Document text
Principal Investigator: Asok Antony
Organization: RLR VA MEDICAL CENTER
Fiscal Year: 2021
Funding agency: Veterans Affairs
Despite the advent of effective anti-Human Papillomavirus (HPV) vaccines, there are no biological agents to
reliably prevent ~80 million Americans from transmitting their infectious HPV viral particles to sexual partners.
Earlier we determined that the post-translational homocysteinylation of an mRNA-binding protein
(heterogenous nuclear ribonucleoprotein-E1, hnRNP-E1) can transform hnRNP-E1 into a moiety with high
affinity for a HPV16 57-nucleotide (nt) RNA cis-element under conditions of folate deficiency; this interaction
led to a profound inhibition of both HPV16 L1 and L2 viral capsid proteins that are essential for HPV16-
encapsidation (and infectivity). We have patented a powerful mutant of hnRNP-E1 [DomPos-E1(C293S)] that
functions like homocysteinylated-hnRNP-E1 under folate-replete conditions. Because DomPos-E1(C293S)] has
such a strong likelihood to eliminate HPV16 viral capsid proteins and thereby function as an anti-HPV agent, we
wish to test its therapeutic potential both in vitro and in our novel HPV16-xenograft model in Beige Nude mice.
In Specific Aim 1 we will compare effects of the interaction of DomPos-E1(C293S)-protein [relative to
control wild-type(wt)-like-E1(G292A)-proteins] with HPV16 57-nt cis-element in eliminating HPV16 L1 and L2
viral capsid protein expression. We will also extend these studies to assess the interaction of DomPos-E1(C293S)
with similar cis-elements from low risk HPV6 and 11 and high-risk types (HPV18, 31, 33, 45, 52, 58). Next, we
will confirm the greater impact of DomPos-E1(C293S)- over control wt-like-E1(G292A)- expression in reducing
HPV16 L1 and L2 after stable transduction into HPV16-harboring keratinocytes that are also transformed into
HPV16-organotypic rafts; then we can evaluate the extent in reduction of infectious HPV16 viral particles in 18-
day old rafts and whether there is any increase in genomic integration by amplified capsid-less HPV16 episomes.
In Specific Aim 2, we will subcutaneously implant these DomPos-E1(C293S)- or control wt-like-
E1(G292A))- expressing rafts in Beige Nude mice using our recently published model. This will allow us to assess
the relative effects of DomPos-E1(C293S)- over control wt-like-E1(G292A) in reducing both HPV16 viral capsid
proteins and infectious viral particles of HPV16 over the ensuing 8 weeks in vivo; evaluating if this reduces the
capacity of the implanted HPV16-raft to auto-infect itself; determining changes in genomic integration by
amplified capsid-less HPV16 episomes; and in prolonging the expected time of rafts to develop HPV16-cancers.
In Specific Aim 3, we will determine if DomPos-E1(C293S) is significantly more effective than control wt-
like-E1(G292A) in preventing transmission of HPV16 to adjacent tissue. We will adapt our in vivo model to assess
HPV16-infectivity wherein the effectiveness of transmission of infectious HPV16 from one donor tissue to an
uninfected recipient tissue is assessed over 8 weeks in Beige Nude mice.
These studies will help determine if DomPos-E1(C293S) or its mutant derivatives can be moved forward
as first-in-class agents to help reduce transmission of infectious HPV16 viral particles from an infected host.
Terms: <Affinity><American><Assay><Athymic Mice><Athymic Nude Mouse><Binding Proteins><Bioassay><Biologic Assays><Biologic Products><Biological Agent><Biological Assay><Biological Products><Body Tissues><Cancer Model><CancerModel><Cancers><Capsid><Capsid Protein L2><Capsid Proteins><Cell Body><Cells><Coat Proteins><Development><Dose><Effectiveness><Elements><Episome><Exhibits><Folate><Folic Acid><Folic Acid Deficiency><Gel><Generations><Genital><Genital Organs><Genitalia><Genitourinary><Genitourinary system><Genomics><HPV><HPV 16><HPV 18><HPV 6><HPV L2><HPV L2 oncogene viral capsid protein><HPV Vaccine><HPV infection><HPV-16><HPV-18><HPV-High Risk><HPV16><HPV18><HPV6><Heterogeneous-Nuclear Ribonucleoproteins><High Risk Oncogenic HPV><High risk HPV><High risk Human Papillomavirus><High risk Human papilloma virus><Histology><Human Papilloma Virus><Human Papilloma Virus Vaccine><Human Papillomavirus><Human papilloma virus 6><Human papilloma virus infection><Human papilloma virus type 16><Human papilloma virus type 18><Human papilloma virus type 6><Human papillomavirus 16><Human papillomavirus 18><Human papillomavirus 6><Human papillomavirus Vaccine><Human papillomavirus infection><Human papillomavirus type 16><Human papillomavirus type 18><Human papillomavirus type 6><Implant><In Vitro><Individual><Infection><Infectious Human Wart Virus><Informofer><L2 viral capsid protein><Legal patent><Ligand Binding Protein><Ligand Binding Protein Gene><Low risk HPV><Low risk Human Papillomavirus><Low risk Human papilloma virus><Malignant Neoplasms><Malignant Oropharyngeal Neoplasm><Malignant Oropharyngeal Tumor><Malignant Tumor><Messenger RNA><Modeling><New Agents><Newly Diagnosed><Non-Polyadenylated RNA><Nuclear><Nucleotides><Nude Mice><Oncogenic><Oropharnyx Cancers><Oropharyngeal><Oropharyngeal Cancer><Oropharyngeal Carcinoma><Oropharynx><Oropharynx Cancer><Oropharynx Carcinoma><Oropharynxs><Patents><Protein Binding><Proteins><Pteroylglutamic Acid><Publishing><RNA><RNA Gene Products><RNA-Protein Interaction><Reporter><Ribonucleic Acid><Ribonucleoproteins><Risk><Role><Safety><Sexual Partners><Sexual Transmission><Standardization><Teen><Teenagers><Testing><Therapeutic><Time><Tissue Donors><Tissues><Transmission><Urogenital><Urogenital System><Veterans><Viral><Viral Coat Proteins><Viral Outer Coat Protein><Virion><Virus><Virus Particle><Vitamin M><Xenograft Model><biopharmaceutical><biotherapeutic agent><bound protein><density><developmental><experiment><experimental research><experimental study><folate deficiency><high risk><hnRNP><human papilloma virus 16><human papilloma virus 18><human papilloma virus L2><human papillomavirus L2><implantation><in vivo><in vivo Model><innovate><innovation><innovative><keratinocyte><mRNA><malignancy><malignant oropharynx neoplasm><malignant oropharynx tumor><mouse model><murine model><mutant><neoplasm/cancer><novel><oral pharyngeal><particle><prevent><preventing><protein expression><response><sex partner><sexually transmitted><social role><subcutaneous><subdermal><teen years><teenage><transmission process><tumor><type 16 Human papilloma virus><type 16 Human papillomavirus><viral transmission><virus transmission><vitamin Bc><wart virus><xenograft transplant model><xenotransplant model>