Inhibitors of HIV cellular fusion

Abstract

HIV infection continues to be a major global health problem. Current anti-HIV therapies targeting reverse transcriptase and protease enzymes suffer from high cost, a high probability of engendering resistance and adverse side effects following prolonged use. Thus, we are faced with the need to develop new antiviral strategies with more potent compounds and/or novel antiviral targets. The recent characterisation of the HIV cell-fusion mechanism and initial mapping of the interactions of the proteins involved in this process has provided an opportunity to identify and take advantage of chemokine co-receptors as new antiviral targets. The HIV fusogenic particle consists of virus-derived gp120, gp41 and cell-derived CD4 and chemokine co-receptors, all of which must interact in a concerted fashion to allow entry of the virus into the cell. The structural analysis of these components has resulted in the identification of a number of new antiviral fusion targets that are distinct from gp120:CD4 binding. Three types of fusogenic particle antagonists have emerged: (1) ribozyme based gene therapy targeting the chemokine co-receptors; (2) peptide-based antagonists targeting either domains of gp41 or chemokine co-receptors; and (3) small molecule inhibitors targeting the virus:co-receptor interaction. In summary, HIV fusion inhibitors, like the current clinically approved agents, will need to be used in combinations consisting of antivirals that target all aspects of the HIV replication cycle and components of the fusogenic particle, to obtain optimum therapeutic effect.

• AIDS
• chemokine receptors
• fusion inhibitors
• gp41
• HIV