Advances in Targeting HPV Infection as Potential Alternative Prophylactic Means

Abstract

Infection by oncogenic human papillomavirus (HPV) is the primary cause of cervical cancer and other anogenital cancers. The majority of cervical cancer cases occur in low- and middle- income countries (LMIC). Concurrent infection with Human Immunodeficiency Virus (HIV) further increases the risk of HPV infection and exacerbates disease onset and progression. Highly effective prophylactic vaccines do exist to combat HPV infection with the most common oncogenic types, but the accessibility to these in LMIC is severely limited due to cost, difficulties in accessing the target population, cultural issues, and maintenance of a cold chain. Alternative preventive measures against HPV infection that are more accessible and affordable are therefore also needed to control cervical cancer risk. There are several efforts in identifying such alternative prophylactics which target key molecules involved in early HPV infection events. This review summarizes the current knowledge of the initial steps in HPV infection, from host cell-surface engagement to cellular trafficking of the viral genome before arrival in the nucleus. The key molecules that can be potentially targeted are highlighted, and a discussion on their applicability as alternative preventive means against HPV infection, with a focus on LMIC, is presented.

Keywords: cervical cancer; human papillomavirus (HPV); low- and middle- income countries (LMIC); prophylactic vaccines.

Figure 1

Schematic illustration of the early stages of human papillomavirus (HPV) infection, indicating the sites of inhibition of various anti-HPV molecules. Briefly: binding to heparan sulfate proteoglycans (HSPGs) results in conformational changes of the viral capsid, which facilitates interactions between the capsid and cyclophilin B (CyPB) and cleavage by kallikrein-8 (KLK8). This results in the exposure of the L2 N-terminus, containing a conserved site which is cleaved by furin. This is followed by dissociation of the capsid from HSPGs and exposure of a binding site in L1, potentially needed for recognition by an unknown entry receptor complex. The viral capsid undergoes ligand induced endocytosis (which is clathrin-, caveolin-, cholesterol- and dynamin-independent) and depends on the reorganization of the actin cytoskeleton. Membrane protrusion of the L2 capsid protein is chaperoned by γ-secretase, which allows L2 to interact with host cell factors in the cytosol during transport. HPVs localize with early antigen 1 (EEA10) compartments in a Rab5 GTPase-dependent manner. The early endosome matures into the late endosome when it fuses with lysosomes. Lysosomal degradation is driven by the formation of multivesicular bodies (MVBs). Most of the contents are degraded by lysosomal degradation, including the majority of the L1 capsid protein. Endosomal escape and subsequent post-endocytic trafficking of high-risk HPVs is regulated by CD63-syntenin-1-ALIX, which traffics HPV to these multivesicular endosomes. Here, the capsids disassemble in a pH-dependent manner, and egress from the late endosome. The L2/vDNA cargo enters the TGN, where the protruding L2 protein interacts with SNX17, SNX27 and retromer complex.