[Frontiers in Bioscience 11, 89-112, January 1, 2006]

HIV-1 inactivation by nucleic acid aptamers

Daniel M. Held 1, 3, Jay D. Kissel 1, James T. Patterson 2, David G. Nickens 2 and Donald H. Burke 2, 3

Departments of 1 Biology and 2 Chemistry, Indiana University, Bloomington, IN 47405, 3 Department of Molecular Microbiology and Immunology, University of Missouri School of Medicine, Columbia, MO 65212


1. Abstract
2. Nucleic acid aptamers
3. Inhibition of HIV-1 enzymatic function
3.1. Reverse Transcriptase.
3.1.1. Anti-RT drugs, side effects and resistance
3.1.2. RNA aptamers in vitro
3.1.3. Anti-RT ssDNA aptamers in vitro
3.1.4. Anti-RT RNA aptamers in cells
3.2. Protease
3.2.1. Protease aptamers
3.3. Integrase
3.3.1. Integrase aptamers in vitro
4. Inhibition of HIV-1 gene expression: transcriptional regulation and RNA transport
4.1. Rev
4.1.1. Rev aptamers in vitro
4.1.2. Non-aptamer Rev decoys in vivo
4.1.3. Rev aptamers in vivo
4.2. Tat
4.2.1. Tat aptamers in vitro
4.2.2. Tat aptamers and TAR decoys in vivo
4.3. TAR, RRE and other structured viral RNAs
5. Inhibition of viral packaging
5.1. Nucleocapsid and p55Gag polyprotein
5.1.1. NC and p55Gag aptamers in vitro
5.1.2. NC aptamers and decoys in vivo
6. Inhibition of viral entry
6.1. Glycoproteins gp120 and gp41
6.1.1. gp120 aptamers in vitro and in antiviral assay
7. Further considerations
8. References


Although developments in small-molecule therapeutics for HIV-1 have been dramatic in recent years, the rapid selection of drug-resistant viral strains and the adverse side effects associated with long-term exposure to current treatments propel continued exploration of alternative anti-HIV-1 agents. Non-coding nucleic acids have emerged as potent inhibitors that dramatically suppress viral function both in vitro and in cell culture. In particular, RNA and DNA aptamers inhibit HIV-1 function by directly interfering with essential proteins at critical stages in the viral replication cycle (Figure 1). Their antiviral efficacy is expected to be a function, in part, of the biochemical properties of the aptamer-target interaction.

Accordingly, we present an overview of biochemical and cell culture analyses of the expanding list of aptamers targeting HIV-1. Our discussion focuses on the inhibition of viral enzymes (reverse transcription, proteolytic processing, and chromosomal integration), viral expression (Rev/RRE and Tat/TAR), viral packaging (p55Gag, matrix and nucleocapsid), and viral entry (gp120) (Table 1). Additional nucleic acid-based strategies for inactivation of HIV-1 function (including RNAi, antisense, and ribozymes) have also demonstrated their utility. These approaches are reviewed in other chapters of this volume and elsewhere (1-5).