Homologous recombination plays a crucial role to repair DNA strand breaks that may occur spontaneously upon replication fork collapse, during the course of radio- or chemotherapy or in a programmed manner during meiosis. Understanding the molecular mechanisms of re-combinational repair is thus very important not only from a basic research viewpoint, but it is also highly relevant for human health. Here, we will define the function of nucleases in homol-ogous recombination. First, we will study the initial steps in this pathway. We could show previously that the S. cerevisiae Sae2 protein promotes the endonuclease activity of the Mre11-Rad50-Xrs2 (MRX) complex near protein blocked DNA ends. This initiates nucleolytic resection of DNA breaks and activates homologous recombination. Our biochemical setup will be instrumental to define how is the activity of Sae2 regulated by phosphorylation on a mech-anistic level and how physiological protein blocks direct the Mre11 endonuclease. We will ex-tend the study to the human system, and attempt to apply the gained knowledge to improve the efficiency of genome editing by activating recombination in conjunction with the CRISPR-Cas9 nuclease system. Second, we will study how homologous recombination promotes gen-eration of genetic diversity during sexual reproduction. DNA strand breaks are introduced in-tentionally during the prophase of the first meiotic division. They are then processed by the recombination machinery into Holliday junction intermediates. These joint molecules are preferentially converted into crossovers in meiosis, resulting in exchange of genetic infor-mation between the maternal and paternal DNA molecules. This is dependent on the Mlh1-Mlh3 nuclease through a yet unknown mechanism. We will study how Mlh1-Mlh3 in complex with other proteins guarantee crossover outcome to promote diversity of the progeny.

ZIKAlliance is a multidisciplinary project with a global "One Health" approach, built: on a multi-centric network of clinical cohorts in the Caribbean, Central & South America; research sites in countries where the virus has been or is currently circulating (Africa, Asia, Polynesia) or at risk for emergence (Reunion Island); a strong network of European and Brazilian clinical & basic research institutions; and multiple interfaces with other scientific and public health programmes. ZIKAlliance will addrees three key objectives relating to (i) impact of Zika virus (ZIKV) infection during pregnancy and short & medium term effects on newborns, (ii) associated natural history of ZIKV infection in humans and their environment in the context of other circulating arboviruses and (iii) building the overall capacity for preparedness research for future epidemic threats in Latin America & the Caribbean. The project will take advantage of large standardised clinical cohorts of pregnant women and febrile patients in regions of Latin America and the Caribbean were the virus is circulating, expanding a preexisting network established by the IDAMS EU project. I will also benefit of a very strong expertise in basic and environmental sciences, with access to both field work and sophisticated technological infrastructures to characterise virus replication and physiopathology mechanisms. To meet its 3 key objectives, the scientific project has been organised in 9 work packages, with WP2/3 dedicated to clinical research (cohorts, clinical biology, epidemiology & modeling), WP3/4 to basic research (virology & antivirals, pathophysiology & animal models), WP5/6 to environmental research (animal reservoirs, vectors & vector control) , WP7/8 to social sciences & communication, and WP9 to management. The broad consortium set-up allow gathering the necessary expertise for an actual interdisciplinary approach, and operating in a range of countries with contrasting ZIKV epidemiological status.

Many HIV vaccine concepts and several efficacy trials have been conducted in the prophylactic and therapeutic fields with limited success. There is an urgent need to develop better vaccines and tools predictive of immunogenicity and of correlates of protection at early stage of vaccine development to mitigate the risks of failure. To address these complex and challenging scientific issues, the European HIV Vaccine Alliance (EHVA) program will develop a Multidisciplinary Vaccine Platform (MVP) in the fields of prophylactic and therapeutic HIV vaccines. The Specific Objectives of the MVP are to build up: 1.Discovery Platform with the goal of generating novel vaccine candidates inducing potent neutralizing and non-neutralizing antibody responses and T-cell responses, 2. Immune Profiling Platform with the goal of ranking novel and existing (benchmark) vaccine candidates on the basis of the immune profile, 3. Data Management/Integration/Down-Selection Platform, with the goal of providing statistical tools for the analysis and interpretation of complex data and algorithms for the efficient selection of vaccines, and 4. Clinical Trials Platform with the goal of accelerating the clinical development of novel vaccines and the early prediction of vaccine failure. EHVA project has developed a global and innovative strategy which includes: a) the multidisciplinary expertise involving immunologists, virologists, structural biology experts, statisticians and computational scientists and clinicians; b) the most innovative technologies to profile immune response and virus reservoir; c) the access to large cohort studies bringing together top European clinical scientists/centres in the fields of prophylactic and therapeutic vaccines, d) the access to a panel of experimental HIV vaccines under clinical development that will be used as benchmark, and e) the liaison to a number of African leading scientists/programs which will foster the testing of future EHVA vaccines through EDCTP