A Major Role for the Minor Capsid Protein of Human Papillomavirus Type 16 in Immune Escape

Fahey, Laura; Raff, Adam B.; Silva, Diane M. Da; Kast, W. Martin

doi:10.4049/jimmunol.0902145

Cited by 47 publications

(68 citation statements)

References 31 publications

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“…Similar to what we have previously observed on epithelial cells, L1 VLP enter LC less efficiently than L1L2 VLP (Fig. 2A) (38, 40). Notably, similar internalization was observed between baseline L1 VLP internalization and SLPI-blocked L1L2 VLP internalization, suggesting that when A2t is blocked, the L1L2 VLP may default to a pathway utilized by L1 VLP.…”

Section: Resultssupporting

confidence: 90%

“…Collectively, these studies suggest that a specific L2 receptor and receptor-specific mechanism exist for HPV16 uptake into LC. (23, 40), and our previous report points to A2t as a potential candidate as it is the only identified L2-specific receptor (38). A2t is found at the cell surface as a heterotetramer consisting of two annexin A2 (anxA2) monomers and an S100A10 dimer (43–46), which are co-expressed by LC (47).…”

Section: Introductionmentioning

confidence: 87%

“…Interestingly, the presence of L2 in the viral capsid has been shown to double the rate of HPV16 entry into LC, and is responsible for HPV16-induced suppression of LC immune function (40). To date, no specific L2 receptor on LC has been identified.…”

Section: Introductionmentioning

confidence: 99%

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Inhibition of Langerhans Cell Maturation by Human Papillomavirus Type 16: A Novel Role for the Annexin A2 Heterotetramer in Immune Suppression

Woodham

Raff

et al. 2014

The Journal of Immunology

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High-risk human papillomaviruses (HPV) are sexually transmitted viruses causally associated with several cancers. During its natural life cycle, HPV16, the most common high-risk genotype, infects the epithelial basal cellsin a process facilitated through a recently identified receptor, the annexin A2 heterotetramer (A2t). During infection, HPV16 also interacts with Langerhans cells (LC), the antigen presenting cells of the epithelium, inducing immune suppression, which is mediated by the HPV16 L2 minor capsid protein. Despite the importance of these virus-immune cell interactions, the specific mechanisms of HPV16 entry into LC and HPV16-induced immune suppression remain undefined. An N-terminal peptide of HPV16 L2 (aa 108-126) has been shown to specifically interact with A2t. Here, we show that incubation of human LC with this peptide blocks binding of HPV16. Inhibiting this interaction with an A2t ligand or by siRNA downregulation of A2t, significantly decreases HPV16 internalization into LC in an L2-dependent manner. A2t is associated with suppression of LC maturation as demonstrated through attenuated secretion of Th1-associated cytokines and decreased surface expression of MHC II on LC exposed to A2t. Conversely, small molecule inhibition of A2t prevents HPV16-induced suppression of LC immune function as indicated by significantly increased secretion of inflammatory cytokines and surface expression of CD86 in HPV16 treated LC pre-exposed to A2t inhibitors. These results demonstrate that HPV16 suppresses LC maturation through an interaction with A2t, revealing a novel role for this protein.

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Section: Resultssupporting

confidence: 90%

Section: Introductionmentioning

confidence: 87%

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Inhibition of Langerhans Cell Maturation by Human Papillomavirus Type 16: A Novel Role for the Annexin A2 Heterotetramer in Immune Suppression

Woodham

Raff

et al. 2014

The Journal of Immunology

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“…The uptake of HPV VLPs by Langerhans cells can trigger immunesuppressing or activating responses. The minor capsid protein L2 in VLPs and pseudoviruses is responsible for preventing functional maturation of skin Langerhans cells leading to a potential local immune escape for HPV infection [24]. In the absence of L2, HPV VLP antigens potently activate both antigen-presenting cells and subsequent adaptive immunity including humoral and CD8+ cytotoxic T lymphocytes (CTLs).…”

Section: Immunization To Activate Innate Immunity To Hpv Infections Amentioning

confidence: 99%

Vaccines and Immunization against Human Papillomavirus

Christensen

Budgeon²

2014

Human Papillomavirus

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Prophylactic and therapeutic immunization strategies are an effective method to control human papillomavirus (HPV)-associated diseases and cancers. Current protective virus-like particle and capsid-based vaccines are highly protective against vaccine-matched HPV types, and continued improvements in second-generation vaccines will lead to broader protection and cross-protection against the cancer-associated types. Increasing the effectiveness of broadly cross-protective L2-based immunogens will require adjuvants that activate innate immunity to thus enhance adaptive immunity. Therapeutic immunization strategies are needed to control and cure clinical disease and HPV-associated cancers. Significant advances in strategies to improve induction of cell-mediated immunity to HPV early (and capsid) proteins have been pretested in preclinical animal papillomavirus models. Several of these effective protocols have translated into successful therapeutic immune-mediated clearance of clinical lesions. Nevertheless, there are significant challenges in activating immunity to cancer-associated lesions due to various immune downregulatory events that are triggered by persistent HPV infections. A better understanding of immune responses to HPV lesions in situ is needed to optimize immune effector T cells that efficiently locate to sites of infection and which should lead to an effective immunotherapeutic management of this important human viral pathogen. The most effective immunization strategy may well require combination antiviral and immunotherapeutic treatments to achieve complete clearance of HPV infections and associated cancers.

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“…La protéine L2 de la capside facilite à la fois l'infection en se liant à un récepteur de la membrane de la cellule épithéliale mais inhibe aussi l'activation des cellules de Langerhans [76]. Ces dernières ne peuvent alors jouer leur rôle de présentatrices pour initier une réponse des lymphocytes T [77][78][79].…”

Section: Infections à Papillomavirusunclassified

Immunité innée et adaptative du tractus génital féminin

Lepargneur¹,

Abbal²

2012

Journal de Gynécologie Obstétrique et Biologie de la Reproducti

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A Major Role for the Minor Capsid Protein of Human Papillomavirus Type 16 in Immune Escape

Cited by 47 publications

References 31 publications

Inhibition of Langerhans Cell Maturation by Human Papillomavirus Type 16: A Novel Role for the Annexin A2 Heterotetramer in Immune Suppression

Inhibition of Langerhans Cell Maturation by Human Papillomavirus Type 16: A Novel Role for the Annexin A2 Heterotetramer in Immune Suppression

Vaccines and Immunization against Human Papillomavirus

Immunité innée et adaptative du tractus génital féminin

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