Fighting HIV infection by defining mechanisms to remodel semen-derived amyloid fibrils / Laura M. Castellano.

Format:

Book

Manuscript

Thesis/Dissertation

Author/Creator:

Castellano, Laura M., author.

Contributor:

Shorter, James, degree supervisor.

Kohli, Rahul, 1985- degree committee member.

Jordan-Sciutto, Kelly, degree committee member.

Lemmon, Mark, 1889-1975, degree committee member.

Marks, Michael, degree committee member.

University of Pennsylvania. Department of Pharmacology, degree granting institution.

Language:

English

Subjects (All):

Penn dissertations--Pharmacology.

Pharmacology--Penn dissertations.

Local Subjects:

Penn dissertations--Pharmacology.

Pharmacology--Penn dissertations.

Physical Description:

xi, 113 leaves : illustrations (some color) ; 29 cm

Production:

[Philadelphia, Pennsylvania] : University of Pennsylvania, 2015.

Summary:

Human immunodeficiency virus (HIV) is a major public health threat worldwide, with 80% of infections acquired through sexual transmission. Semen is the principal vector for the transmission of HIV and several endogenous peptides in semen, including fragments of prostatic acid phosphatase (PAP248-286 and PAP85-120) and semenogelins (SEM1 and SEM2), assemble into amyloid fibrils that promote HIV infection. Semen-derived amyloid fibrils enhance infectivity by capturing HIV virions and facilitating their attachment and fusion to target cells. Deciphering methods to dissolve seminal amyloid fibrils would provide a novel preventative strategy for reducing HIV infection via sexual transmission. Three previously described anti-amyloid agents were used to disassemble and/or counteract seminal amyloid fibrils: 1) Hsp104, an amyloid-remodeling factor from yeast, 2) CLR01, a lysine-specific molecular tweezer, and 3) EGCG, a small molecule polyphenol from green tea. Each strategy was found to antagonize seminal amyloid activity through diverse mechanisms. For instance, Hsp104 and a potentiated Hsp104 variant, Hsp104 A503V, remodeled seminal amyloid fibrils into non-fibrillar aggregates and catalytically inactive Hsp104 scaffolds clustered fibrils into larger assemblies. Additionally, Hsp104 was modified to interact with the chambered protease ClpP, to enable coupled remodeling and degradation of seminal amyloid. CLR01 remodeled pre-formed amyloid fibrils through disruption of critical lysine residues, neutralized the cationic fibril surface charge, and exhibited a direct anti-viral effect via disruption of the viral membrane. Finally, epigallocatechin gallate (EGCG) is the first small molecule that can eradicate all four classes of seminal amyloid. Thus, all three strategies were highly effective at antagonizing seminal amyloid fibrils and could have therapeutic utility. Altogether, these findings provide insight into developing microbicidal agents that can abolish the infection-enhancing capabilities of seminal amyloid and counter HIV transmission.

Notes:

Ph. D. University of Pennsylvania 2015.

Department: Pharmacology.

Supervisor: James Shorter.

Includes bibliographical references.

OCLC:

950058359