A stabilized HIV-1 envelope glycoprotein trimer fused to CD40 ligand targets and activates dendritic cells
| Autor: | Mark Melchers, Thijs van Montfort, Ben Berkhout, Ilja Bontjer, Dirk Eggink, Carolien E. van de Sandt, John P. Moore, Katie Matthews, Kathryn B. David, Robert P. de Vries, Rogier W. Sanders |
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| Přispěvatelé: | Medical Microbiology and Infection Prevention, Other departments, Amsterdam institute for Infection and Immunity |
| Jazyk: | angličtina |
| Rok vydání: | 2011 |
| Předmět: |
lcsh:Immunologic diseases. Allergy
Recombinant Fusion Proteins Cellular differentiation Protein subunit CD40 Ligand Biology Gp41 DNA vaccination Immune system Glycoprotein complex Virology Humans Cells Cultured CD40 Protein Stability Research env Gene Products Human Immunodeficiency Virus Cell Differentiation Dendritic Cells Molecular biology Fusion protein Cell biology Infectious Diseases HIV-1 biology.protein Cytokines lcsh:RC581-607 |
| Zdroj: | Retrovirology, Vol 8, Iss 1, p 48 (2011) Retrovirology Retrovirology, 8(1). BioMed Central |
| ISSN: | 1742-4690 |
| DOI: | 10.1186/1742-4690-8-48 |
| Popis: | Background One reason why subunit protein and DNA vaccines are often less immunogenic than live-attenuated and whole-inactivated virus vaccines is that they lack the co-stimulatory signals provided by various components of the more complex vaccines. The HIV-1 envelope glycoprotein complex (Env) is no exception to this rule. Other factors that limit the induction of neutralizing antibodies against HIV-1 lie in the structure and instability of Env. We have previously stabilized soluble trimeric mimics of Env by introducing a disulfide bond between gp120 and gp41 and adding a trimer stabilizing mutation in gp41 (SOSIP.R6 gp140). Results We further stabilized the SOSIP.R6 gp140 using a GCN4-based isoleucine zipper motif, creating SOSIP.R6-IZ gp140. In order to target SOSIP.R6-IZ to immune cells, including dendritic cells, while at the same time activating these cells, we fused SOSIP.R6-IZ to the active domain of CD40 ligand (CD40L), which may serve as a 'cis-adjuvant'. The Env component of the SOSIP.R6-IZ-CD40L fusion construct bound to CD4 and neutralizing antibodies, while the CD40L moiety interacted with CD40. Furthermore, the chimeric molecule was able to signal efficiently through CD40 and induce maturation of human dendritic cells. Dendritic cells secreted IL-6, IL-10 and IL-12 in response to stimulation by SOSIP.R6-IZ-CD40L and were able to activate naïve T cells. Conclusions Chimeric HIV-1 gp140 - CD40L trimers can target and activate dendritic cells. Targeting and activating immune cells using CD40L and other 'cis-adjuvants' may improve subunit protein vaccine immunogenicity for HIV-1 and other infectious diseases. |
| Databáze: | OpenAIRE |
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