Human T Lymphotropic Virus Type 1 SU Residue 195 Plays a Role in Determining the Preferential CD4+ T Cell Immortalization/Transformation Tropism
Human T Lymphotropic Virus Type 1 SU Residue 195 Plays a Role in Determining the Preferential CD4+ T Cell Immortalization/Transformation Tropism
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DOI：
10.1128/jvi.01079-13
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发表时间：
2013-08-01
影响因子：
5.4
通讯作者：
Green，Patrick L.
中科院分区：
文献类型：
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作者：
Kannian，Priya;Fernandez，Soledad;Green，Patrick L.
人类 T 淋巴细胞病毒 1 型 (HTLV-1) 主要引起成人 T 细胞白血病，并主要使培养物中的 CD4+T 细胞永生化/转化。 HTLV-2 是白血病细胞，主要使培养物中的 CD8+T 细胞永生化/转化。我们之前已经证明，病毒包膜是培养物中 T 细胞向性差异的遗传决定因素。 HTLV-1 包膜的表面成分 (SU) 负责与细胞受体结合并进入。在这里，我们进一步剖析 HTLV-1 SU，以确定参与确定永生向性的关键域。我们生成了包含 HTLV-2 SU 结构域的 HTLV-1 包膜重组病毒。 HTLV-1/SU2能够感染培养物中新鲜分离的外周血单核细胞并使其永生化。 HTLV-1/SU2 将野生型 HTLV-1 (wtHTLV-1) 的 CD4+T 细胞永生化倾向转变为 CD8+T 细胞偏好。此外，HTLV-1 SU (Ach.195) 中的单个氨基酸取代 N195D 导致 CD8+T 细胞永生化倾向偏好的转变。体外转化过程的纵向表型分析显示，在 wtHTLV-1 培养物中，CD4+T 细胞在第 5 周时成为主要群体，而 CD8+T 细胞分别在 wtHTLV-2 和 Ach.195 培养物中在第 4 周和第 7 周时成为主要群体。我们的结果表明，SU 结构域独立影响优先 T 细胞永生化向性，与包膜对应的跨膜 (TM) 结构域无关。我们进一步表明，HTLV-1 SU 中第 195 位的天冬酰胺参与决定这种 CD4+T 细胞永生化倾向。在 Ach.195 感染的培养物中 CD8+T 细胞优势的出现较慢表明其他残基/结构域有助于这种向性偏好。
Human T lymphotropic virus type 1 (HTLV-1) mainly causes adult T cell leukemia and predominantly immortalizes/transforms CD4+T cells in culture. HTLV-2 is aleukemic and predominantly immortalizes/transforms CD8+T cells in culture. We have shown previously that the viral envelope is the genetic determinant of the differential T cell tropism in culture. The surface component (SU) of the HTLV-1 envelope is responsible for binding to the cellular receptors for entry. Here, we dissect the HTLV-1 SU further to identify key domains that are involved in determining the immortalization tropism. We generated HTLV-1 envelope recombinant virus containing the HTLV-2 SU domain. HTLV-1/SU2 was capable of infecting and immortalizing freshly isolated peripheral blood mononuclear cells in culture. HTLV-1/SU2 shifted the CD4+T cell immortalization tropism of wild-type HTLV-1 (wtHTLV-1) to a CD8+T cell preference. Furthermore, a single amino acid substitution, N195D, in HTLV-1 SU (Ach.195) resulted in a shift to a CD8+T cell immortalization tropism preference. Longitudinal phenotyping analyses of thein vitrotransformation process revealed that CD4+T cells emerged as the predominant population by week 5 in wtHTLV-1 cultures, while CD8+T cells emerged as the predominant population by weeks 4 and 7 in wtHTLV-2 and Ach.195 cultures, respectively. Our results indicate that SU domain independently influences the preferential T cell immortalization tropism irrespective of the envelope counterpart transmembrane (TM) domain. We further showed that asparagine at position 195 in HTLV-1 SU is involved in determining this CD4+T cell immortalization tropism. The slower emergence of the CD8+T cell predominance in Ach.195-infected cultures suggests that other residues/domains contribute to this tropism preference.