The Impact of Macrophage Nucleotide Pools on HIV-1 Reverse Transcription, Viral Replication, and the Development of Novel Antiviral Agents

• Type of Material: Article
• Authors: Christina Gavegnano, Emory University; Edward M. Kennedy, University of Rochester; Baek Kim, Emory University; Raymond F Schinazi, Emory University
• Language: English
• Date: 2012-04-23
• Publisher: Hindawi Publishing Corporation
• Publication Version: Final Published Version
• Copyright Statement: © 2012 Christina Gavegnano et al.
• License: Creative Commons Attribution 3.0 Unported
• Final Published Version (URL): http://www.hindawi.com/journals/mbi/2012/625983/
• Title of Journal or Parent Work: Molecular Biology International
• ISSN: 2090-2190
• Volume: 2012
• Issue: 2012
• Start Page: 1
• End Page: 8
• Grant/Funding Information: This work was supported in part by NIH Grant 5P30-AI-50409 (CFAR), 5R01-AI-071846-03, T32GM008602, by the Howard Hughes Medical Institute Translational Research Program, AI-049781 and AI-077401 to B.Kim, and by the Department of Veterans Affairs.
• Research Categories: Biology, Microbiology; Health Sciences, Immunology; Health Sciences, Pharmacology

Abstract

Macrophages are ubiquitous and represent a significant viral reservoir for HIV-1. Macrophages are nondividing, terminally differentiated cells, which have a unique cellular microenvironment relative to actively dividing T lymphocytes, all of which can impact HIV-1 infection/replication, design of inhibitors targeting viral replication in these cells, emergence of mutations within the HIV-1 genome, and disease progression. Scarce dNTPs drive rNTP incorporation into the proviral DNA in macrophages but not lymphocytes. Furthermore, the efficacy of a ribose-based inhibitor that potently inhibits HIV-1 replication in macrophages, has prompted a reconsideration of the previously accepted dogma that 2′-deoxy-based inhibitors demonstrate effective inhibition of HIV-1 replication. Additionally, higher levels of dUTP and rNTP incorporation in macrophages, and lack of repair mechanisms relative to lymphocytes, provide a further mechanistic understanding required to develop targeted inhibition of viral replication in macrophages. Together, the concentrations of dNTPs and rNTPs within macrophages comprise a distinctive cellular environment that directly impacts HIV-1 replication in macrophages and provides unique insight into novel therapeutic mechanisms that could be exploited to eliminate virus from these cells.