This Article Full Text (PDF) Other Versions of this Article: JVI.00614-07v1 81/17/8891    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints and Permissions Copyright Information Books from ASM Press MicrobeWorld Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Kuwata, T. Articles by Hirsch, V. M. Search for Related Content PubMed PubMed Citation Articles by Kuwata, T. Articles by Hirsch, V. M.

 Previous Article  |  Next Article 

J. Virol. doi:10.1128/JVI.00614-07
Copyright (c) 2007, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

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

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

^* To whom correspondence should be addressed. Email: vhirsch{at}nih.gov.

	Abstract

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 terminal plasma of a RP macaque. Inoculation of macaques with a representative clone, SIVsmH635FC, resulted in a persistent viremia, comparable to the 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 wild type SIVsmE543-3 at two RP-specific sites and slower reversion of another three sites. SIVsmH635FC was not sufficient to cause rapid progression even following co-inoculation with SIVsmE543-3, despite acute depletion of memory CD4⁺ T cells. SIVsmH635FC competed efficiently during primary infection in the co-inoculated 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 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, whereas the parental SIVsmE543-3 was highly resistant. This study suggests that the evolution of RP-specific variants is the end result of replication in a severely immune compromised host, rather than the direct cause of rapid progression.