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Journal of Virology, September 2002, p. 8518-8531, Vol. 76, No. 17
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.17.8518-8513.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Molecular Characterization of Preintegration Latency in Human Immunodeficiency Virus Type 1 Infection

Theodore C. Pierson, Yan Zhou, Tara L. Kieffer, Christian T. Ruff, Christopher Buck, and Robert F. Siliciano*

Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205

Received 6 March 2002/ Accepted 19 May 2002

Most current evidence suggests that the infection of resting CD4+ T cells by human immunodeficiency virus type 1 (HIV-1) is not productive due to partial or complete blocks in the viral life cycle at steps prior to integration of the viral genome into the host cell chromosome. However, stimulation of an infected resting T cell by antigen, cytokines, or microenvironmental factors can overcome these blocks and allow for the production of progeny virions. In this study, we sought to understand the structure and fate of the virus in unstimulated resting CD4+ T cells. Using a novel linker-mediated PCR assay designed to detect and characterize linear unintegrated forms of the HIV-1 genome, we demonstrate that reverse transcription can proceed to completion following the infection of resting T cells, generating the substrate for the retroviral integration reaction. However, reverse transcription in resting T cells is far slower than in activated T cells, requiring 2 to 3 days to complete. The delay in completing reverse transcription may make the viral DNA genome more susceptible to competing decay processes. To explore the relationship between the formation of the linear viral genome and the stability of the preintegration state, we employed a recombinant HIV-1 virus expressing the enhanced green fluorescent protein to measure the rate at which HIV-1 decays in the preintegration state. Our results demonstrate that the preintegration state is labile and decays rapidly (half-life = 1 day) following the entry of HIV-1 into a resting T cell, with significant decay occurring during the slow process of reverse transcription.

* Corresponding author. Mailing address: Department of Medicine, Johns Hopkins University School of Medicine, 1049 Ross Building, 720 Rutland Ave., Baltimore, MD 21205. Phone: (410) 955-2958. Fax: (410) 955-0964. E-mail: rsilicia{at}welch.jhu.edu.

Journal of Virology, September 2002, p. 8518-8531, Vol. 76, No. 17
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.17.8518-8513.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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