New targets and novel antiretrovirals

Highly active antiretroviral therapy (HAART) has to date been based on use of a triple combination of drugs chosen from three classes of antiretrovirals (ARVs), nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (PIs). These ARV classes target two of the three virally encoded enzymes necessary for viral replication after entry of HIV into the host cell. A greater understanding of the viral-host interactions necessary for new infection of CD4 cells has led to the development of compounds able to inhibit viral entry. The novel fusion inhibitor T-20 has entered clinical use and has a particular role in salvage therapy of patients with HIV strains resistant to present classes of ARVs. Co-receptor inhibitors have shown in vivo antiviral activity and are now entering phase III development. Integrase (IN), the third viral enzyme encoded by the pol gene, has remained an elusive target. Compounds with low toxicity and able to inhibit (IN) are now entering phase II clinical development. These new HIV treatment modalities represent a significant advance in and addition to our anti-HIV armamentarium. This review will outline the mechanisms of action of entry inhibitors and IN inhibitors and discuss the lead compounds within each class. Southern African Journal of HIV Medicine Vol. 6 (4) 2005: pp. 49-5