Measles (MV) is an aerosol-transmitted virus that affects more than 10 million children each year and accounts for approximately 120,000 deaths1,2. While it was long believed to replicate in the respiratory epithelium before disseminating, it was recently shown to initially infect macrophages and dendritic cells of the airways using the signaling lymphocytic activation molecule (SLAM, CD150) as receptor3-6. These cells then cross the respiratory epithelium and ferry the infection to lymphatic organs where MV replicates vigorously7. How and where the virus crosses back into the airways has remained unknown. Based on functional analyses of surface proteins preferentially expressed on virus-permissive epithelial cell lines, we identified nectin-48 (poliovirus-receptor-like-4) as a candidate host exit receptor. This adherens junction protein of the immunoglobulin superfamily interacts with the viral attachment protein with high affinity through its membrane-distal domain. Nectin-4 sustains MV entry and non-cytopathic lateral spread in well-differentiated primary human airway epithelial sheets infected basolaterally. It is down-regulated in infected epithelial cells, including those of macaque tracheas. While other viruses use receptors to enter hosts or transit through their epithelial barriers, we suggest that MV targets nectin-4 to emerge in the airways. Nectin-4 is a cellular marker of several types of cancer9-11, which has implications for ongoing MV-based clinical trials of oncolysis12.

Histone deacetylase 2 (HDAC2) is relevant for homeostasis and plays a critical role in gastrointestinal cancers. Here, we report that post-translational modification of endogenous HDAC2 with small ubiquitin-related modifier 1 (SUMO1) is a new regulatory switch for the tumor suppressor p53. Sumoylation of HDAC2 at lysine 462 allows binding of HDAC2 to p53. Moreover, sumoylated HDAC2 is a previously not recognized biologically relevant site-specific deacetylase for p53. Deacetylation of p53 at lysine 320 by sumoylated HDAC2 blocks recruitment of p53 into promoter-associated complexes and p53-dependent expression of genes for cell cycle control and apoptosis. Thereby, catalytically active sumoylated HDAC2 restricts p53 functions and attenuates DNA damage-induced apoptosis. Genotoxic stress evokes desumoylation of HDAC2, enabling p53-dependent gene expression. Our data show a new molecular mechanism involving a dynamically controlled HDAC2-sumoylation/p53-acetylation switch that regulates cell fate decisions following genotoxic stress.

Playing a central role in both innate and adaptive immunity, CD4+ T cells are a key target for genetic modifications in basic research and immunotherapy. In this article, we describe novel lentiviral vectors (CD4-LV) that have been rendered selective for human or simian CD4+ cells by surface engineering. When applied to PBMCs, CD4-LV transduced CD4+ but not CD4− cells. Notably, also unstimulated T cells were stably genetically modified. Upon systemic or intrasplenic administration into mice reconstituted with human PBMCs or hematopoietic stem cells, reporter gene expression was predominantly detected in lymphoid organs. Evaluation of GFP expression in organ-derived cells and blood by flow cytometry demonstrated exclusive gene transfer into CD4+ human lymphocytes. In bone marrow and spleen, memory T cells were preferentially hit. Toward therapeutic applications, we also show that CD4-LV can be used for HIV gene therapy, as well as for tumor therapy, by delivering chimeric Ag receptors. The potential for in vivo delivery of the FOXP3 gene was also demonstrated, making CD4-LV a powerful tool for inducible regulatory T cell generation. In summary, our work demonstrates the exclusive gene transfer into a T cell subset upon systemic vector administration opening an avenue toward novel strategies in immunotherapy.

؉ 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. V accination is the administration of one or more immunogens, the vaccine, into patients to trigger antigen-specific adaptive immune responses to prevent (prophylactic vaccination) or to treat (therapeutic vaccination) disease. Vaccines can be classified into several subtypes. Among these are live attenuated replicating vaccines, inactivated vaccines, subunit vaccines, DNA vaccines, or recombinant vector vaccines (for review, see reference 1). Wellknown live attenuated vaccines are, e.g., those against measles (2) or mumps (3). These vaccines replicate but have been attenuated to become apathogenic. The immune responses triggered by live attenuated vaccines are similar to those induced by the pathogenic form of the microbe (4, 5) and involve both the cellular and humoral arms of the immune system. However, attenuated replicating pathogens may carry an inherent risk of reversion to the parental virulent form by in vivo passaging during vaccination, as observed for the Sabin strain used as a polio vaccine (6), or may still be pathogenic in highly immunocompromised patients (7), depending on the respective degree of attenuation of the vaccine strains. On the other hand, inoculation of solely proteinaceous antigens (such as the hepatitis B virus vaccine [8]) or antigenencoding genes (as a DNA vaccine) is regarded as safe but relatively inefficient (9).As an alternative to such vaccines, the genes encoding an antigen can be transferred into cells and thereby presented to the immune system by using recombinant vaccine vectors. For that purpose, an attenuated vector is utilized as a carrier for the antigen-encoding sequences of another pathogen. Thereby, they are