Recombinant Human Papilloma Virus type 33 L1 protein (VLP)

Human papillomavirus (HPV) can be categorized into five genera: α, β, γ, μ, and ν. HPV α and γ genera infect the skin and mucous membrane tissues, while β, μ, and ν genera infect the skin area. High-risk HPVs that can cause cancer belong to the α genus, such as HPV33. HPV is an unenveloped epitheliotropic virus with an icosahedron of 72 capsomers on the outside and a double-stranded circular DNA genome on the inside. The HPV genome is divided into three regions: early (E), late (L), and long control region (LCR), with the E region encoding early proteins responsible for replication, transcription, viral release, and the creation of favorable conditions for the virus. The L region encodes the L1 and L2 capsid proteins, with L2 being more conserved than the L1 genome, and the non-coding LCR being involved in viral replication and gene expression regulation.

The virus reaches the basal lamina through subtle wounds in the epithelium, and HPV can only infect dividing keratin-forming cells of the basal lamina. First the major capsid protein L1 binds to laminin-332 on the basement membrane, which is subsequently cleaved by KLK8 leading to a conformational change, followed by fusion of L1 with heparan sulfate proteoglycans (HSPGs). Interaction between positively charged lysine residues in L1 and negatively charged HSPGs further affects the conformation of L1 and L2, exposing the N-terminus of the L2 protein to furin cleavage in the presence of CyPB, which leads to a decrease in the affinity of capsid protein for HSPGs. Subsequently L2 mediates the endocytosis of HPV into cells in a clathrin protein-independent form. Upon entry into the cell, viral DNA is released from the capsid and transported to the nucleus, where it takes advantage of the rupture of the nuclear membrane at the beginning of mitosis to enter the nucleus. Vesicles containing viral DNA, L2 and possibly L1, are transported along microtubules, attached to the mitotic chromatin, and at the end of mitosis become part of newly formed promyelocytic leukemia nucleosomes (PML NBs), which protect the viral DNA from damage by host restriction endonucleases. The L1 and L2 genes are expressed in the upper layer of terminally differentiated cells of epithelial cells.

Figure 1. The life cycle of HPV
(Source: Mlynarczyk-Bonikowska B, et al. 2024)

Persistent HPV infection is necessary for the development of cervical cancer, but the disease can be prevented by vaccination and regular screening. The L1 protein was chosen as the centerpiece of HPV vaccine development due to its ability to form virus-like particles (VLPs) on its own, and almost all available HPV prophylactic vaccines contain recombinant L1 protein. The HPV vaccine currently on the market prevents more than 90% of cervical, vulvar, and penile intraepithelial neoplasia caused by the HPV types covered by the vaccine.

Human Papilloma Virus 33 L1 protein
HPV 33 L1 protein