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

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.

Published ahead of print on 8 November 2006.

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