Grant: Operating Grant

The human immunodeficiency virus (HIV) pandemic remains an important global problem. Despite the remarkable success in the development of anti-retroviral drugs (ARVs), by far not everyone benefits from available treatments and new infections are inadequately prevented. In the absence of a cure, infected individuals have to take ARVs for the rest of their lives. The enormous variability of the virus is also tightly associated with the emergence of drug resistance that can cause treatment failure if patients do not adhere to their drug regimen. Resistance conferring mutations can reduce susceptibility to each of the available classes of drugs, although the more recently approved combinations of ARVs appear to better control this problem. However, we are currently witnessing a paradigm-shift in ways antiretrovirals are used. Ongoing difficulties in the development of vaccines triggered the use of ARVs also in prophylaxis to reduce the risk of transmission and to prevent new infections. For these reasons, it will be important to continue to develop novel drugs with limited cross-resistance to the approved ARVs. The major objective of the proposed studies is to form a concrete basis for the development of novel inhibitors of HIV reverse transcriptase (RT) using mechanism-driven approaches.