Abstract Invasive fungal infections cause over 1.5 million deaths worldwide. Despite increases in fungal infections as well as the numbers of individuals at risk, there are no clinically approved fungal vaccines. We produced a "pan-fungal" peptide, NXT-2, based on a previously identified vaccine candidate and homologous sequences from Pneumocystis, Aspergillus,Candida, and Cryptococcus. We evaluated the immunogenicity and protective capacity of NXT-2 in murine and nonhuman primate models of invasive aspergillosis, systemic candidiasis, and pneumocystosis. NXT-2 was highly immunogenic and immunized animals had decreased mortality and morbidity compared to nonvaccinated animals following induction of immunosuppression and challenge with Aspergillus, Candida, or Pneumocystis. Data in multiple animal models support the concept that immunization with a pan-fungal vaccine prior to immunosuppression induces broad, cross-protective antifungal immunity in at-risk individuals.
Abstract Extracellular vesicles (EVs) transfer bioactive molecules between cells in a process reminiscent of enveloped viruses. EV cargo delivery is thought to occur by protein-mediated and pH-dependent membrane fusion of the EV and the cellular membrane. However, there is a lack of methods to identify the fusion proteins and resolve their mechanism. We developed and benchmarked an in vitro biophysical assay to investigate EV membrane fusion. The assay was standardized by directly comparing EV and viral fusion with liposomes. We show that EVs and retroviruses fuse with liposomes mimicking the membrane composition of the late endosome in a pH- and protein-dependent manner. Moreover, we directly visualize the stages of membrane fusion using cryo-electron tomography. We find that, unlike most retroviruses, EVs remain fusogenic after acidification and reneutralization. These results provide novel insights into the EV cargo delivery mechanism and an experimental approach to identify the EV fusion machinery.
Introducción: This volume comprises revised presentations from the 2014 symposium plus an additional contribution by Melanie Wasmuth, this introduction, and an overall critical assessment by R. J. van der Spek, who was also present at the symposium. We regret that not all of the participants of the symposium were able to contribute to this publication, especially with the resulting loss of discussion of certain areas of the empire (sadly even the heartland itself), but we trust the ones collected here profitably explore the issues from a variety of perspectives. The collection begins with a discussion of the Kingdom-cum-Satrapy of Lydia. Eduard Rung considers the notable lack of Lydian independence efforts through two topics; two early appointments by Cyrus the Great (Tabalus and Pactyes) and the early (and only attested) Lydian revolt by Pactyes. In his analysis, native elites were totally replaced from the Lydian administration following the revolt leading to the memory of Croesus's kingdom losing any local political effectiveness.
Stabilized HIV-1 envelope glycoproteins (Env) that resemble the native Env are utilized in vaccination strategies aimed at inducing broadly neutralizing antibodies (bNAbs). To limit the exposure of rare isolate-specific antigenic residues/determinants we generated a SOSIP trimer based on a consensus sequence of all HIV-1 group M isolates (ConM). The ConM trimer displays the epitopes of most known bNAbs and several germline bNAb precursors. The crystal structure of the ConM trimer at 3.9 Å resolution resembles that of the native Env trimer and its antigenic surface displays few rare residues. The ConM trimer elicits strong NAb responses against the autologous virus in rabbits and macaques that are significantly enhanced when it is presented on ferritin nanoparticles. The dominant NAb specificity is directed against an epitope at or close to the trimer apex. Immunogens based on consensus sequences might have utility in engineering vaccines against HIV-1 and other viruses. ; This project has received funding from the European Union's Horizon 2020 research and innovation program under grant agreement No. 681137 (to R.S., R.W.S., G.S., M.C., and J.A.). This work was also supported by the U.S. National Institutes of Health Grant P01 AI110657 (to J.P.M., A.B.W., I.A.W., and R.W.S.) and NIAID Contract #HHSN27201100016C (to D.C.M.); by the International AIDS Vaccine Initiative (IAVI); by the Bill and Melinda Gates Foundation through the Collaboration for AIDS Vaccine Discovery (CAVD), grants OPP1111923 and OPP1132237 (to J.P.M. and R.W.S.) and OPP1115782 (A.B.W.); by the Aids Fonds Netherlands, Grant #2016019 (to R.W.S.); and by the Fondation Dormeur, Vaduz (to R.W.S. and to M.J.v.G.). R.W.S. is a recipient of a Vici grant from the Netherlands Organization for Scientific Research (NWO). This work was partially supported by the Spanish Plan Nacional R+D+I [RD16/0017/0037] and FIS [PI16/1355], co-financed by ISCIII-Subdirección General de Evaluación y el Fondo Europeo de Desarrollo Regional (FEDER). This work was also supported by the Global Frontier Project (grant number: NRF-2013M-3A6A-4043695) and the Tumor Microenvironment Global Core Research Center (grant number: 2011–0030001) funded through the National Research Foundation from the Ministry of Science and ICT of Korea (to B.W.H). M.J.v.G. is a recipient of an AMC Fellowship and a Mathilde Krim Fellowship from the American Foundation for AIDS Research (amfAR) (109514–61-RKVA). J.MC-S. is a recipient of a fellowship from the Consejo Nacional de Ciencia y Tecnología of Mexico (CONACYT). The electron microscopy data were collected at Electron Microscopy Facility of The Scripps Research Institute. The Amsterdam Cohort Studies on HIV infection and AIDS, a collaboration between the Amsterdam Health Service, the Academic Medical Center of the University of Amsterdam, Sanquin Blood Supply Foundation, Medical Center Jan van Goyen and the HIV Focus Center of the DC-Clinics, are part of the Netherlands HIV Monitoring Foundation and financially supported by the Center for Infectious Disease Control of the Netherlands National Institute for Public Health and the Environment. X-ray data sets were collected at the Advanced Photon Source, Argonne National Laboratory (beamline 23 ID-D). GM/CA CAT is funded in whole or in part with federal funds from the National Cancer Institute (Y1-CO-1020) and NIGMS (Y1-GM-1104). Use of the Advanced Photon Source was supported by the U.S. Department of Energy (DOE), Basic Energy Sciences, Office of Science, under contract no. DE-AC02–06CH11357. ; Sí
