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Abstract: HIV-exposed seronegative individuals (HESNs) are persons who remain seronegative despite repeated exposure to HIV, suggesting an in vivo resistance mechanism to HIV. Elucidation of endogenous factors responsible for this phenomenon may aid in the development of new classes of microbicides and therapeutics. We compared cervicovaginal protein abundance profiles between high-risk HESN and two control groups: low-risk HESN and HIV-positives. Four iTRAQ-based quantitative experiments were performed using samples classified based on presence/absence of particular gynaecological conditions. After statistical analysis, two proteins were shown to be differentially abundant between high-risk HESNs and control groups. Serpin A5, a serine proteinase inhibitor and Myeloblastin, a serine protease, were up- and downregulated, respectively. Commercially available ELISA assays were used to confirm differential Serpin A5 levels. These results suggest that HIV resistance in CVF of HESNs is the result of a delicate balance between two complementary mechanisms: downregulation of serine proteinases and upregulation of their inhibitors. [Copyright &y& Elsevier]

Proteinase 3 and neutrophil elastase are serine proteinases of the polymorphonuclear neutrophils, which are considered to have both similar localization and ligand specificity because of their high sequence similarity. However, recent studies indicate that they might have different and yet complementary physiologic roles. Specifically, proteinase 3 has intracellular specific protein substrates resulting in its involvement in the regulation of intracellular functions such as proliferation or apoptosis. It behaves as a peripheral membrane protein and its membrane expression is a risk factor in chronic inflammatory diseases. Moreover, in contrast to human neutrophil elastase, proteinase 3 is the preferred target antigen in Wegener’s granulomatosis, a particular type of vasculitis. We review the structural basis for the different ligand specificities and membrane binding mechanisms of both enzymes, as well as the putative anti-neutrophil cytoplasm autoantibody epitopes on human neutrophil elastase 3. We also address the differences existing between murine and human enzymes, and their consequences with respect to the development of animal models for the study of human proteinase 3-related pathologies. By integrating the functional and the structural data, we assemble many pieces of a complicated puzzle to provide a new perspective on the structure–function relationship of human proteinase 3 and its interaction with membrane, partner proteins or cleavable substrates. Hence, precise and meticulous structural studies are essential tools for the rational design of specific proteinase 3 substrates or competitive ligands that modulate its activities. [ABSTRACT FROM AUTHOR]