Novel approaches to inhibiting HIV-1 replication. a

Novel approaches to inhibiting HIV-1 replication.

Considerable success has been achieved in the treatment of HIV-1 infection, and more than two-dozen antiretroviral drugs are available targeting several distinct steps in the viral replication cycle. However, resistance to these compounds emerges readily, even in the context of combination therapy. Drug toxicity, adverse drug-drug interactions, and accompanying poor patient adherence can also lead to treatment failure. These considerations make continued development of novel antiretroviral therapeutics necessary. In this article, the authors highlight a number of steps in the HIV-1 replication cycle that represent promising targets for drug discovery. These include lipid raft microdomains, the RNase H activityof the viral enzyme reverse transcriptase, uncoating of the viral core, host cell machinery involved in the integration of the viral DNA into host cell chromatin, virus assembly, maturation, and budding, and the functions of several viral accessory proteins. The authors discuss the relevant molecular and cell biology, and describe progress to date in developing inhibitors against these novel targets.

inside the cell, HIV takes advantage of host cell factors and pathways, harnessing our machinery to promote its own replication. Having described the HIV life cycle, this article briefly reviews the classes of drugs that we currently have (more than 20 antiretroviral drugs have been licensed to date): entry inhibitors (fusion inhibitors and CCR5 antagonists), reverse transcriptase inhibitors (non-nucleoside and nucleoside, i.e. NNRTI and NRTI), protease inhibitors, and integrase inhibitors. Then, accompanied by many colourful figures, the authors present an array of potential new therapeutic targets that include viral-host protein interactions or cellular targets. It will be a challenge for virology and biology (chemical, structural, molecular, and cell) to determine whether we can block HIV’s use of these interactions or cellular targets for multiple steps of its own replication without creating toxicity for us, since we need these proteins and cellular factors for a variety of our own functions.