Highly active antiretroviral therapy is effective at controlling HIV-1 replication, however emergence and transmission of drug-resistant viruses is increasing, including viruses resistant to the newly developped integrase catalytic inhibitors. It is essential that new antiretrovirals (ARVs) become available. Most ARVs in development belong to the classes of viral enzyme inhibitors. Since HIV requires cellular cofactors for its replication cycle, we aim to develop novel classes of ARVs inhibiting specific virus-host interactions. Because host cell factors mutate rarely, this new class of ARVs should be less vulnerable to resistance. We selected two cellular targets, LEDGF/p75 and Transportin-SR2 (Trn-SR2), cofactors of Integrase (IN) and Capsid (CA) respectively, important for viral integration and nuclear transport. Partners of this consortium, R. Benarous, P. Cherepanov, A. Fassati and S. Emiliani, discovered, with others, these targets and elucidated their structure and function. Partner 1 SME BIODIM (FR), consortium leader, has developped small compound inhibitors of IN-LEDGF interaction. BIODIM compounds have a clear structure activity relationship, nanomolar ARV activity and are based on a new, structurally defined pharmacophore. The objectives of this project are to 1) Advance BIODIM IN-LEDGF inhibitors up to the proof of concept (POC) in man in a phase I/IIa clinical trial with partner 6 J. Gatell (SP) 2) Discover small compounds targeting the Trn-SR2 pathway in HIV-1 infection using a high throughput screening assay validated by partner 2 A. Fassati (UK), determine the pharmacophore by solving the 3D structure of Trn-SR2 with partner 3 P. Cherepanov (UK) and optimize the compounds up to the POC in a humanized mouse model of HIV infection with partner 5, B. Berkhout (NL) 3) Elucidate with partner 4 Emiliani/Saïb (FR) the network of interactions in which Trn-SR2 is involved with CA from uncoating to the pre-integration complex to provide new ARV drug targets.