PMID- 26085166 OWN - NLM STAT- MEDLINE DCOM- 20160429 LR - 20181113 IS - 1098-5514 (Electronic) IS - 0022-538X (Print) IS - 0022-538X (Linking) VI - 89 IP - 17 DP - 2015 Sep TI - Lentiviral Protein Transfer Vectors Are an Efficient Vaccine Platform and Induce a Strong Antigen-Specific Cytotoxic T Cell Response. PG - 9044-60 LID - 10.1128/JVI.00844-15 [doi] AB - To induce and trigger innate and adaptive immune responses, antigen-presenting cells (APCs) take up and process antigens. Retroviral particles are capable of transferring not only genetic information but also foreign cargo proteins when they are genetically fused to viral structural proteins. Here, we demonstrate the capacity of lentiviral protein transfer vectors (PTVs) for targeted antigen transfer directly into APCs and thereby induction of cytotoxic T cell responses. Targeting of lentiviral PTVs to APCs can be achieved analogously to gene transfer vectors by pseudotyping the particles with truncated wild-type measles virus (MV) glycoproteins (GPs), which use human SLAM (signaling lymphocyte activation molecule) as a main entry receptor. SLAM is expressed on stimulated lymphocytes and APCs, including dendritic cells. SLAM-targeted PTVs transferred the reporter protein green fluorescent protein (GFP) or Cre recombinase with strict receptor specificity into SLAM-expressing CHO and B cell lines, in contrast to broadly transducing vesicular stomatitis virus G protein (VSV-G) pseudotyped PTVs. Primary myeloid dendritic cells (mDCs) incubated with targeted or nontargeted ovalbumin (Ova)-transferring PTVs stimulated Ova-specific T lymphocytes, especially CD8(+) T cells. Administration of Ova-PTVs into SLAM-transgenic and control mice confirmed the observed predominant induction of antigen-specific CD8(+) T cells and demonstrated the capacity of protein transfer vectors as suitable vaccines for the induction of antigen-specific immune responses. IMPORTANCE: This study demonstrates the specificity and efficacy of antigen transfer by SLAM-targeted and nontargeted lentiviral protein transfer vectors into antigen-presenting cells to trigger antigen-specific immune responses in vitro and in vivo. The observed predominant activation of antigen-specific CD8(+) T cells indicates the suitability of SLAM-targeted and also nontargeted PTVs as a vaccine for the induction of cytotoxic immune responses. Since cytotoxic CD8(+) T lymphocytes are a mainstay of antitumoral immune responses, PTVs could be engineered for the transfer of specific tumor antigens provoking tailored antitumoral immunity. Therefore, PTVs can be used as safe and efficient alternatives to gene transfer vectors or live attenuated replicating vector platforms, avoiding genotoxicity or general toxicity in highly immunocompromised patients, respectively. Thereby, the potential for easy envelope exchange allows the circumventing of neutralizing antibodies, e.g., during repeated boost immunizations. CI - Copyright (c) 2015, American Society for Microbiology. All Rights Reserved. FAU - Uhlig, Katharina M AU - Uhlig KM AD - Oncolytic Measles Viruses and Vaccine Vectors, Paul-Ehrlich-Institut, Langen, Germany. FAU - Schulke, Stefan AU - Schulke S AD - Molecular Allergology, Paul-Ehrlich-Institut, Langen, Germany. FAU - Scheuplein, Vivian A M AU - Scheuplein VA AD - Oncolytic Measles Viruses and Vaccine Vectors, Paul-Ehrlich-Institut, Langen, Germany. FAU - Malczyk, Anna H