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Repurposing Hsp104 to Antagonize Seminal Amyloid and Counter HIV Infection
Laura M Castellano1, Stephen M Bart2, Veronica M Holmes3
1Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Pharmacology Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Abstract:
Naturally occurring proteolytic fragments of prostatic acid phosphatase (PAP248-286 and PAP85-120) and semenogelins (SEM1 and SEM2) form amyloid fibrils in seminal fluid, which capture HIV virions and promote infection. For example, PAP248-286 fibrils, termed SEVI (semen-derived enhancer of viral infection), can potentiate HIV infection by several orders of magnitude. Here, we design three disruptive technologies to rapidly antagonize seminal amyloid by repurposing Hsp104, an amyloid-remodeling nanomachine from yeast. First, Hsp104 and an enhanced engineered variant, Hsp104(A503V), directly remodel SEVI and PAP85-120 fibrils into non-amyloid forms. Second, we elucidate catalytically inactive Hsp104 scaffolds that do not remodel amyloid structure, but cluster SEVI, PAP85-120, and SEM1(45-107) fibrils into larger assemblies. Third, we modify Hsp104 to interact with the chambered protease ClpP, which enables coupled remodeling and degradation to irreversibly clear SEVI and PAP85-120 fibrils. Each strategy diminished the ability of seminal amyloid to promote HIV infection, and could have therapeutic utility.
Insights
Yeast Hsp104 protein was repurposed to disrupt seminal amyloid fibrils that enhance HIV infection. These strategies reduced viral capture by amyloid, offering potential therapeutic applications against HIV transmission.
Area of Science:
- Biochemistry
- Virology
- Structural Biology
Background:
- Proteolytic fragments of prostatic acid phosphatase (PAP) and semenogelins form amyloid fibrils in seminal fluid.
- These seminal amyloids, such as semen-derived enhancer of viral infection (SEVI), capture HIV virions and significantly enhance infection.
- Existing methods to counteract seminal amyloids are limited.
Purpose of the Study:
- To develop novel technologies to antagonize seminal amyloids.
- To repurpose yeast Hsp104, an amyloid-remodeling nanomachine, for therapeutic applications against HIV transmission enhancement by seminal amyloids.
Main Methods:
- Utilized wild-type and engineered Hsp104 variants to remodel SEVI and PAP85-120 fibrils.
- Developed catalytically inactive Hsp104 scaffolds to cluster seminal amyloid fibrils.
- Modified Hsp104 to couple with ClpP protease for amyloid remodeling and degradation.
Main Results:
- Hsp104 and its variant Hsp104(A503V) successfully remodeled SEVI and PAP85-120 fibrils into non-amyloid forms.
- Inactive Hsp104 scaffolds effectively clustered SEVI, PAP85-120, and SEM1(45-107) fibrils.
- Hsp104-ClpP interaction led to coupled remodeling and degradation of SEVI and PAP85-120 fibrils.
- All three strategies significantly reduced the ability of seminal amyloid to promote HIV infection.
Conclusions:
- Repurposing yeast Hsp104 offers a promising strategy to disrupt seminal amyloids that enhance HIV infection.
- The developed technologies demonstrate potential therapeutic utility in preventing HIV transmission.
- Targeting seminal amyloid formation and function presents a novel avenue for HIV prevention.
