Effects of Cross-Presentation, Antigen Processing, and Peptide Binding in HIV Evasion of T Cell Immunity.
Effects of Cross-Presentation, Antigen Processing, and Peptide Binding in HIV Evasion of T Cell Immunity.
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DOI：
10.4049/jimmunol.1701523
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发表时间：
2018-03-01
期刊：
影响因子：
--
通讯作者：
Berzofsky JA
中科院分区：
文献类型：
--
作者：
Frey BF;Jiang J;Sui Y;Boyd LF;Yu B;Tatsuno G;Billeskov R;Solaymani-Mohammadi S;Berman PW;Margulies DH;Berzofsky JA
与病毒感染细胞对病毒抗原的胞质处理和呈递不同，抗原首先在受感染的非专业抗原呈递细胞（例如 HIV 中的 CD4+ T 细胞）中表达，然后被树突状细胞摄取，然后进行交叉呈递。这通常需要通过内吞途径进入，内体蛋白酶首先进入内吞途径进行加工。因此，了解病毒在交叉呈递过程中的逃逸需要了解对内体蛋白酶（如组织蛋白酶 S）的抗性。我们通过将免疫显性表位 IGPGRAFYTT 的 V3 环中的关键组织蛋白酶 S 切割位点 T322T323 突变为 IGPGRAFYVV，对 HIV-1MN gp120 (gp120MN) 进行了修饰，以防止消化。我们发现这种突变促进了交叉呈递，并从 MHC 结合和 X 射线晶体结构研究中提供了证据，表明这是由于表位的保留而不是对 I 类 MHC 分子的表位亲和力增加所致。相反，当蛋白质由痘苗病毒在胞浆中表达时，野生型蛋白质具有免疫原性，而没有这种突变。这些结果证明，像HIV这样的病毒主要感染非专业呈递细胞，可以通过掺入组织蛋白酶S切割位点来逃避T细胞识别，当抗原经历内体交叉呈递时，该切割位点会导致免疫显性表位被破坏。
Unlike cytosolic processing and presentation of viral antigens by virus-infected cells, antigens first expressed in an infected non-professional antigen-presenting cell, such as CD4+ T cells in the case of HIV, and then taken up by dendritic cells are cross-presented. This generally requires entry through the endocytic pathway, where endosomal proteases have first access for processing. Thus, understanding virus escape during cross-presentation requires an understanding of resistance to endosomal proteases such as cathepsin S. We have modified HIV-1MN gp120 (gp120MN) by mutating a key cathepsin S cleavage site T322T323 in the V3 loop of the immunodominant epitope IGPGRAFYTT to IGPGRAFYVV to prevent digestion. We found this mutation to facilitate cross-presentation, and provide evidence from both MHC-binding and X-ray crystallographic structural studies that this results from preservation of the epitope rather than an increased epitope affinity for the class I MHC molecule. In contrast, when the protein is expressed by a vaccinia virus in the cytosol, the wild type protein is immunogenic without this mutation. These results demonstrate proof-of-concept that a virus like HIV, infecting predominantly non-professional presenting cells, can escape T cell recognition by incorporating a cathepsin S cleavage site that leads to destruction of an immunodominant epitope when the antigen undergoes endosomal cross-presentation.
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影响因子：
4.4
作者：
Honda, Mitsuo;Wang, Rui;Nabel, Gary J.
通讯作者：
Nabel, Gary J.
影响因子：
5.6
作者：
Li, HM;Natarajan, K;Mariuzza, RA
通讯作者：
Mariuzza, RA
癌症免疫疗法。树突状细胞疫苗增加了黑色素瘤新抗原特异性T细胞的广度和多样性。
DOI：
10.1126/science.aaa3828
发表时间：
2015-05-15
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Carreno BM;Magrini V;Becker-Hapak M;Kaabinejadian S;Hundal J;Petti AA;Ly A;Lie WR;Hildebrand WH;Mardis ER;Linette GP
通讯作者：
Linette GP
影响因子：
29.7
作者：
Blum JS;Wearsch PA;Cresswell P
通讯作者：
Cresswell P
DOI：
10.1107/s0907444909052925
发表时间：
2010-02
期刊：
Acta crystallographica. Section D, Biological crystallography
影响因子：
--
作者：
Adams PD;Afonine PV;Bunkóczi G;Chen VB;Davis IW;Echols N;Headd JJ;Hung LW;Kapral GJ;Grosse-Kunstleve RW;McCoy AJ;Moriarty NW;Oeffner R;Read RJ;Richardson DC;Richardson JS;Terwilliger TC;Zwart PH
通讯作者：
Zwart PH