Anti-HIV-1 therapeutics: from FDA-approved drugs to hypothetical future targets

Abstract

More than twenty-five years after its discovery, HIV-1 remains one of the world’s most formidable and destructive pathogens. Several classes of anti-HIV-1 agents are currently in widespread clinical use in developed nations; however, viral resistance to these drugs limits their effectiveness in a growing number of patients. It is therefore imperative that novel drugs be developed. Recent advances in the fields of HIV-1 molecular virology and cell biology have revealed possible new targets for drug discovery. The current status of antiretroviral therapy and some of the promising new targets against which novel antiviral agents could be developed are discussed.

Figure 1.

The HIV-1 replication cycle. Major steps of HIV-1 replication are numbered. The HIV-1 replication cycle begins with viral entry into the target cell. Entry occurs upon fusion of the viral lipid envelope with the host cell plasma membrane, a process mediated by a non-covalent complex of viral (Env) glyco-proteins gp120 and gp41. First, gp120 binds the cellular receptor CD4, and then interacts with the CCR5 or CXCR4 coreceptor. Coreceptor binding by gp120 triggers a series of conformational changes in both gp120 and gp41 that lead to membrane fusion. Following fusion, the viral core, composed of a capsid (CA) shell containing the dimeric single-stranded RNA genome in complex with the reverse transcriptase (RT) and integrase (IN) enzymes, is deposited into the cell. The core uncoats, and RT copies the RNA genome into a double-stranded DNA copy. This viral DNA is then transported into the cell nucleus where it is integrated into the host cell genome by the IN enzyme. Subsequent transcription and translation lead to production of the viral components that assemble into new particles. The assembly process, which occurs at the plasma membrane, is directed by the Gag polyprotein precursor. To promote the budding and release of newly assembled virus particles, HIV-1 hijacks cellular endosomal sorting machinery (referred to as the “ESCRT” complexes) that normally functions to promote the budding of vesicles into late endosomes to form multivesicular bodies. Following release, the viral protease (PR) cleaves the Gag polyprotein precursor into individual Gag domains, thereby triggering a maturation process that is absolutely required for particle infectivity. Host factors that play a positive role in HIV-1 replication are indicated in green; factors that can restrict HIV-1 replication are in red. Adapted and reprinted with permission from Elsevier (1), © 2004.

Eric O. Freed, PhD, is currently Chief of the Virus-Cell Interaction Section of the HIV Drug Resistance Program, National Cancer Institute (NCI) in Frederick, MD. He received his doctoral degree from the University of Wisconsin, Madison with Rex Risser and performed postdoctoral research with Howard Temin in Madison and Malcolm Martin at the NIAID/NIH in Bethesda, MD. He received tenure in the NIAID in 2002 and in 2003 moved to the NCI. His research focuses on the molecular biology of HIV-1 replication. He has made a number of key discoveries in the field of HIV-1 assembly and release. E-mail efreed@nih.gov; fax 301-846-6777.

Catherine S. Adamson, PhD, is currently a postdoctoral fellow in Eric Freed’s laboratory within the HIV Resistance Program, National Cancer Institute (NCI) in Frederick, MD, USA. She received her doctoral degree from the University of Manchester, UK with Jayne Brookman. Before joining Eric Freed’s lab she performed postdoctoral research with Professor Ian Jones at both the Oxford Institute of Virology and the University of Reading, UK. Her research interests focus on retrovirus particle assembly, release, and maturation. Recently she has made significant contributions to development of the novel HIV-1 maturation inhibitor, bevirimat. E-mail cadamson@ncifcrf.gov; fax 301-846-6013.