Summary Dendritic cells (DCs) play a critical role in the immune response to viral infection through the facilitation of cell intrinsic antiviral activity and the activation of adaptive immunity. HIV-1 infection of DCs triggers an IRF3-dependent innate immune response, which requires the activity of cyclic GAMP synthase (cGAS). We report the results of a targeted RNAi screen utilizing primary human monocyte-derived DCs (MDDCs) to identify immune regulators that directly interface with HIV-1-encoded features to initiate this innate response. Polyglutamine binding protein 1 (PQBP1) emerged as a strong candidate through this analysis. We found that PQBP1 directly binds to reverse-transcribed HIV-1 DNA and interacts with cGAS to initiate an IRF3-dependent innate response. MDDCs derived from Renpenning Syndrome patients, who harbor mutations in the PQBP1 locus, possess a severely attenuated innate immune response to HIV-1 challenge, underscoring the role of PQBP1 as a proximal innate sensor of a HIV-1 infection.

Although MERS-CoV has not yet acquired extensive distribution, being mainly confined to the Arabic and Korean peninsulas, it could adapt to spread more readily among humans and thereby become pandemic. Therefore, the development of a vaccine is mandatory. The integration of antigen-coding genes into recombinant MV resulting in coexpression of MV and foreign antigens can efficiently be achieved. Thus, in combination with the excellent safety profile of the MV vaccine, recombinant MV seems to constitute an ideal vaccine platform. The present study shows that a recombinant MV expressing MERS-S is genetically stable and induces strong humoral and cellular immunity against MERS-CoV in vaccinated mice. Subsequent challenge experiments indicated protection of vaccinated animals, illustrating the potential of MV as a vaccine platform with the potential to target emerging infections, such as MERS-CoV.

The Middle East respiratory syndrome coronavirus (MERS-CoV In 2012 a novel human betacoronavirus associated with severe respiratory disease emerged in Saudi Arabia (1). Due to its geographic distribution, this new virus was classified as Middle East respiratory syndrome coronavirus (MERS-CoV) (2). MERS-CoV is associated with high fatality rates (3, 4), and case numbers globally have increased to 909 laboratory-confirmed cases with 331 fatalities (as of 21 November 2014 [http://www.who.int/csr/don/ 21-november-2014-mers/en/]). In parallel, the geographic distribution has expanded (4). MERS-CoV is the second emerging CoV with severe pathogenicity in humans within 10 years after the severe acute respiratory syndrome coronavirus (SARS-CoV) that infected approximately 8,000 people worldwide during its spread in 2003 (5). Human-to-human transmissions have been reported for MERS-CoV, but transmissibility seems to be inefficient (6, 7). MERS-CoV persists in animal reservoirs, i.e., dromedary camels (8), and transmission events between camels and contact persons have been reported (7-10). Thus, MERS-CoV infection of men has zoonotic origins, similar to SARS-CoV, but unlike SARS-CoV, where bats have been identified as the original virus reservoir, bats have been reported to host only closely related viruses of MERSCoV (11). However, the only small-animal model developed so far involves type I interferon receptor (IFNAR)-deficient mice expressing human dipeptidyl peptidase 4 (huDPP4; CD26), the entry receptor of MERS-CoV (12), in the lung after intranasal administration of huDPP4-expressing adenoviral vectors (13). MERS-CoV causes symptoms in humans similar to those of SARS-CoV infection, such as severe pneumonia with acute respi-

SAMHD1 is a critical restriction factor for HIV-1 in non-cycling cells and its antiviral activity is regulated by T592 phosphorylation. Here, we show that SAMHD1 dephosphorylation at T592 is controlled during the cell cycle, occurring during M/G1 transition in proliferating cells. Using several complementary proteomics and biochemical approaches, we identify the phosphatase PP2A-B55α responsible for rendering SAMHD1 antivirally active. SAMHD1 is specifically targeted by PP2A-B55α holoenzymes during mitotic exit, in line with observations that PP2A-B55α is a key mitotic exit phosphatase in mammalian cells. Strikingly, as HeLa or activated primary CD4+ T cells enter the G1 phase, pronounced reduction of RT products is observed upon HIV-1 infection dependent on the presence of dephosphorylated SAMHD1. Moreover, PP2A controls SAMHD1 pT592 level in non-cycling monocyte-derived macrophages (MDMs). Thus, the PP2A-B55α holoenzyme is a key regulator to switch on the antiviral activity of SAMHD1.

