Original Article
Loading dendritic cells with gold nanoparticles (GNPs) bearing HIV-peptides and mannosides enhance HIV-specific T cell responses

https://doi.org/10.1016/j.nano.2017.11.009Get rights and content

Abstract

Gold nanoparticles (GNPs) decorated with glycans ameliorate dendritic cells (DC) uptake, antigen-presentation and T-cells cross-talk, which are important aspects in vaccine design. GNPs allow for high antigen loading, DC targeting, lack of toxicity and are straightforward prepared and easy to handle. The present study aimed to assess the capacity of DC to process and present HIV-1-peptides loaded onto GNPs bearing high-mannoside-type oligosaccharides (P1@HM) to autologous T-cells from HIV-1 patients. The results showed that P1@HM increased HIV-specific CD4+ and CD8+ T-cell proliferation and induced highly functional cytokine secretion compared with HIV-peptides alone. P1@HM elicits a highly efficient secretion of pro-TH1 cytokines and chemokines, a moderate production of pro-TH2 and significant higher secretion of pro-inflammatory cytokines such as TNF‐α and IL-1β. Thus, co-delivery of HIV-1 antigens and HM by GNPs is an excellent vaccine delivery system inducing HIV-specific cellular immune responses in HIV+ patients, being a promising approach to improve anti-HIV-1 vaccines.

Graphical Abstract

Schematic representation of ex vivo assays performed with formulations based on HLA-A*0201-restricted HIV-peptides and Mannosides co-conjugated to GNPs (P1@HM). P1@HM interaction, process and antigen presentation by DC derived from blood monocytes of HIV+ individuals, promotes T-cell proliferation of autologous lymphocytes obtained from the same HLA-A*0201 HIV-1+ individuals. P1@HM treatment consistently enhances highly functional pro-TH1 cytokines, pro-TH1 chemokines, pro-inflammatory cytokine and several pro-TH2 cytokines as important immune factors that could potentiate a high adjuvant effect in an HIV vaccine context.

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Section snippets

Ethics statement

This study received the approval of the Committee of Ethics and Clinical Investigation of the Hospital Clinic Universitari (Barcelona, Spain). All the subjects participating in the study were recruited at the Service of Infectious Diseases & AIDS Unit of this Hospital and gave their informed written consent.

Study individuals

Samples of EDTA-anticoagulated venous blood samples were obtained from 9 chronic asymptomatic HIV-1-infected patients HLA A*0201 positives with baseline CD4+ T cell counts >450 cells/mm3,

Preparation of GNPs bearing the HIV Gag p17 and CMV pp65 immunogenic peptides and mannosides or glucosides

In this work we have loaded gold nanoparticles (GNPs) with HIV-peptides or CMV-peptides and mannosides and challenged them through ex vivo assays with monocyte derived dendritic cells (MDDCs) and autologous lymphocytes from HIV + −infected patients in search for specific T cell responses (Figure 1, A).

GNPs compound were prepared using a well-established methodology. Briefly, KKWK tagged P1 and P2 HLA-A*0201-restricted peptides, from HIV and CMV, respectively (Figure 1, B) were covalently linked

Discussion

We found that MDDCs pulsed with nanoparticles P1@HM or P2@HM exhibit enhanced capacities in stimulating virus antigen-specific CD8+ and CD4+ T-cell proliferation. These results suggest that co-delivery of high mannose ligands (HM) with the HIV peptides antigen coated on GNPs has an enhanced adjuvant effect, inducing strong T cell proliferative responses following ex vivo pulsing and after full maturation of autologous DC, whereas no addition of maturation agents or GNPs without P1 or P2

Acknowledgments

We appreciate the help of L. Liz-Marzan with nanoparticles analysis, advice and preparation of the paper, Cristina Rovira and Carmen Hurtado for their technical assistance in sample processing.

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    Conflicts of interests: The authors have declared that no competing interest exists.

    This study was partially supported by grants: FIS PI12/00969, PI15/00480 and PI15/00641, from Plan Nacional de I+D and co-financed by ISCIII-Subdirección General de Evaluación and Fondo Europeo de Desarrollo, Regional (FEDER) RD16/0025/0002, SAF2013-45232-R, SAF2015-66193-R, RIS, and HIVACAT.

    RIS: Red Temática Cooperativa de Grupos de Investigación en Sida del Fondo de Investigación Sanitaria (FIS).

    HIVACAT: HIV Vaccine Development Program in Catalonia.

    IDIBAPS: Institut d'Investigacions Biomèdiques August Pi i Sunyer.

    Prior presentation of abstracts at meetings: An abstract regarding this research entitled “Loading Dendritic Cells with Gold Nanoparticles (GNPs) Bearing HIV-peptides and Mannosides Enhance HIV-specific T Cell Responses” has been presented at “HIV Research for Prevention 2016, Chicago, United States, October 17 - 21, 2016”.

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