Novel approaches to inhibiting HIV-1 replication

Abstract

Considerable success has been achieved in the treatment of HIV-1 infection, and more than twodozen 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, we 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 activity of 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. We discuss the relevant molecular and cell biology, and describe progress to date in developing inhibitors against these novel targets.Keywords virus entry; virus assembly; retrovirus; drug resistance; HIV-1 drug therapy A. Introduction A1. Overview of HIV-1 ReplicationThe replication cycle of human immunodeficiency virus type 1 (HIV-1) is a complex multistep process that depends on both viral and host cell factors (Figs. 1 and 2) . Replication begins with viral entry into the target cell. Entry proceeds by fusion of the viral lipid envelope and the cellular plasma membrane (Doms, 2000;Melikyan, 2008). The viral component that mediates fusion is the envelope (Env) glycoprotein spike, which is composed of a trimeric, non-covalently associated complex of the surface glycoprotein gp120 and the transmembrane glycoprotein gp41 (Roux and Taylor, 2007). Fusion is initiated by binding of gp120 to the cellular receptor CD4 and a subsequent interaction with the CCR5 or CXCR4 coreceptor (Berger, Murphy, and Farber, 1999;Doms, 2000). Coreceptor binding triggers a series of conformation changes in both gp120 and gp41 that mediate membrane fusion (Doms, 2000;Melikyan, 2008). Fusion delivers the viral core into the cytoplasm of the target cell. The viral core is composed of a capsid (CA) protein shell that encapsidates the single-stranded, dimeric viral RNA genome in complex with the viral nucleocapsid (NC) protein and the viral Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. (Adamson and Freed, 2007;GanserPornillos, Yeager, and Sundquist, 2008). The core uncoats (Warrilow and Harrich, 2007) and RT copies the RNA genome into a ...

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