Human papillomaviruses (HPV) form a large family of viruses some of which are associated with various forms of cancer, including cervical carcinoma. They induce more than seven per cent of all cancers in women worldwide. Especially, HPV pose a burden to women in underdeveloped regions in the world due to a lack of access to cancer screening programs. The long term goal of this research is to understand early events of HPV infection with the focus on events occurring on the cell surface. The major capsid protein, L1, of HPV type 16 is primarily responsible for initial binding of virus to heparan sulfate proteoglycan (HSPG) present on cell surface and extracellular matrix (ECM). Attachment to HSPG induces a shift in the conformation of L1 and the minor capsid protein, L2, both of which we can now detect with monoclonal antibodies. X-ray structure analysis in collaboration with X. Chen identified several HSPG binding sites on the viral capsid. Our preliminary data suggest their sequential use in primary attachment and secondary binding events as well for inducing conformational shifts. In addition, we collected evidence for an involvement of Cyclophilin B (CyPB) in two distinct steps during HPV infection: mediating L2 conformational changes on the cell surface and facilitating uncoating of the viral genome.
Aim 1 will test our hypothesis that two HS binding sites on the viral capsid are sequentially used during cell surface events of HPV infection. This will be achieved by a structure-guided mutagenesis of HS binding sites.
Aim 2 is intended to delineate the function of Cyclophilins in HPV infection using siRNA knock down and small molecule inhibitors combined with biochemical and cell biological approaches.
Aim 3 is dedicated to understand the processes underlying the conformational shifts affecting both capsid proteins in molecular detail. Understanding these events in detail will allow the development of interfering strategies to fight HPV-induced malignant lesions.
HPV induce a variety of cancers, including cervical carcinoma. We will investigate how the virus exploits host cell factors for attachment to host cells and subsequent events leading to successful infection. This should allow identification of cellular targets for drug therapies to prevent HPV induced cancers.
|DiGiuseppe, Stephen; Bienkowska-Haba, Malgorzata; Guion, Lucile G M et al. (2017) Human papillomavirus major capsid protein L1 remains associated with the incoming viral genome throughout the entry process. J Virol :|
|Bienkowska-Haba, Malgorzata; Luszczek, Wioleta; Keiffer, Timothy R et al. (2017) Incoming human papillomavirus 16 genome is lost in PML protein-deficient HaCaT keratinocytes. Cell Microbiol 19:|
|DiGiuseppe, Stephen; Bienkowska-Haba, Malgorzata; Guion, Lucile G et al. (2017) Cruising the cellular highways: How human papillomavirus travels from the surface to the nucleus. Virus Res 231:1-9|
|DiGiuseppe, Stephen; Luszczek, Wioleta; Keiffer, Timothy R et al. (2016) Incoming human papillomavirus type 16 genome resides in a vesicular compartment throughout mitosis. Proc Natl Acad Sci U S A 113:6289-94|
|DiGiuseppe, Stephen; Bienkowska-Haba, Malgorzata; Sapp, Martin (2016) Human Papillomavirus Entry: Hiding in a Bubble. J Virol 90:8032-5|
|DiGiuseppe, Stephen; Keiffer, Timothy R; Bienkowska-Haba, Malgorzata et al. (2015) Topography of the Human Papillomavirus Minor Capsid Protein L2 during Vesicular Trafficking of Infectious Entry. J Virol 89:10442-52|
|Richards, Kathleen F; Mukherjee, Santanu; Bienkowska-Haba, Malgorzata et al. (2014) Human papillomavirus species-specific interaction with the basement membrane-resident non-heparan sulfate receptor. Viruses 6:4856-79|
|DiGiuseppe, Stephen; Bienkowska-Haba, Malgorzata; Hilbig, Lydia et al. (2014) The nuclear retention signal of HPV16 L2 protein is essential for incoming viral genome to transverse the trans-Golgi network. Virology 458-459:93-105|
|Spoden, Gilles; Kühling, Lena; Cordes, Nicole et al. (2013) Human papillomavirus types 16, 18, and 31 share similar endocytic requirements for entry. J Virol 87:7765-73|
|Sapp, Martin J (2013) HPV virions hitchhike a ride on retromer complexes. Proc Natl Acad Sci U S A 110:7116-7|
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