The cysteine protease inhibitors cystatins inhibit herpes simplex virus type 1-induced apoptosis and virus yield in HEp-2 cells

Abstract

The role of cystatins in herpes simplex virus (HSV)-induced apoptosis and viral replication has been studied. Human epithelial (HEp-2) cells infected with wild-type HSV-1 (F), with a deletion virus lacking the anti-apoptotic gene Us3 (R7041) or with a deletion virus lacking the anti-apoptotic genes Us3 and ICP4 (d120) were treated with cystatin A, C or D. Cells and culture media were studied at different time points for replicating HSV-1 and for apoptosis. Cystatins C and D inhibited the yield of replicative HSV-1 significantly in HEp-2 cells. In addition, cystatin D inhibited R7041 and d120 virus-induced apoptosis. Moreover, cystatin A inhibited R7041-induced apoptosis. These inhibitory effects of cystatins on virus replication and apoptosis are likely to be separate functions. Cystatin D treatment decreased cellular cathepsin B activity in HSV-1 infection, suggesting that cathepsin B is involved in virus-induced apoptosis.

Imiquimod Suppresses Propagation of Herpes Simplex Virus 1 by Upregulation of Cystatin A via the Adenosine Receptor A1Pathway

“…Exogenously added cystatin A suppressed propagation of HSV-1 as reported previously (24), which suggested that it internalized into FL cells (Fig. 5).…”

“…A serine protease inhibitor prevents the release of viral DNA from the capsid and suppresses HSV-1 replication. Peri et al reported that cystatins partially inhibit HSV-1 propagation (24). They speculated that the ubiquitin-specific cysteine protease UL36 USP , which is an N-terminal fragment generated by proteolytic cleavage of pUL36 of HSV-1, is a target for cystatins.…”

“…Proteolytic cleavage steps are essential for the infectious processes of various viruses, including hepatitis C (3), human immunodeficiency (39), and influenza (16) viruses. There are reports regarding the ability of the cystatin family to prevent viral replication, in which the antiviral activities of several cystatins were evaluated by inhibiting the cysteine protease activities of viruses (1,2,4,24). The HSV-1 tegument protein VP1-2 must be cleaved by a serine or cysteine protease in order for the viral DNA to be released into the nucleus (12).…”

Lysosomal membrane permeabilization in cell death

“…In addition, several viral proteins such as Nef from human immunodeficiency virus-1, protein U7 from human papillomavirus type-16, parvovirus H1 and herpes simplex virus infection induce LMP-and cathepsin-dependent cell death (Kaznelson et al, 2004;Di Piazza et al, 2007;Laforge et al, 2007). Cystatin C can block the enhanced CB activity observed in herpes simplex virus type-1-infected cells and concomitantly inhibits herpes simplex virus type-1 replication and host cell apoptosis (Peri et al, 2007). The protein E7 encoded by human papillomavirus type-16 can induce caspase-dependent apoptosis in different cell lines.…”

Differential Analysis of the Secretome of WRL68 Cells Infected with the Chikungunya Virus

“…CTS3 is a secreted cysteine protease inhibitor extensively distributed in the extracellular matrix. It functions in the regulation of apoptosis and exert inhibitory effects against viral replication and RNA virus induced apoptosis [31, 32]. The observed decrease in abundance of CTS3, together with the cathepsins, may have an effect in promoting CHIKV dissemination.…”