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Journal of Virology, January 2002, p. 96-104, Vol. 76, No. 1
0022-538X/01/$04.00+0     DOI: 10.1128/JVI.76.1.96-104.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Rev-Independent Simian Immunodeficiency Virus Strains Are Nonpathogenic in Neonatal Macaques

Agneta S. von Gegerfelt,¹ Vladimir Liska,^2,3 Pei-Lin Li,^2,3 Harold M. McClure,⁴ Kyoji Horie,⁵ Filomena Nappi,⁵ David C. Montefiori,⁶ George N. Pavlakis,⁵ Marta L. Marthas,⁷ Ruth M. Ruprecht,^2,3 and Barbara K. Felber^1*

Human Retrovirus Pathogenesis Section,¹ Human Retrovirus Section, National Cancer Institute, Frederick, Maryland 21702-1201,⁵ Dana-Farber Cancer Institute,² Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115,³ Yerkes Regional Primate Research Center, Emory University, Atlanta, Georgia 30322,⁴ Department of Surgery, Duke University Medical Center, Durham, North Carolina 27710,⁶ California Regional Primate Research Center and Department of Veterinary Pathology, Microbiology and Immunology, University of California, Davis, California 95616-8542⁷

Received 1 August 2001/ Accepted 26 September 2001

The viral protein Rev is essential for the export of the subset of unspliced and partially spliced lentiviral mRNAs and the production of structural proteins. Rev and its RNA binding site RRE can be replaced in both human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) by the constitutive RNA transport element CTE of the simian type D retroviruses. We used neonatal macaques as a sensitive animal model to evaluate the pathogenicity of a pair of SIV mutant strains generated from Rev-independent molecular clones of SIVmac239 which differ only in the presence of the nef open reading frame. After high primary viremia, all animals remained persistently infected at levels below the threshold of detection. All macaques infected as neonates developed normally, and none showed any signs of immune dysfunction or disease during follow-up ranging from 2.3 to 4 years. Therefore, the Rev-RRE regulatory mechanism plays a key role in the maintenance of high levels of virus propagation, which is independent of the presence of nef. These data demonstrate that Rev regulation plays an important role in the pathogenicity of SIV. Replacement of Rev-RRE by the CTE provides a novel approach to dramatically lower the virulence of a pathogenic lentivirus. These data further suggest that antiretroviral strategies leading to even a partial block of Rev function may modulate disease progression in HIV-infected individuals.

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* Corresponding author. Mailing address: Bldg. 535, Rm. 110, NCI-FCRDC, Frederick, MD 21702-1201. Phone: (301) 846-5159. Fax: (301) 846-7146. E-mail: felber{at}mail.ncifcrf.gov.

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Journal of Virology, January 2002, p. 96-104, Vol. 76, No. 1
0022-538X/01/$04.00+0     DOI: 10.1128/JVI.76.1.96-104.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

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