Papillomavirus pathogenesis and treatment in WHIM syndrome

About This Grant

Project Summary/Abstract This proposed research project focuses on understanding the pathogenesis of papillomavirus infection in WHIM syndrome and how one can use the mechanisms to develop curative treatment to alleviate papillomavirus infection in WHIM syndrome. The proposed studies will form the foundation for a future research program that focuses on investigating underlying mechanisms of papillomavirus pathogenesis in WHIM and developing curative treatment for them to alleviate papillomavirus-related malignancies. Research: Mouse papillomavirus (MmuPV1) models high-risk human papillomavirus (HPV) infection and associated cancers in mice. This project will use MmuPV1 and a WHIM mutation knock-in mice to understand keratinocyte-intrinsic mechanism of WHIM mutation contributing to papillomavirus pathogenesis, as well as to test whether reversing leukopenia caused by the mutation will clear infection. To determine if rescuing leukopenia is sufficient to clear pre-existing infection, CRISPER/Cas9 will be used to inactivate WHIM allele in hematopoietic stem cells and test if edited hematopoietic stem cell transfer can cure or slow down papillomavirus-induced disease in infected unconditioned WHIM hosts. MmuPV1 and WHIM mutant mice become powerful pre-clinical disease model for WHIM patients and can provide informative data guiding future clinical testing. In addition to pre-clinical testing, this model will also be used to answer whether there is crosstalk between myeloid cells and lymphoid cells that are contributing to infection clearance. This question has been raised from a reported case of chromothriptic cure of WHIM syndrome where the patient spontaneously cleared warts with only recovered myeloid cell count while remained lymphopenia. It is hypothesized that mutation corrected myeloid cells can interact with lymphoid cells bearing WHIM mutation, recruiting them to infected sites to overcome lymphoid cell shortage to clear viral infection. In addition to immune cells, this project also aims to understand how WHIM mutation contributes to papillomavirus life cycle in infected keratinocytes. This project will use in vitro culture of primary mouse keratinocytes derived from WHIM mice and investigate how WHIM mutation affects newly infected MmuPV1 entry, maintenance and amplification. Drugs targeting affected pathways will be tested in vivo to determine if current approved drug for WHIM syndrome is sufficient to treat papillomavirus-related malignancies. The data generated by proposed studies will provide insights into how current CXCR4 inhibitor works, and help design strategies to cure papillomavirus-related malignancies, which is a significant cause of fatality in WHIM syndrome.