title: Papillomavirus capsid mutation to escape dendritic cell-dependent innate immunity in cervical cancer.
abstract: Infection with oncogenic human papillomaviruses (HPVs), typified by HPV type 16 (HPV16), is a necessary cause of cervical cancer. Prophylactic vaccination with HPV16 L1 virus-like particles (VLPs) provides immunity. HPV16 VLPs activate dendritic cells and a potent neutralizing immunoglobulin G (IgG) response, yet many cervical cancer patients fail to generate detectable VLP-specific IgG. Therefore, we examined the role of the innate recognition of HPV16 L1 in VLP-induced immune responses and its evasion during carcinogenesis. Nonconservative mutations within HPV16 L1 have been described in isolates from cervical cancer and its precursor, high-grade cervical intraepithelial neoplasia (CIN). We determined the effect of mutations in L1 upon in vitro self-assembly into VLPs and their influence upon the induction of innate and adaptive immune responses in mice. Several nonconservative mutations in HPV16 L1 isolated from high-grade CIN or cervical carcinoma prevent self-assembly of L1 VLPs. Intact VLPs, but not assembly-defective L1, activate dendritic cells to produce proinflammatory factors, such as alpha interferon, that play a critical role in inducing adaptive immunity. Indeed, effective induction of L1-specific IgG1 and IgG2a was dependent upon intact VLP structure. Dendritic cell activation and production of virus-specific neutralizing IgG by VLPs requires MyD88-dependent signaling, although the L1 structure that initiates MyD88-mediated signaling is distinct from the neutralizing epitopes. We conclude that innate recognition of the intact L1 VLP structure via MyD88 is critical in the induction of high-titer neutralizing IgG. Tumor progression is associated with genetic instability and L1 mutants. Selection for assembly-deficient L1 mutations suggests the evasion of MyD88-dependent immune control during cervical carcinogenesis.
authors.affiliation: Department of Pathology, The Johns Hopkins School of Medicine, 720 Rutland Avenue, Baltimore, MD 21205, USA.
authors.forename: Rongcun
authors.initials: R
authors.lastname: Yang
authors.forename: Cosette M
authors.initials: CM
authors.lastname: Wheeler
authors.forename: Xiaojiang
authors.initials: X
authors.lastname: Chen
authors.forename: Satoshi
authors.initials: S
authors.lastname: Uematsu
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Takeda
authors.forename: Shizuo
authors.initials: S
authors.lastname: Akira
authors.forename: Diana V
authors.initials: DV
authors.lastname: Pastrana
authors.forename: Raphael P
authors.initials: RP
authors.lastname: Viscidi
authors.forename: Richard B S
authors.initials: RB
authors.lastname: Roden
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000914:Antibodies, Viral / Q000096:biosynthesis; D000943:Antigens, Differentiation / Q000235:genetics; D036022:Capsid Proteins / Q000737:chemistry / Q000235:genetics* / Q000276:immunology* / Q000502:physiology; D003713:Dendritic Cells / Q000276:immunology*; D005260:Female; D005814:Genes, Viral; D006801:Humans; D007113:Immunity, Innate; D017578:Immunoglobulin Class Switching; D007074:Immunoglobulin G / Q000096:biosynthesis; D007371:Interferon-gamma / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008958:Models, Molecular; D009154:Mutation; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B / Q000378:metabolism; D009500:Neutralization Tests; D009856:Oncogene Proteins, Viral / Q000737:chemistry / Q000235:genetics* / Q000276:immunology* / Q000502:physiology; D027383:Papillomaviridae / Q000235:genetics* / Q000276:immunology* / Q000472:pathogenicity; D030361:Papillomavirus Infections / Q000276:immunology* / Q000821:virology*; D011487:Protein Conformation; D011971:Receptors, Immunologic / Q000172:deficiency / Q000235:genetics; D015398:Signal Transduction; D002583:Uterine Cervical Neoplasms / Q000276:immunology* / Q000821:virology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000914:Antibodies, Viral; D000943:Antigens, Differentiation; D036022:Capsid Proteins; D007074:Immunoglobulin G; C507779:MYD88 protein, human; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; D009856:Oncogene Proteins, Viral; D011971:Receptors, Immunologic; C063317:L1 protein, Human papillomavirus type 16; D007371:Interferon-gamma