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

α-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. IMPORTANCE Although the antiviral activity of α-defensins against enveloped viruses can be largely explained by interference with receptor binding and fusion, a common mechanism for inhibition of nonenveloped viruses remains elusive. In studies of a prominent human α-defensin that is expressed in the gut and in the male and female genitourinary tract, we discovered striking parallels between the mechanisms of inhibition of HPV and human adenovirus infection. Thus, detailed studies of the impact of α-defensins on the intracellular trafficking of two disparate viruses support a general mechanism of α-defensin antiviral activity against nonenveloped viruses.