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Journal of Virology, September 2007, p. 8891-8904, Vol. 81, No. 17
0022-538X/07/$08.00+0     doi:10.1128/JVI.00614-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

A Rapid Progressor-Specific Variant Clone of Simian Immunodeficiency Virus Replicates Efficiently In Vivo Only in the Absence of Immune Reponses

Takeo Kuwata,¹ Russell Byrum,² Sonya Whitted,¹ Robert Goeken,¹ Alicia Buckler-White,¹ Ronald Plishka,¹ Ranjini Iyengar,¹ and Vanessa M. Hirsch^1*

Laboratory of Molecular Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland,¹ Bioqual, Inc., Rockville, Maryland²

Received 22 March 2007/ Accepted 13 June 2007

A subset of simian immunodeficiency virus (SIV)-infected macaques progresses rapidly to disease with transient SIV-specific immune responses and high viral loads. Unique SIV variants with convergent Env mutations evolve in these rapid progressor (RP) macaques. To address the pathogenic significance of RP-specific variants, we generated infectious molecular clones from the terminal-phase plasma of an RP macaque. Inoculation of macaques with a representative clone, SIVsmH635FC, resulted in a persistent viremia, comparable to that produced by pathogenic SIVsmE543-3, and a chronic disease with progressive loss of CD4⁺ T cells. However, SIVsmH635FC did not reproduce the rapid-disease phenomenon. Molecular analyses of viruses from these macaques revealed rapid reversion to the wild-type SIVsmE543-3 sequence at two RP-specific sites and slower reversion at another three sites. SIVsmH635FC infection was not sufficient to cause rapid progression even following coinoculation with SIVsmE543-3, despite acute depletion of memory CD4⁺ T cells. SIVsmH635FC competed efficiently during primary infection in the coinoculated macaques, but SIVsmE543-3 predominated after the development of SIV-specific immune responses. These data suggest that the replication fitness of the RP variant was similar to that of SIVsmE543-3 in a naïve host; however, SIVsmH635FC was at a disadvantage following the development of SIV-specific immune responses. Consistent with these findings, neutralization assays revealed that SIVsmH635FC was highly sensitive to neutralization but that the parental SIVsmE543-3 strain was highly resistant. This study suggests that the evolution of RP-specific variants is the result of replication in a severely immunocompromised host, rather than the direct cause of rapid progression.

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* Corresponding author. Mailing address: Laboratory of Molecular Microbiology, NIAID, NIH, Building 4, Rm. B1-33, 4 Center Drive, Bethesda, MD 20892. Phone: (301) 496-2976. Fax: (301) 480-3129. E-mail: vhirsch{at}nih.gov

Published ahead of print on 27 June 2007.

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Journal of Virology, September 2007, p. 8891-8904, Vol. 81, No. 17
0022-538X/07/$08.00+0     doi:10.1128/JVI.00614-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

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