The Role of Serpin and Cystatin Antiproteases in Mucosal Innate Immunity and their Defense against HIV Lindsay Aboud 1 , Terry Blake Ball 1,2,3 , Annelie Tjernlund 4 , Adam Burgener 1,3 1 Department of Medical Microbiology, University of Manitoba, Winnipeg, Manitoba, Canada; 2 Department of Immunology, University of Manitoba, Winnipeg, Manitoba, Canada; 3 National HIV and Retrovirology laboratory, Public Health Agency of Canada, Winnipeg, Manitoba, Canada; 4 Department Medicine, Karolinska Institute, Solna, Sweden Keywords Cystatins, female genital tract, HIV, innate mucosal immunity, serpins Correspondence Adam Burgener, Department of Medical Microbiology, University of Manitoba, 507-745 Bannatyne Ave. Basic Medical Sciences Building, Winnipeg, Manitoba R3E 0W3, Canada. E-mail: burgener@cc.umanitoba.ca Submission July 22, 2013; accepted September 16, 2013. Citation Aboud L, Ball TB, Tjernlund A, Burgener A. The role of serpin and cystatin antiproteases in mucosal innate immunity and the defense against HIV. Am J Reprod Immunol 2014; 71: 12–23 doi:10.1111/aji.12166 Antiproteases play diverse roles in nature, from regulating protease activity to innate defense against microorganisms. Recently, antiproteas- es have been shown to play important roles in HIV pathogenesis includ- ing, inhibiting HIV binding and replication and reducing activation and inflammation of susceptible cells. They have also been implicated as one of the initial host responders, in plasma, to control replication of HIV. More recently, antiproteases expressed at the mucosal surface have been linked to reduced susceptibility to HIV infection in HIV-exposed sero- negative individuals. These factors are expressed in the epithelial layer of the female genital tract, thus at the frontline of defense against muco- sal infection. This review focuses on the specific antimicrobial roles of antiproteases, focusing on serpins and cystatins, with an emphasis on their known and potential roles in HIV infection. Their potential as ther- apeutic interventions to combat HIV is also discussed. Introduction Mucosal Protection Mechanisms in the Female Genital Tract from HIV The mechanism of HIV transmission, through vaginal mucosa, is not entirely understood. HIV is thought to cross the intact epithelial barrier through either direct infection of CD4 + T cells following migration of these cells to the epithelial layer of the mucosa or through infection of intermediary cells (Dendritic cells (DCs) or monocytes) present within the mucosal layer, before infection of CD4 + T cells. HIV may also directly infect epithelial cells followed by transcytosis through the epithelial layer or HIV 1 can directly dis- rupt the integrity of the mucosal epithelial barrier, resulting in translocation of additional virus particles through the mucosal layer. 2 Once the virus has infected its target cells, it undergoes local amplifica- tion, followed by dissemination to draining lymph nodes and subsequent systemic infection. 3 One important component of protection offered by the FGT is conferred by the soluble components in mucosal secretions. The FGT produces a hydro- philic layer of glycoproteins and glycolipids, referred to as the glycocalyx, as well as a layer of thick hydrophobic glycoprotein mucus, both of which act as barriers to invading potential pathogens. 4 Within these secretions, there is a plethora of antimicrobial agents, the majority of which are broad-spectrum microbicides. Many of these factors, including anti- leukoproteinase (SLPI), specific serpins and cystatins, defensins, and heat-shock proteins, have shown in vitro inhibitory activity against HIV. 5–8 In spite of American Journal of Reproductive Immunology 71 (2014) 12–23 ª 2013 John Wiley & Sons Ltd 12 REVIEW ARTICLE