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Journal of Virology, January 2007, p. 893-902, Vol. 81, No. 2
0022-538X/07/$08.00+0     doi:10.1128/JVI.01635-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Loss of Naïve Cells Accompanies Memory CD4+ T-Cell Depletion during Long-Term Progression to AIDS in Simian Immunodeficiency Virus-Infected Macaques{triangledown}

Yoshiaki Nishimura,1 Tatsuhiko Igarashi,1 Alicia Buckler-White,1 Charles Buckler,1 Hiromi Imamichi,3 Robert M. Goeken,1 Wendy R. Lee,1 Bernard A. P. Lafont,1 Russ Byrum,4 H. Clifford Lane,2 Vanessa M. Hirsch,1 and Malcolm A. Martin1*

Laboratory of Molecular Microbiology,1 Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892,2 Science Applications International Corporation—Frederick, Inc., Frederick, Maryland 21702,3 Bioqual, Rockville, Maryland 208504

Received 31 July 2006/ Accepted 24 October 2006

Human immunodeficiency virus and simian immunodeficiency virus (SIV) induce a slow progressive disease, characterized by the massive loss of memory CD4+ T cells during the acute infection followed by a recovery phase in which virus replication is partially controlled. However, because the initial injury is so severe and virus production persists, the immune system eventually collapses and a symptomatic fatal disease invariably occurs. We have assessed CD4+ T-cell dynamics and disease progression in 12 SIV-infected rhesus monkeys for nearly 2 years. Three macaques exhibiting a rapid progressor phenotype experienced rapid and irreversible loss of memory, but not naïve, CD4+ T lymphocytes from peripheral blood and secondary lymphoid tissues and died within the first 6 months of virus inoculation. In contrast, SIV-infected conventional progressor animals sustained marked but incomplete depletions of memory CD4+ T cells and continuous activation/proliferation of this T-lymphocyte subset. This was associated with a profound loss of naïve CD4+ T cells from peripheral blood and secondary lymphoid tissues, which declined at rates that correlated with disease progression. These data suggest that the persistent loss of memory CD4+T cells, which are being eliminated by direct virus killing and activation-induced cell death, requires the continuous differentiation of naïve into memory CD4+ T cells. This unrelenting replenishment process eventually leads to the exhaustion of the naïve CD4+T-cell pool and the development of disease.

* Corresponding author. Mailing address: Laboratory of Molecular Microbiology, NIAID, NIH, Bethesda, MD 20892. Phone: (301) 496-4012. Fax: (301) 402-0226. E-mail: malm{at}nih.gov.

{triangledown} Published ahead of print on 8 November 2006.

Journal of Virology, January 2007, p. 893-902, Vol. 81, No. 2
0022-538X/07/$08.00+0     doi:10.1128/JVI.01635-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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