Novel inhibitors of the early steps of the HIV-1 life cycle

Considerable advances have been made on compounds that are active as inhibitors of HIV entry and fusion. The discovery of chemokines a few years ago focused the attention on coreceptor inhibitors in addition to fusion and attachment blockers. During the last 5 years, there has been an intense research activity from both private companies and academic institutions to find effective compounds that are capable of inhibiting the initial steps in the HIV life cycle. Some of the presented compounds demonstrated in vitro synergism, thus there is the rationale of their combined use in HIV-infected individuals. Many entry and fusion inhibitors of HIV are being investigated in controlled clinical trials and there are a number of them that are bioavailable as oral formulations. This is an essential feature for an extended use of these compounds with the purpose of ameliorating patients' adherence to medications; therefore, preventing the development of drug resistance. Among the many compounds that are being investigated, some are in the preclinical arena and others are more advanced in development stages. Overall, the main aim is to establish the action of these compounds on the immune system (e.g., the balance of the system after shutting off CCR5 or CXCR4 coreceptors) and the possible burden of unexplained side effects. This review focuses on the recent developments in this field with a particular attention on promising compounds in preclinical and clinical trials.