HIV fusion and its inhibition

HIV infection remains a significant issue in global health. Intensive research is focused on vaccine strategies and targets, but novel therapeutic drugs are urgently needed to ameliorate the disease course in currently infected individuals. HAART is extending disease-free life for many infected individuals. However, drug resistance and toxicity limit the utility of HAART for increasing numbers of people. Several novel antiviral drugs are being developed that target the HIV entry process. The compounds described herein fall into three categories: inhibitors of CD4 binding, coreceptor interaction, and fusion. A few of the entry/fusion inhibitors are currently in clinical trials, including the peptide-based fusion inhibitors T20 and T1249, the tetrameric immunoglobulin-CD4 fusion protein PRO 542, and the CXCR4 antagonist AMD3100. Other compounds are being evaluated in pre-clinical studies. With the addition of the entry/fusion inhibitors, the arsenal of anti-HIV drugs has been increased from three classes of compounds to six. Studies have shown synergistic antiviral effects among the newer compounds as well as between the new and existing drugs. These new agents provide hope for salvage therapy for individuals failing HAART, as well as alternatives for initial therapy for newly infected individuals. The success of fusion/entry inhibitors in HIV therapeutics has also sparked development of analogous antiviral agents targeting binding and fusion of other fusogenic viruses.