HIV-1 infection impairs cell cycle progression of CD4+ T cells without affecting early activation responses
Scott F. Sieg, … , Clifford V. Harding, Michael M. Lederman
Scott F. Sieg, … , Clifford V. Harding, Michael M. Lederman
Published September 1, 2001
Citation Information: J Clin Invest. 2001;108(5):757-764. https://doi.org/10.1172/JCI12685.
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Article

HIV-1 infection impairs cell cycle progression of CD4+ T cells without affecting early activation responses

Abstract

Failure of CD4+ T cells to proliferate in response to antigenic stimulation is a characteristic of HIV infection. Analysis of the proliferation defect has been hampered by an inability to identify CD4+ cells with T cell receptor specificity for antigen. To focus only on cells that had been stimulated through the T cell receptor, CD4+ T cells were stimulated with an anti-Vβ3 Ab that activates approximately 3–5% of peripheral blood T cells. This approach revealed proliferation defects in cells from HIV-infected patients that were not appreciated using anti-CD3 Ab stimulation and provided the capacity to examine responses on a single cell basis. After anti-Vβ3 Ab stimulation, CD4+Vβ3+ cells from HIV-infected patients demonstrated defects in expression of cell cycle–associated proteins, D-type cyclins, and cyclin A. However, the expression of early activation markers, CD69 and CD25, was not significantly impaired in cells from most patients. Thus, CD4+ T cell proliferation failure in HIV disease is characterized by dysregulated activation that precludes cell cycle progression. This proliferation defect was most apparent in patients with diminished CD4+ T cell numbers and higher plasma HIV RNA levels. CD4+ T cell proliferation failure may be a key determinant of immune impairment in HIV disease.

Authors

Scott F. Sieg, Clifford V. Harding, Michael M. Lederman

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Figure 1

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Comparison of anti-CD3, anti-Vβ3, and TT responses in cells from HIV-inf...
Comparison of anti-CD3, anti-Vβ3, and TT responses in cells from HIV-infected patients and a healthy control. PBMCs from two HIV-infected patients and a healthy donor were labeled with PKH tracking dye and stimulated with either anti-CD3 Ab, anti-Vβ3 Ab, or TT. Other cells were left in medium alone. After 8 days, the cells were stained with Ab’s specific for CD4, Vβ3, or CD25. Cells that stained positive for cell surface markers were selected by gating, and frequency distribution histograms were generated for PKH dye fluorescence. Movement from right to left on the above histograms is evidence for cell division. The stimulus is shown to the left of the histograms, and the cells that were gated on for analysis are shown to the right of the histograms.