Inhibitors of HIV cellular fusion

HIV infection continues to be a major global health problem. Current anti-H IV therapies targeting reverse transcriptase and protease enzymes suffer fr om high cost, a high probability of engendering resistance and adverse side effects following prolonged use. Thus, we are faced with the need to devel op new antiviral strategies with more potent compounds and/or novel antivir al targets. The recent characterisation of the HIV cell-fusion mechanism an d initial mapping of the interactions of the proteins involved in this proc ess 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-recepto rs, 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 resul ted in the identification of a number of new antiviral fusion targets that are distinct from gp120:CD4 binding. Three types of fusogenic particle anta gonists have emerged: (1) ribozyme based gene therapy targeting the chemoki ne 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 combinatio ns consisting of antivirals that target all aspects of the HIV replication cycle and components of the fusogenic particle, to obtain optimum therapeut ic effect.