Sieg S F, Harding C V, Lederman M M
Department of Medicine, Division of Infectious Diseases, Center for AIDS Research, Case Western Reserve University, Cleveland, Ohio, USA.
J Clin Invest. 2001 Sep;108(5):757-64. doi: 10.1172/JCI12685.
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-Vbeta3 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-Vbeta3 Ab stimulation, CD4(+)Vbeta3(+) 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.
CD4(+) T细胞对抗抗原刺激的增殖失败是HIV感染的一个特征。由于无法识别对抗原具有T细胞受体特异性的CD4(+)细胞，对增殖缺陷的分析受到了阻碍。为了仅关注通过T细胞受体被刺激的细胞，用一种能激活约3 - 5%外周血T细胞的抗Vbeta3抗体刺激CD4(+) T细胞。这种方法揭示了HIV感染患者细胞中的增殖缺陷，而使用抗CD3抗体刺激时并未发现这些缺陷，并且提供了在单细胞水平上检测反应的能力。在用抗Vbeta3抗体刺激后，HIV感染患者的CD4(+)Vbeta3(+)细胞在细胞周期相关蛋白、D型细胞周期蛋白和细胞周期蛋白A的表达上表现出缺陷。然而，大多数患者细胞中早期激活标志物CD69和CD25的表达并未受到显著损害。因此，HIV疾病中CD4(+) T细胞增殖失败的特征是激活失调，这阻止了细胞周期的进展。这种增殖缺陷在CD4(+) T细胞数量减少且血浆HIV RNA水平较高的患者中最为明显。CD4(+) T细胞增殖失败可能是HIV疾病中免疫损害的关键决定因素。
