Human Immunodeficiency Virus Type 1 Stimulates the Expression and Production of Secretory Leukocyte Protease Inhibitor (SLPI) in Oral Epithelial Cells: a Role for SLPI in Innate Mucosal Immunity

Abstract

The innate immune response is a key barrier against pathogenic microorganisms such as human immunodeficiency virus type 1 (HIV-1). Because HIV-1 is rarely transmitted orally, we hypothesized that oral epithelial cells participate in the innate immune defense against this virus. We further hypothesized that secretory leukocyte protease inhibitor (SLPI), a 12-kDa mucosal antiviral protein, is a component of the host immune response to this virus. Here we demonstrated constitutive expression and production of SLPI in immortalized human oral keratinocytes. Brief exposure of cells to HIV-1 BaL and HXB2 significantly increased SLPI mRNA and protein production compared to that in mock-exposed cells (P < 0.01), as evaluated by real-time quantitative reverse transcription-PCR and enzyme-linked immunosorbent assay. HIV-1-mediated stimulation of SLPI occurred at the transcriptional level, was dose and time dependent, was elicited by heat-inactivated and infectious viruses, and did not depend on cellular infection. Experiments with purified retroviral proteins showed that the stimulatory effect was induced specifically by external envelope glycoproteins from HIV-1 and simian immunodeficiency virus. SLPI responsiveness to HIV-1 was also observed in an unrelated oral epithelial cell line and in normal (nonimmortalized) human oral epithelial cells isolated from healthy uninfected gingival tissues. In this first report of SLPI regulation by HIV-1, we show that the expression and production of the antimicrobial and anti-inflammatory protein can be stimulated in oral epithelial cells by the virus through interactions with gp120 in the absence of direct infection. These findings indicate that SLPI is a component of the oral mucosal response to HIV-1.

Herpes Simplex Virus Downregulates Secretory Leukocyte Protease Inhibitor: a Novel Immune Evasion Mechanism

“…To examine whether the loss of SLPI was specific for HSV, CaSki cells were also infected with VSV or exposed to 50 ng Previous studies have demonstrated that exposure of human oral epithelial cells or keratinocytes to HIV-1 BaL resulted in an increase in SLPI production, although the effects on genital tract epithelial cells were not examined (24). As an additional control, the cells were treated with the Toll-like receptor 3 (TLR3) agonist poly(I:C), which has been shown to augment SLPI production in the genital tract (1).…”

“…J. VIROL. may contribute to the poor oral transmission of HIV (24). Possibly, the more modest increase in SLPI following exposure of cervical epithelial cells to HIV-1 contributes to the increased risk of genital versus oral mucosal transmission.…”

“…Importantly, SLPI possesses potent anti-HIV-1 activity at physiological concentrations found in saliva (24,35,50), which is presumed to contribute to the endogenous anti-HIV activity of oral secretions. A recent study found that brief exposure of human oral keratinocytes and epithelial cells to HIV-1 stimulated SLPI mRNA and protein production in the absence of direct infection, suggesting that upregulation of SLPI by the virus may protect the oral cavity against HIV infection (24).…”

WFDC1/ps20 Is a Novel Innate Immunomodulatory Signature Protein of Human Immunodeficiency Virus (HIV)-Permissive CD4+CD45RO+Memory T Cells That Promotes Infection by Upregulating CD54 Integrin Expression and Is Elevated in HIV Type 1 Infection

“…WAPs are mostly secreted factors in mucosal tissue with pleiotropic functions implicated in innate immunity; some are serine protease inhibitors with anti-infective activity (20,27). One WAP, secretory lymphocyte protease inhibitor (SLPI), detected in macrophages but not CD4 T cells, exhibits anti-HIV activity by binding to the phospholipid binding protein annexin II, which is a cofactor for macrophage HIV infection (33,35) and is associated with reduced HIV transmission (22,28). ps20, a secreted WAP of approximately 23 kDa with a characteristic N-terminal signal peptide that targets it for extracellular secretion, is reported to modulate cell proliferation, migration, and the formation of multicellular spheroids (31,32,40) and to induce angiogenesis in cancer-associated reactive stroma in vivo (34).…”

Short Communication: Increased Expression of Secretory Leukocyte Protease Inhibitor in Oral Mucosa of Colombian HIV Type 1-Exposed Seronegative Individuals

“…6 It was previously shown that HIV-1 stimulates production of SLPI in oral epithelial cells by interacting with the viral glycoprotein gp120, impairing the establishment of infection. 7 In addition, McNeely et al showed that recombinant SLPI or SLPI derived from saliva protected human monocyte-derived macrophages and CD4…”