Herpes simplex virus downregulation of secretory leukocyte protease inhibitor enhances human papillomavirus type 16 infection

Abstract

Herpes simplex virus (HSV) was originally implicated in the aetiology of cervical cancer, and although high-risk human papillomavirus (HPV) is now the accepted causative agent, the epidemiological link between HSV and HPV-associated cancers persists. The annexin A2 heterotetramer (A2t) has been shown to mediate infectious HPV type 16 (HPV16) uptake by human keratinocytes, and secretory leukocyte protease inhibitor (SLPI), an endogenous A2t ligand, inhibits HPV16 uptake and infection. Interestingly, HSV infection induces a sustained downregulation of SLPI in epithelial cells, which we hypothesized promotes HPV16 infection through A2t. Here, we show that in vitro infection of human keratinocytes with HSV-1 or HSV-2, but not with an HSV-1 ICP4 deletion mutant that does not downregulate SLPI, leads to a .70 % reduction of SLPI mRNA and a .60 % decrease in secreted SLPI protein.Consequently, we observed a significant increase in the uptake of HPV16 virus-like particles and gene transduction by HPV16 pseudovirions (two-and 2.5-fold, respectively) in HSV-1-and HSV-2-infected human keratinocyte cell cultures compared with uninfected cells, whereas exogenously added SLPI reversed this effect. Using a SiMPull (single-molecule pulldown) assay, we demonstrated that endogenously secreted SLPI interacts with A2t on epithelial cells in an autocrine/paracrine manner. These results suggested that ongoing HSV infection and resultant downregulation of local levels of SLPI may impart a greater susceptibility for keratinocytes to HPV16 infection through the host cell receptor A2t, providing a mechanism that may, in part, provide an explanation for the aetiological link between HSV and HPV-associated cancers.

Secretory Leukocyte Protease Inhibitor Expression and High-Risk HPV Infection in Anal Lesions of HIV-Positive Patients

“…17,18 Conversely, reductions in the amount of SLPI secreted by epithelial cells was shown to promote HPV16 infection through annexin A2 in vitro . 19 …”

ФЕНОТИПОВИЙ СКЛАД ЛІМФОЦИТІВ ПЕРИФЕРИЧНОЇ КРОВІ У ХВОРИХ НА ПАПІЛОМАВІРУСНУ ІНФЕКЦІЮ ШИЙКИ МАТКИ, В ЯКИХ ВИЯВЛЯЛИ IgG АНТИТІЛА ДО ВІРУСІВ ПРОСТОГО ГЕРПЕСУ

“…Cofactor action of Herpesviruses in HPV-induced tumor diseases is connected not only with their influence on HPV oncoproteins Е6 and та Е7 [13] but inflammation [14] and immune suppression development [15]. Genital herpes is one of the most wide-spread common disease with sexual way of transmission, and differs from other disease of this group by its life carriage.…”

Secretory leukocyte protease inhibitor and its role in virus induced head and neck cancers

“…Do kraja 1970-ih smatralo se da je etiološki agens u cervikalnom i oralnom karcinomu Herpes Simplex virus. Iako je visokorizični HPV sada identifikovan kao uzrok karcinoma grlića materice, HSV se smatra važnim kofaktorom u njegovoj pojavi 24 . Svetska prevalencaija OSCC-a, koja je bila pozitivna za HSV-1, bila je oko 15%; najveća prevalenca ija od 55% zabeležena je u Velikoj Britaniji.…”

“…Ispitanici pozitivni na HPV infekciju koji su takođe seropozitivni na HSV -1 imaju dvostruko veći rizik od razvoja karcinoma skvamoznih ćelija u poređenju sa HSV -1-seronegativnim osobama sa sličnom izloženošću HPV-u. Ovi nalazi pokazuju da HSV i HPV mogu delovati sinergistički u razvoju karcinoma 24 .…”