Human Papillomavirus infectious uptake is facilitated through A2t
I started out my career in laboratory of Dr. W Martin Kast studying the basic science behind Human Papillomavirus uptake and infection through the Annexin A2 heterotetramer (A2t).
As a brief summary of the viral life cycle of HPV: microwound formations caused by sexual activity or a chemical disruption of the epidermis facilitate the seeding of HPV allowing viral access to the basement membrane and the target basal cells. Successful infection of this cell type marks the the beginning of the replication cycle of HPV, which is highly dictated by the changing mRNA profiles of the epithelial cells as they mature and are pushed towards the upper layers of the tissue. Progeny virus is then shed from the surface of infected epithelium and then can re-infect the host or are passed onto another person.
The Basic Science Behind HPV Uptake
After microwound formation and successful localization of the virus to the basement membrane, HPV undergoes a series of interactions with different proteins found on the surface of basal cells. These interactions lead to several key events including a conformational change that enhances the affinity of the virus to its uptake receptor due to an increased exposure of the L2 capsid protein. This receptor, the Annexin A2/S100A10 heterotetramer (A2t), is highly expressed by epithelial cells at the basal layer (figure on left, adapted from Pena-Alonso et al 2007), and can interact specifically with the L2 capsid protein through its S100A10 subunit (1).
After capsid binding and internalization, A2t has been shown to aid in endosomal escape and facilitate intracellular trafficking of the viral genome to the nucleus of the cell (2). What makes this area of work so exciting is that we now have a direct way to target and prevent the initial steps requisite for HPV infection, which not only could help prevent the spread of the virus through the population but could also be used as a therapeutic measure to prevent persistent infection and help patients clear the virus.
This initial identification of A2t as an uptake receptor and several associated studies then lead to my Master’s Thesis work, a study which provided a molecular mechanism that explained nearly 50 years worth of epidemiologic data linking the Herpes Simplex Virus with HPV-induced cancers.
1. Woodham, A.W., Da Silva, D.M., Skeate, J.G., Raff, A.B., Ambroso, M.R., Brand, H.E., Isas, M., Langen, R., & Kast, W.M. (2012). The S100A10 Subunit of the Annexin A2 Heterotetramer Facilitates L2-Mediated Human Papillomavirus Infection. PLoS ONE 7, e43519.
2. Dziduszko, A. & Ozbun, M. A. (2013). Annexin A2 and S100A10 Regulate Human Papillomavirus Type 16 Entry and Intracellular Trafficking in Human Keratinocytes. J Virol 87, 7502-7515.