inhibitor with high potential.

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“…These nanoparticles and polymers were far more efficient for inhibiting SEVI‐enhanced HIV infection than monomeric and pentameric 6‐methylbenzothiazole aniline, proposing a critical role of steric hindrance in the design of effective SEVI neutralizing agents. A very recent study suggested that a nanoparticle formulation of hydrophobic polymers diminished SEVI amyloid‐mediated HIV infection, and that the use of hydrophobic interactions to alter structures of amyloid fibrils at the level of the secondary structures may be an useful approach to neutralize the SEVI function …”

Section: Inhibition Of Sevi‐enhanced Hiv Viral Infectionmentioning

confidence: 99%

“…A very recent study suggested that a nanoparticle formulation of hydrophobic polymers diminished SEVI amyloid-mediated HIV 31 infection, and that the use of hydrophobic interactions to alter structures of amyloid fibrils at the level of the secondary structures may be an useful approach to neutralize the SEVI function. 52…”

Section: Development Of Agents To Suppress Hiv Interaction With Sevi mentioning

confidence: 99%

Semen‐derived amyloidogenic peptides—Key players of HIV infection

Lee

Ramamoorthy

2018

Protein Science

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Misfolding and amyloid aggregation of intrinsically disordered proteins (IDPs) are implicated in a variety of diseases. Studies have shown that membrane plays important roles on the formation of intermediate structures of IDPs that can initiate (and/or speed-up) amyloid aggregation to form fibers. The process of amyloid aggregation also disrupts membrane to cause cell death in amyloid diseases like Alzheimer's disease and type-2 diabetes. On the other hand, recent studies reported the membrane fusion properties of amyloid fibers. Remarkably, amyloid-fibril formation by short peptide fragments of highly abundant prostatic acidic-phosphatase (PAP) in human semen and are capable of boosting the rate of HIV infection up to 400,000-fold during sexual contact. Unlike the least toxic fully matured fibers of most amyloid proteins, the semen-derived enhancer of virus infection (SEVI) amyloid-fibrils of PAP peptide fragments are highly potent in rendering the maximum rate of HIV infection. This unusual property of amyloid fibers has witnessed increasing number of studies on the biophysical aspects of fiber formation and fiber-membrane interactions. NMR studies have reported a highly disordered partial helical structure in a membrane environment for the intrinsically disordered PAP peptide that promotes the fusion of the viral membrane with that of host cells. The purpose of this review article is to unify and integrate biophysical and immunological research reported in the previous studies on SEVI. Specifically, amyloid aggregation, dramatic HIV infection enhancing properties, membrane fusion properties, high resolution NMR structure, and approaches to eliminate the enhancement of HIV infection of SEVI peptides are discussed.

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Hydrophobic Nanoparticles Reduce the β-Sheet Content of SEVI Amyloid Fibrils and Inhibit SEVI-Enhanced HIV Infectivity

Cited by 11 publications

References 61 publications

Structure, function and antagonism of semen amyloids

Structure, function and antagonism of semen amyloids

3-Hydroxyphthalic Anhydride- Modified Rabbit Anti-PAP IgG as a Potential Bifunctional HIV-1 Entry Inhibitor

Semen‐derived amyloidogenic peptides—Key players of HIV infection

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