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.

There is uncertainty about the viral loads of infectious individuals required to transmit COVID-19 via aerosol. In addition, there is a lack of both quantification of the influencing parameters on airborne transmission and simple-to-use models for assessing the risk of infection in practice, which furthermore quantify the influence of non-medical preventive measures. In this study, a dose–response model was adopted to analyze 25 documented outbreaks at infection rates of 4–100%. We show that infection was only possible if the viral load was higher than 108 viral copies/mL. Based on mathematical simplifications of our approach to predict the probable situational attack rate (PARs) of a group of persons in a room, and valid assumptions, we provide simplified equations to calculate, among others, the maximum possible number of persons and the person-related virus-free air supply flow necessary to keep the number of newly infected persons to less than one. A comparison of different preventive measures revealed that testing contributes the most to the joint protective effect, besides wearing masks and increasing ventilation. In addition, we conclude that absolute volume flow rate or person-related volume flow rate are more intuitive parameters for evaluating ventilation for infection prevention than air exchange rate.

EUROPRISE is a Network of Excellence sponsored from 2007 to 2011 by the European Commission within the 6th Framework Program. The Network encompasses a wide portfolio of activities ranging from an integrated research program in the field of HIV vaccines and microbicides to training, dissemination and advocacy. The research program covers the whole pipeline of vaccine and microbicide development from discovery to early clinical trials. The Network is composed of 58 partners representing more than 65 institutions from 13 European countries; it also includes three major pharmaceutical companies (GlaxoSmithKline, Novartis and Sanofi-Pasteur) involved in HIV microbicide and vaccine research. The Network displays a dedicated and informative web page: http://www.europrise.org. Finally, a distinguishing trait of EUROPRISE is its PhD School of students from across Europe, a unique example in the world of science aimed at spreading excellence through training.EUROPRISE held its second annual conference in Budapest in November, 2009. The conference had 143 participants and their presentations covered aspects of vaccine and microbicide research, development and discovery. Since training is a major task of the Network, the students of the EUROPRISE PhD program summarized certain presentations and their view of the conference in this paper.

Currently, airborne transmission is seen as the most important transmission path for SARS-CoV-2. In this investigation, a classic dose-response model is used on the one hand to find out retrospectively the probable viral load of the infectious source patient at the time of transmission in 25 documented outbreaks. We showed that an infection due to airborne transmission at a distance from the infectious person was probably only possible in the 25 outbreaks examined, with attack rates of 4-100%, if the viral load had been higher than 1E+08 viral copies/ml. This demonstrates that the viral load estimated from the swab might overestimate a person’s infectivity via aerosol, because a person is generally considered infectious, independent of the transmission way, when the viral load from the swab is 1E+06 viral copies/ml.On the other hand, a possible approach is presented to predict the probable situational Attack Rate (PARs) of a group of persons in a room through aerosol particles emitted by an infectious source patient. Four main categories of influence on the risk of infection are formed: First the emitted viruses, depending on the viral load and the amount of respiratory particles, and necessary number of reproducible viruses for infection, second the room-specific data and duration of stay of the group of people, third the activity of the exposed persons, and fourth the effect of personal protection (e.g. wearing masks from infectious and/or susceptible person).Furthermore, a simplified method is presented to calculate either the maximum possible number of persons in a room, so that probably a maximum of one person becomes infected when an infectious person is in the room, or the PARs,simple for a given number of persons, ventilation rate and time of occupancy. We additionally show, taking into account organizational preventive measures, which person-related virus-free supply air flow rates are necessary to keep the number of newly infected persons to less than 1. The simple approach makes it easy to derive preventive organizational and ventilation measures. Our results show that the volume flow rate or a person-related flow rate is a much more effective parameter to evaluate ventilation for infection prevention than the air change rate. We suggest to monitor the CO2 concentration as an easy to implement and valid measurement system for indoor spaces.Finally, we show that of the three measures, besides of wearing masks and increasing ventilation, testing contributes the most to the joint protective effect. This corresponds to the classic approach to implement protection concepts: preventing the source from entering the room and emitting viruses at all. In summary, a layered approach of different measures is recommended to mutually compensate for possible failures of any one measure (e.g. incorrect execution of tests, incorrect fit of masks or irregular window opening), to increase the degree of protection and thus reduce the risk of transmission of SARS-CoV-2.