Innate Sensing and Restriction of Retroviruses
DFG priority program.
Retroviruses comprise a diverse group of exogenous and endogenous viruses defined by their unique replication strategy to reverse-transcribe their RNA genome into a complementary DNA. Millions of years of coevolution with their mammalian hosts gave rise to highly pathogenic as well as apathogenic members of this family of viruses. Evidence is emerging that cell-type specific cell-autonomous components of the innate immune system, including specialized pattern recognition receptors (PRRs) and broadly antiviral restriction factors (RFs), represent key determinants of the fundamentally different outcomes of retroviral infections. Specific parameters under consideration include the efficiency of cross- and intra-species transmission, pathogenesis, virus evolution, and the ability to establish a chronic infection in a new host.
The recent identification of a first set of PRRs and RFs that contribute to cell-autonomous immunity against retroviruses has provided a strong impetus for the establishment of an interdisciplinary national research network. This priority program aims at the identification of the full molecular sensing and restriction machinery involved, its regulation, evolved virus-encoded countermeasures, and pathophysiological consequences. To this end we will integrate retrovirologists, immunologists, and experts in key technologies to accomplish these goals in collaborative projects. Pathogenic and apathogenic retroviruses will be investigated in cell systems ranging from monotypic cell cultures to complex ex vivo and animal models (Fig. 1). These integrated efforts will establish an unprecedented spatio-temporal resolution of innate immune recognition of retroviruses, quantify and visualize the composition and dynamics of cellular and viral nucleotides, and exploit physiological models of transmission and pathogenesis.
Insight into these fundamental processes of ongoing coevolution of retroviruses and their hosts will not only close gaps in the landscape of innate immunity and interdisciplinary methodology, but will inspire efforts to specifically modulate and exploit cell-autonomous recognition events for the development of preventive and therapeutic strategies, for example in disease caused by infection with Human Immunodeficiency Virus (HIV). Since recently emerging evidence links anti-retroviral cell-autonomous immunity to tumor development and autoimmune disease, knowledge gained within this program will be applicable to fields far beyond retrovirology.
Fig. 1: Topology of the addressed field of research at the interface of retrovirus biology and cell-autonomous immunity. Work in classical cell culture systems (left) seeks to identify and understand at the molecular level the full set of cell-autonomous recognition factors of retroviruses and resulting effector functions at high spatio-temporal resolution. These events underlie cell system-specific regulation and their relevance will be evaluated in primary cell and organotypic infection models (middle). The impact of innate recognition will be defined for retroviral cross-species and human-to-human transmission, evolutionary virus-host adaptation including polymorphisms in innate genes/viral antagonists, and pathogenesis in the new host (right).