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Dissertation
Poly(styrene-alt-maleic acid) (PSMA) as an inhibitor of human immunodeficiency virus type 1 (HIV-1) infection and as a partner in safe and effective combination microbicides
Doctor of Philosophy (Ph.D.), Drexel University
Apr 2009
DOI:
https://doi.org/10.17918/00008942
Abstract
Preclinical microbicide development efforts have focused on the development of the polyanionic compound poly(styrene-alt-maleic acid) (alt-PSMA). In vitro experiments demonstrated that alt-PSMA is a potent inhibitor of infection by R5 and X4 strains of HIV-1. alt-PSMA was shown to be an effective inhibitor of HIV-1 laboratory strains and clinical isolates, as well as both cell-free and cell-associated forms of infectivity. In keeping with the development of a safe inhibitor, alt-PSMA was also characterized as having low cytotoxicity. High levels of HIV-1 inhibition and low levels of cytotoxicity were confirmed in assays using primary human peripheral blood mononuclear cells (PBMCs). Furthermore, in compound washout experiments designed to mimic product leakage and the loss of active compounds following application, there were no adverse effects associated with the use of alt-PSMA. This was not true of other polyanionic HIV-1 inhibitors (including carrageenan, cellulose sulfate, and polystyrene sulfonate), which caused increases in HIV-1 infection subsequent to compound removal in experiments using cell lines and human PBMCs in conjunction with R5 and X4 viruses. The favorable attributes of alt-PSMA-potent inhibition of HIV-1, low cytotoxicity, no adverse effects in washout assays-suggested the continued development of alt-PSMA not only as a single agent but also as a component of a combination microbicide. The successes achieved using highly active antiretroviral therapy (HAART) have suggested that higher efficacy can be achieved by using compound combinations in microbicides. In investigations of potential compound combinations, the activity of alt-PSMA was assessed in combination with a fusion inhibitor (cyanovirin), an entry inhibitor (polystyrene sulfonate), or a reverse transcriptase inhibitor (efavirenz). Analyses performed using CalcuSyn and MacSynergy software indicated that the greatest degree of synergistic antiviral activity was achieved by the combination of alt-PSMA and cyanovirin. These results suggest that synergy with alt-PSMA is established in a combination that also includes a compound with a similar but non-overlapping mechanism of action. These combination studies, as well as experiments focused on the activity of alt-PSMA as a single compound, strongly indicate that alt-PSMA is a compound that deserves further assessment as a potential candidate microbicide and a partner in a combination microbicide.
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Details
- Title
- Poly(styrene-alt-maleic acid) (PSMA) as an inhibitor of human immunodeficiency virus type 1 (HIV-1) infection and as a partner in safe and effective combination microbicides
- Creators
- Vanessa Pirrone
- Contributors
- Brian Wigdahl (Advisor) - Drexel University, Drexel University (1970-)
- Awarding Institution
- Drexel University
- Degree Awarded
- Doctor of Philosophy (Ph.D.)
- Publisher
- Drexel University; Philadelphia, Pennsylvania
- Number of pages
- xviii, 281 pages
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- Microbiology and Immunology; College of Medicine; Drexel University
- Other Identifier
- 991021889103604721