Role of DC‐SIGN in the activation of dendritic cells by HPV‐16 L1 virus‐like particle vaccine

Abstract

Dendritic cell-specific intercellular adhesion molecule-grabbing non-integrin (DC-SIGN), a specific C-type lectin expressed on DC, binds and transmits different pathogens to susceptible cells. In the present study, we examined the role of DC-SIGN in the capture of human papillomavirus (HPV) pseudovirions and activation of DC. We demonstrate that HPV virus-like particles (VLP) bind to DC-SIGN expressed on transfected Raji cells and that antibodies against DC-SIGN block this interaction. DC take up VLP, which activate expression of costimulatory markers and cytokines/ chemokines. Although our results indicate that DC-SIGN is not the major receptor for VLP in DC, this interaction contributes to the activation of DC surface antigens (HLA class I) and of various cytokines/chemokines, particularly TNF-a, IL-6, and RANTES. Induction of these markers in DC by VLP was significantly abrogated when binding to DC-SIGN was blocked by anti-DC-SIGN antibodies. These results suggest that DC-SIGN has a functional role in DC activation induced by HPV-16 L1-VLP, and thus highlight new aspects of DC interactions with HPV VLP. IntroductionThe C-type lectin dendritic cell-specific intercellular adhesion molecule-grabbing non-integrin (DC-SIGN; CD209) is a pathogen recognition receptor that interacts with mannose residues of glycoproteins in a calciumdependent manner via its C-terminal carbohydrate recognition domain [1,2]. DC-SIGN acts both as an adhesion molecule and pathogen recognition receptor, facilitating DC binding and internalization of several viruses, including HIV-1 [3].In addition to HIV, DC-SIGN was recently shown to bind a variety of microorganisms such as CMV [4], Ebola virus [5], Dengue virus [6], hepatitis C virus [7,8], simian immunodeficiency virus [9], Leishmania [10], Candida albicans [11], Mycobacterium [12][13][14] and Schistosoma [15]. Some pathogens subvert DC functions to escape immune surveillance [16]. DC-SIGN is abundantly expressed primarily on DC, including those derived from monocytes and those located beneath the genital surface [3].Human papillomavirus (HPV) virus-like particles (VLP) are a promising vaccine candidate for HPV and cervical cancer [17][18][19][20]. Recent clinical trials have shown that VLP afford excellent protection against persistent infection [20,21]. Because of the lack of a suitable cell culture system for in vitro propagation of HPV and the unavailability of virions, HPV VLP have been used as soluble surrogates for native virus particles. The routes of HPV-16 L1-VLP entry in DC and the nature of cellular receptors involved in capture have been studied but remain to be fully characterized. HPV VLP Here, we report that HPV-16 L1-VLP particles bind to DC-SIGN in transfected cell lines, and to a lesser extent in DC, and that this interaction participates in L1-VLPinduced activation of DC. Thus, DC-SIGN is likely involved in DC activation by HPV VLP. Results and discussion HPV L1-VLP bind to DC-SIGN in DC-SIGN-transfected cell linesTo study interactions between L1-VLP and DC-SIGN, we...

Cytokine and Chemokine Profiles following Vaccination with Human Papillomavirus Type 16 L1 Virus-Like Particles

“…The pattern of cytokine expression observed in this study is in agreement with results demonstrating the ability L1 VLP to induce potent B cell responses and dendritic cell activation (2,6,8,16,17,20,27). Alternatively, cytokine responses to L1 VLP observed prior to vaccination and in some of the placebo recipients during the study could be due to natural HPV infection that resulted in priming of the PBMCs to the L1 HPV antigens.…”

Noninfectious papilloma virus–like particles inhibit HIV-1 replication: implications for immune control of HIV-1 infection by IL-27

“…TLR signaling links the innate and adaptive arms of immune response against invading pathogens 50,51 and induces anti-HIV-1 cytokines such as IFN-␣, IL-10, IFN-␥, and MCP-2. 27,28 In the present study, we demonstrated that VLPs can bind to monocytes/ macrophages and induced a novel anti-HIV-1 cytokine, IL-27. To X4-infected CD4 ϩ T cells were cultured for 7 days in the absence or presence of 100 ng/mL recombinant IL-27.…”

“…26 Recent studies demonstrate that human papillopma virus-like particles (HPV-VLPs) bind to dendritic cells and are able to induce a range of responses in immune cells, notably the expression of anti-HIV-1 cytokines such as interferon-␣ (IFN-␣), interleukin-10 (IL-10), interferon-␥ (IFN-␥), and monocyte chemotactic protein 2 (MCP-2). 27,28 The HPV-VLP vaccine has been demonstrated to be protective against HPV infection. 29-31 HPV-type 16 (HPV16) represents the primary causative agent of cervical cancer.…”

Baculovirus-Derived Human Immunodeficiency Virus Type 1 Virus-Like Particles Activate Dendritic Cells and Induce Ex Vivo T-Cell Responses

“…The apparent discordance of these results could be due to a different optimal timing for the sample collection and needs to be evaluated by more extensive observations. Nevertheless, the production of IFN-␥ by DCs induced with enveloped or nonenveloped VLP produced in different expression systems (prokaryotic, yeast, and baculovirus) is still a debated issue (18,28,30,49,53,54). In particular, Yang et al (53), reported that the CD8␣ ϩ…”