Exploring new mechanisms underlying ineffective antibody responses in human and mouse viral infections

Integration of innate and adaptive responses, as well as coordination between humoral and cellular immunity are key for proper viral clearance. However, in some infections, like lymphocytic choriomeningitis virus (LCMV) in mice, or human immunodeficency virus (HIV) or hepatitis B and C virus in humans, the adaptive immune response is unbalanced and results in weak and insufficient antibody responses. Although the cellular response is usually sufficient to control a primary viral infection, in some cases clearance is not complete and persistent infections ensue. The mechanisms responsible for diversification of immune responses to viral infections rely on many different factors, some intrinsic to viral structural properties, others related to their pathogenicity and replication features. Experimental work employing advanced imaging techniques has uncovered additional molecular mechanisms whereby some viruses fail to induce early and strong antibody responses, thus hampering the overall immune response and viral clearance. For example, spatiotemporal regulation of type I IFNs is a major determinant directing adaptive immunity to viruses. Here we propose to merge the expertise of two research units – Kuka Lab in mouse viral immunology, and De Biasi Lab in human viral immunology – to address novel mechanisms responsible for inefficient antibody responses to mouse and human viral infections. First, we aim to characterize and dissect the molecular mechanism whereby a new molecular player – IFN-γ - suppresses T follicular helper cells and antibody responses to LCMV infection. Moreover, we will study whether IFN-γ plays a role also in other infection/immunization settings. Second, we will explore novel innate and adaptive immune mechanisms responsible for impaired Abresponses in the context of HIV infection. In this regard, we will take advantage of state-of-the-art technology for the accurate quantification of different subpopulations of cells in individuals who started antiretroviral therapy vs. those who are in the chronic phase of the infection. The analysis of T cell phenotypic and immuno-metabolic activities, Ab production and their potential anti-HIV neutralizing or blocking activities together with the evaluation of the dynamic perturbations of innate and adaptive immunity could be relevant to define the immunologic events associated with the lack of production of neutralizing antibodies (nAbs). Our study will help to identify the molecular and cellular signature at the basis of the diversification of the immune response to different viral infection in mouse models and humans. The proposed research has the potential to provide a significant scientific impact as it will create a collaborative network between immunologists and clinicians with the common goal of better understanding the immune dynamics triggered by different infections.