The identification of a series of PRRs and RFs that contribute to cell-autonomous immunity against retroviruses provided a strong impetus for the establishment of the interdisciplinary national research network SPP1923. The overall goal of SPP1923 is to integrate experts in retrovirology and innate immunity to assemble a national network that addresses key open questions on the interplay of retroviruses with the cell-autonomous immune system of their hosts in collaborative projects. By these combined efforts, we aim at the identification of the full molecular sensing and restriction machinery involved, its regulation, evolved virus-encoded countermeasures, and pathophysiological consequences. Pathogenic and apathogenic retroviruses will be investigated in cell systems ranging from monotypic cell cultures to complex ex vivo and animal models (Fig. 1). At these different levels of complexity, SPP1923 aims at dissecting mechanisms of innate immune recognition, viral evasion and counteraction thereof and at defining the functional consequences of these virus-host interactions.