Kanner S B, Haffar O K
Department of Immunodeficiency/Immunosuppression, Bristol-Myers Squibb Pharmaceutical Research Institute, Seattle, WA 98121.
J Immunol. 1995 Mar 15;154(6):2996-3005.
One consequence of HIV type 1 (HIV-1) infection is the gradual loss of responsiveness of T lymphocytes to Ags both in vitro and in vivo. It has been suggested that the underlying mechanism that contributes to this T cell dysfunction before CD4+ cell decline involves down-regulation of surface receptors, alterations in intracellular redox status, interference by viral Ags, and later in infection, the absence or alteration of specific cytokine production. In this report, we demonstrate that infection of the T-lymphocytic cell line H9 with the LAI isolate of HIV-1 results in profoundly altered regulation of CD4-induced costimulation of TCR/CD3-directed signaling. TCR/CD3-induced tyrosine phosphorylation of the intracellular enzyme phospholipase-C gamma 1 and the surface receptor/substrates CD5 and CD6 was unaffected by virus infection, whereas augmented responses normally observed after the co-ligation of CD4 with TCR/CD3 on T lymphocytes were absent in HIV-1-infected H9 cells. Costimulation of TCR/CD3-induced signaling via MHC class II molecules was also down-regulated in virally infected cells. TCR/CD3 and HLA-DR receptor expression remained intact in infected cultures for at least 3 wk, whereas CD4 surface expression was gradually lost but maintained for up to 1 wk, suggesting that the absence of costimulation early in infection was not surface receptor density-dependent. In HIV-1-infected cells, CD4 was not physically linked with its associated tyrosine kinase p56lck, whereas normal levels of p56lck were readily recovered from the cellular cytoplasm. Similar observations were noted in cultures of H9 cells infected with a field isolate of HIV-1 obtained from cultured PBMC from an infected donor. HIV-1 infection of T lymphocytes thus down-regulates potentially critical early signal transduction events by a mechanism that appears to involve interference of CD4 receptor association with p56lck. A potential outcome of these biochemical effects may include the limited responsiveness of infected T cells to antigenic stimulation observed during HIV-1 infection.
1型人类免疫缺陷病毒（HIV-1）感染的一个后果是T淋巴细胞在体外和体内对抗原的反应性逐渐丧失。有人提出，在CD4+细胞数量下降之前导致这种T细胞功能障碍的潜在机制包括表面受体下调、细胞内氧化还原状态改变、病毒抗原干扰，以及在感染后期特定细胞因子产生的缺失或改变。在本报告中，我们证明用HIV-1的LAI分离株感染T淋巴细胞系H9会导致CD4诱导的TCR/CD3定向信号共刺激的调节发生深刻改变。TCR/CD3诱导的细胞内酶磷脂酶Cγ1以及表面受体/底物CD5和CD6的酪氨酸磷酸化不受病毒感染影响，而在HIV-1感染的H9细胞中，T淋巴细胞上CD4与TCR/CD3共连接后通常观察到的增强反应却不存在。病毒感染的细胞中，通过MHC II类分子对TCR/CD3诱导信号的共刺激也下调。在感染培养物中，TCR/CD3和HLA-DR受体表达至少3周保持完整，而CD4表面表达逐渐丧失，但最多维持1周，这表明感染早期共刺激的缺失并非表面受体密度依赖性。在HIV-1感染的细胞中，CD4与其相关的酪氨酸激酶p56lck没有物理连接，而p56lck的正常水平很容易从细胞质中恢复。在用从一名感染供体的培养外周血单核细胞获得的HIV-1现场分离株感染的H9细胞培养物中也观察到类似现象。因此，HIV-1感染T淋巴细胞通过一种似乎涉及CD4受体与p56lck结合受干扰的机制下调潜在关键的早期信号转导事件。这些生化效应的一个潜在结果可能包括HIV-1感染期间观察到的受感染T细胞对抗原刺激的反应性有限。
