Human immunodeficiency virus type-1 (HIV-1), the causative agent of acquired immune deficiency syndrome (AIDS), has infected ~60 million people worldwide and caused over 25 million deaths. Sexual transmission is the major route of HIV-1 infection and factors that promote this infectious route have recently been identified in semen. Fragments of prostatic acid phosphatase are a major component of semen and form amyloid fibrils that bind HIV virions and can promote infection by several orders of magnitude up to 105-fold. Therefore, a potential preventative strategy is to deploy agents that eliminate these amyloid forms, which are termed Semen-derived Enhancer of Virus Infection (SEVI) fibrils. Unfortunately, amyloid fibrils are notoriously stable and difficult to eradicate. In other settings, they are connected with various fatal neurodegenerative disorders. However, various microbes have harnessed the amyloid form for beneficial purposes, and systems have evolved that can rapidly reverse amyloid formation. One natural protein has emerged that resolves amyloid fibrils with unprecedented alacrity: the protein disaggregase, Hsp104. Hsp104 rapidly solubilizes amyloid forms of several proteins, including yeast prion proteins Sup35 and Ure2, as well as ?-synuclein, which forms amyloid fibrils in Parkinson's disease. We hypothesize that Hsp104 or SEVI-optimized variants can be generated to rapidly dissolve or remodel SEVI fibrils and thereby diminish SEVI-enhanced HIV infection. Thus, we aim to: (1) Develop Hsp104 variants that rapidly disassemble SEVI fibrils~ and (2) Determine whether disassembled products have diminished ability to promote HIV infection. These studies will provide the foundations for developing SEVI disaggregases as preventative agents with the ultimate goal of incorporating them into a gel or solution that dissolves SEVI fibrils in semen and reduces sexual transmission of HIV. The ability to reverse fibril formation (rather than simply inhibit it) and blck sexual transmission of HIV will provide a powerful and much needed weapon against the global HIV/AIDS pandemic. Our approach of targeting a host protein conformer (SEVI fibrils) is fundamentally different from traditional microbicidal approaches that target the virus, and this strategy is anticipated to synergize with direct antiviral strategies. PUBLIC HEALTH RELEVANCE: Human immunodeficiency virus type-1 (HIV-1), the virus that causes acquired immune deficiency syndrome (AIDS), is transmitted sexually and HIV-1 infection is enhanced approximately 100,000-fold by fibers formed by host proteins in human semen. Here, we plan to engineer specific enzymes that target and eliminate these host protein fibers and thereby block HIV-1 infection. Realization of our objectives will empower urgently needed new strategies to prevent HIV-1 infection and combat the global HIV/AIDS pandemic.