"Standard therapy of infection with the human immunodeficiency virus type 1 (HIV-1) is based on potent cocktails of drugs targeting viral proteins. This treatment is associated with severe side effects and is almost unaffordable for the patients living in sub-Saharan Africa. Incomplete suppression of HIV replication results in drug-resistance. Therefore, a continued research effort is required to develop more potent, cheaper and less toxic antivirals. The insight has grown that HIV requires cellular proteins to serve as co-factors for viral replication. Our over-all objective is to develop novel drugs by targeting co-factors required for HIV replication. The virus will find it difficult to develop antiviral resistance against drugs targeting interaction between invariable cellular proteins and conserved viral protein domains. We will focus on the cellular proteins that mediate HIV trafficking, nuclear import and integration, such as Lens Epithelium Derived Growth Factor (LEDGF/p75), a novel cofactor of HIV-1 integration. THINC is composed of 3 virologists, 2 medicinal chemists, 1 virologist from South Africa, 1 structural biologist, 1 pharmaceutical company. Our first objective is to identify and validate novel co-factors of HIV trafficking, nuclear import and integration as novel targets for anti-HIV therapy. The second objective is to develop new drugs against the validated cellular target LEDGF/p75. The third objective is to perform this work in the perspective of those who will benefit most: the HIV infected people all over the world. The initial steps of target validation and hit identification will mainly be taken by academic groups, while optimization and (pre)clinical development of drugs requires the participation of Tibotec, a European company devoted to the development of antiviral drugs. The project will also increase our generic understanding of protein-protein interactions (PPI)."