Therapy success has reduced acquired immunodeficiency syndrome (AIDS)-related morbidity and mortality significantly during the last years, but resistance to exisitng drugs is a growing problem. Novel strategies are needed, which should target the human immunodeficiency virus (HIV) in various ways and prevent treatment escape. To this end, fundamental knowledge needs to be acquired on more efficient use of chemical compounds, targeting "classical" viral enzymes, but also by looking at new targets, using molecular biological and immunological approaches. We will investigate the possibility of inhibiting HIV replication using the follwing strategies: 1. Development of advanced bio-informatics tools to predict and counter viral escape under drug and immune pressure. 2. Finding new drug targets that do not suffer from cross resistance with current drugs. 3. Refining the RNA interference (RNAi) technology to prevent escape. 4. Exploring the possibilities of "autologous" immunotherapy, based on transfection of dendritic cells (DC) and other antigen presenting cells (APC) with HIV-derived messenger RNA (mRNA). 5. Development of a suitable small animal model to test these new approaches in vivo.