α-Defensin HD5 Inhibits Human Papillomavirus 16 Infection via Capsid Stabilization and Redirection to the Lysosome.

Mayim E Wiens,Jason G Smith,Michael J Imperiale

doi:10.1128/mbio.02304-16

Abstract

ABSTRACTα-Defensins are an important class of abundant innate immune effectors that are potently antiviral against a number of nonenveloped viral pathogens; however, a common mechanism to explain their ability to block infection by these unrelated viruses is lacking. We previously found that human defensin 5 (HD5) blocks a critical host-mediated proteolytic processing step required for human papillomavirus (HPV) infection. Here, we show that bypassing the requirement for this cleavage failed to abrogate HD5 inhibition. Instead, HD5 altered HPV trafficking in the cell. In the presence of an inhibitory concentration of HD5, HPV was internalized and reached the early endosome. The internalized capsid became permeable to antibodies and proteases; however, HD5 prevented dissociation of the viral capsid from the genome, reduced viral trafficking to the trans-Golgi network, redirected the incoming viral particle to the lysosome, and accelerated the degradation of internalized capsid proteins. This mechanism is equivalent to the mechanism by which HD5 inhibits human adenovirus. Thus, our data support capsid stabilization and redirection to the lysosome during infection as a general antiviral mechanism of α-defensins against nonenveloped viruses.

Highlights

ABSTRACT ␣-Defensins are an important class of abundant innate immune effectors that are potently antiviral against a number of nonenveloped viral pathogens; a common mechanism to explain their ability to block infection by these unrelated viruses is lacking
We tested a prediction of our finding that furin-cleaved virus, in which L2 is processed by furin during virus production, would be resistant to human defensin 5 (HD5); we found that fcHPV16 infection is still blocked by HD5
HD5 concentrations tested were based on previous studies of human papillomavirus (HPV) inhibition and are within the physiological range of HD5 secreted in the female genitourinary tract [2, 17, 18]

Summary

Introduction

ABSTRACT ␣-Defensins are an important class of abundant innate immune effectors that are potently antiviral against a number of nonenveloped viral pathogens; a common mechanism to explain their ability to block infection by these unrelated viruses is lacking. We reported that the ␣-defensin human defensin 5 (HD5) inhibited host furin cleavage of the minor capsid protein L2 of HPV16 at the cell surface and postulated that blocking this cleavage disrupted L2 functions required for productive infection [18]. The capsid proteins were degraded faster during infection in the presence of HD5 This mislocalization of the genome to the lysosome accounts for the inhibition of fcHPV16 as well as wild-type HPV16 and mirrors the effect of HD5 on AdV infection, suggesting that capsid stabilization followed by redirection of the genome to the lysosome is a general mechanism of nonenveloped virus inhibition

Methods

Results

Conclusion