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Naïve T-Cell Dynamics in Human Immunodeficiency Virus Type 1 Infection: Effects of Highly Active Antiretroviral Therapy Provide Insights into the Mechanisms of Naïve T-Cell Depletion

National Institutes of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland,¹ SAIC, Frederick, Maryland,² Clinical Center, National Institutes of Health, Bethesda, Maryland,³ National Cancer Institute-Frederick, National Institutes of Health, Frederick, Maryland⁴

Received 22 October 2005/ Accepted 5 December 2005

Both naïve CD4⁺ and naïve CD8⁺ T cells are depleted in individuals with human immunodeficiency virus type 1 (HIV-1) infection by unknown mechanisms. Analysis of their dynamics prior to and after highly active antiretroviral therapy (HAART) could reveal possible mechanisms of depletion. Twenty patients were evaluated with immunophenotyping, intracellular Ki67 staining, T-cell receptor excision circle (TREC) quantitation in sorted CD4 and CD8 cells, and thymic computed tomography scans prior to and 6 and 18 months after initiation of HAART. Naïve T-cell proliferation decreased significantly during the first 6 months of therapy (P < 0.01) followed by a slower decline. Thymic indices did not change significantly over time. At baseline, naïve CD4⁺ T-cell numbers were lower than naive CD8⁺ T-cell numbers; after HAART, a greater increase in naïve CD4⁺ T cells than naïve CD8⁺ T cells was observed. A greater relative change (n-fold) in the number of TREC⁺ T cells/µl than in naïve T-cell counts was observed at 6 months for both CD4⁺ (median relative change [n-fold] of 2.2 and 1.7, respectively; P < 0.01) and CD8⁺ T cell pools (1.4 and 1.2; P < 0.01). A more pronounced decrease in the proliferation than the disappearance rate of naïve T cells after HAART was observed in a second group of six HIV-1-infected patients studied by in vivo pulse labeling with bromodeoxyuridine. These observations are consistent with a mathematical model where the HIV-1-induced increase in proliferation of naïve T cells is mostly explained by a faster recruitment into memory cells.

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