Steers Nicholas J, Peachman Kristina K, McClain Sasha R, Alving Carl R, Rao Mangala
Henry M Jackson Foundation, Division of Retrovirology, USMHRP, Walter Reed Army Institute of Research, Rockville, MD 20850, USA.
J Virol. 2009 Jul;83(14):7049-61. doi: 10.1128/JVI.00327-09. Epub 2009 Apr 29.
Proteasomes are the major source of proteases responsible for the generation of peptides bound to major histocompatibility complex class I molecules. Antigens, adjuvants, and cytokines can modulate the composition and enzymatic activity of proteasomes and thus alter the epitopes generated. In the present study, we examined the effect of human immunodeficiency virus type 1 (HIV-1) p24 on proteasomes from a dendritic cell line (JAWS II), from a macrophage cell line (C2.3), and from murine primary bone marrow-derived macrophages and dendritic cells. HIV-1 p24 downregulated PA28beta and the beta2i subunit of the immunoproteasome complex in JAWS II cells but did not decrease the immunoproteasome subunits in macrophages, whereas in primary dendritic cells, PA28alpha, beta2i, and beta5i were downregulated. Exposure of JAWS II cells and primary dendritic cells to HIV-1 p24 for 90 min significantly decreased the presentation of ovalbumin to a SIINFEKL-specific CD8(+) T-cell hybridoma. The decrease in antigen presentation and the downmodulation of the immunoproteasome subunits in JAWS II cells and primary dendritic cells could be overcome by pretreating the cells with gamma interferon for 6 h or by exposing the cells to HIV-1 p24 encapsulated in liposomes containing lipid A. These results suggest that early antigen processing kinetics could influence the immunogenicity of CD8(+) T-cell epitopes generated.
蛋白酶体是负责生成与主要组织相容性复合体I类分子结合的肽段的蛋白酶的主要来源。抗原、佐剂和细胞因子可调节蛋白酶体的组成和酶活性，从而改变所产生的表位。在本研究中，我们检测了1型人类免疫缺陷病毒（HIV-1）p24对来自树突状细胞系（JAWS II）、巨噬细胞系（C2.3）以及小鼠原代骨髓来源的巨噬细胞和树突状细胞的蛋白酶体的影响。HIV-1 p24下调了JAWS II细胞中PA28β和免疫蛋白酶体复合物的β2i亚基，但未降低巨噬细胞中的免疫蛋白酶体亚基，而在原代树突状细胞中，PA28α、β2i和β5i均被下调。将JAWS II细胞和原代树突状细胞暴露于HIV-1 p24 90分钟，显著降低了卵清蛋白向SIINFEKL特异性CD8(+) T细胞杂交瘤的呈递。通过用γ干扰素预处理细胞6小时或使细胞暴露于包封在含有脂多糖的脂质体中的HIV-1 p24，可克服JAWS II细胞和原代树突状细胞中抗原呈递的减少和免疫蛋白酶体亚基的下调。这些结果表明，早期抗原加工动力学可能影响所产生的CD8(+) T细胞表位的免疫原性。