AU - Malczyk AH AD - Oncolytic Measles Viruses and Vaccine Vectors, Paul-Ehrlich-Institut, Langen, Germany. FAU - Reusch, Johannes AU - Reusch J AD - Oncolytic Measles Viruses and Vaccine Vectors, Paul-Ehrlich-Institut, Langen, Germany. FAU - Kugelmann, Stefanie AU - Kugelmann S AD - Oncolytic Measles Viruses and Vaccine Vectors, Paul-Ehrlich-Institut, Langen, Germany. FAU - Muth, Anke AU - Muth A AD - Molecular Biotechnology and Gene Therapy, Paul-Ehrlich-Institut, Langen, Germany. FAU - Koch, Vivian AU - Koch V AD - Oncolytic Measles Viruses and Vaccine Vectors, Paul-Ehrlich-Institut, Langen, Germany. FAU - Hutzler, Stefan AU - Hutzler S AD - Oncolytic Measles Viruses and Vaccine Vectors, Paul-Ehrlich-Institut, Langen, Germany. FAU - Bodmer, Bianca S AU - Bodmer BS AD - Oncolytic Measles Viruses and Vaccine Vectors, Paul-Ehrlich-Institut, Langen, Germany. FAU - Schambach, Axel AU - Schambach A AD - Institute of Experimental Hematology, Hannover Medical School, Hannover, Germany. FAU - Buchholz, Christian J AU - Buchholz CJ AD - Molecular Biotechnology and Gene Therapy, Paul-Ehrlich-Institut, Langen, Germany German Cancer Consortium, Heidelberg, Germany. FAU - Waibler, Zoe AU - Waibler Z AD - Novel Vaccination Strategies and Early Immune Responses, Paul-Ehrlich-Institut, Langen, Germany. FAU - Scheurer, Stephan AU - Scheurer S AD - Molecular Allergology, Paul-Ehrlich-Institut, Langen, Germany. FAU - Muhlebach, Michael D AU - Muhlebach MD AD - Oncolytic Measles Viruses and Vaccine Vectors, Paul-Ehrlich-Institut, Langen, Germany Michael.Muehlebach@pei.de. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20150617 PL - United States TA - J Virol JT - Journal of virology JID - 0113724 RN - 0 (Antigens, CD) RN - 0 (G protein, vesicular stomatitis virus) RN - 0 (Membrane Glycoproteins) RN - 0 (Receptors, Cell Surface) RN - 0 (Vaccines, Subunit) RN - 0 (Viral Envelope Proteins) RN - 0 (Viral Fusion Proteins) RN - 147336-22-9 (Green Fluorescent Proteins) RN - 169535-43-7 (Signaling Lymphocytic Activation Molecule Family Member 1) RN - 9006-59-1 (Ovalbumin) RN - EC 2.7.7.- (Cre recombinase) RN - EC 2.7.7.- (Integrases) SB - IM MH - Animals MH - Antigens, CD/biosynthesis/*immunology MH - CHO Cells MH - Cricetulus MH - Dendritic Cells/immunology MH - Genetic Vectors/*genetics MH - Green Fluorescent Proteins/biosynthesis MH - HEK293 Cells MH - Humans MH - Integrases/biosynthesis/genetics MH - Lentivirus/genetics MH - Lymphocyte Activation/immunology MH - Measles virus/genetics MH - Membrane Glycoproteins/biosynthesis/genetics MH - Mice MH - Mice, Knockout MH - Ovalbumin/*immunology MH - Protein Transport MH - Receptors, Cell Surface/biosynthesis/*immunology MH - Signaling Lymphocytic Activation Molecule Family Member 1 MH - T-Lymphocytes, Cytotoxic/*immunology MH - Transfection MH - Vaccines, Subunit/immunology MH - Viral Envelope Proteins/biosynthesis/genetics MH - Viral Fusion Proteins/genetics/*immunology PMC - PMC4524058 EDAT- 2015/06/19 06:00 MHDA- 2016/04/30 06:00 PMCR- 2015/12/17 CRDT- 2015/06/19 06:00 PHST- 2015/03/30 00:00 [received] PHST- 2015/06/14 00:00 [accepted] PHST- 2015/06/19 06:00 [entrez] PHST- 2015/06/19 06:00 [pubmed] PHST- 2016/04/30 06:00 [medline] PHST- 2015/12/17 00:00 [pmc-release] AID - JVI.00844-15 [pii] AID - 00844-15 [pii] AID - 10.1128/JVI.00844-15 [doi] PST - ppublish SO - J Virol. 2015 Sep;89(17):9044-60. doi: 10.1128/JVI.00844-15. Epub 2015 Jun 17.