Date of Completion

12-12-2014

Embargo Period

12-11-2015

Keywords

estriol, keratinization, stratum corneum, foreskin, HaCaT cells

Major Advisor

Rachel J. O'Neill, Ph.D.

Co-Major Advisor

Andrew J. Pask, Ph.D.

Associate Advisor

Lawrence K. Silbart, Ph.D.

Associate Advisor

Judy D. Brown, Ph.D.

Associate Advisor

Brian J. Aneskievich, Ph.D.

Field of Study

Genetics and Genomics

Degree

Doctor of Philosophy

Open Access

Open Access

Abstract

Human immunodeficiency virus (HIV) is a global health concern prompting an urgent need to develop simple, effective, economical preventive measures. The research described in this thesis evaluated the potential for topical estriol to induce keratinization of the inner foreskin, the primary site of HIV entry in uncircumcised males.

We found that topical estriol can induce keratinization of the human inner foreskin by up-regulating the production of keratins per cell, and not through increased skin proliferation. Furthermore, the quantity and position of HIV target cells in the foreskin were not adversely affected by the treatment.

Estrogen receptors (ERs) are transcription factors capable of regulating a substantial number of target genes. Analysis of the genes and proteins differentially affected by the treatment of inner foreskin revealed that estrogen primarily acts on the keratinocyte epidermal differentiation process. Estriol also induced early differentiation of keratinocytes in culture using an immortalized keratinocyte cell line, HaCaT.

Taken together, our results suggest that treatment of the inner foreskin with estrogen increases keratin production in keratinocytes without affecting cellular proliferation. While some adverse effects of the treatment were observed, the results of our Phase 1a Clinical Trial were vastly positive. We recommend the continuation of this line of study with a larger scale clinical trial to determine the long-term effects of treatment. Similarly positive results could have a global impact as they imply that treatment provides a safe, cheap, non-invasive method for reducing the transmission of HIV and simultaneously aid in controlling the spread of HPV.

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