Inhibition of endosomal/lysosomal degradation increases the infectivity of human immunodeficiency virus
Inhibition of endosomal/lysosomal degradation increases the infectivity of human immunodeficiency virus
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DOI：
10.1128/jvi.76.22.11440-11446.2002
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发表时间：
2002-11-01
影响因子：
5.4
通讯作者：
Garcia, JV
中科院分区：
文献类型：
--
作者：
Fredericksen, BL;Wei, BL;Garcia, JV
人类免疫缺陷病毒1型（HIV-1）进入宿主细胞的生产性进入被认为是通过病毒包膜与宿主细胞质膜的融合进行的。有趣的是，大多数与细胞表面结合的HIV-1颗粒通过内吞作用被宿主细胞吸收;然而，这种内化模式通常不会导致感染。据推测，病毒颗粒仍然被困在内吞途径中，并最终被吞噬。退化了在这里，我们证明了用已知提高内体和溶酶体的pH的各种药理学试剂处理细胞允许HIV-1有效地进入并感染宿主细胞。用巴弗洛霉素Al预处理细胞导致HIV-1（SF 2）的感染性增加高达50倍。同样，用金刚烷胺、康卡那霉素A、康卡那霉素B、氯喹和氯化铵预处理靶细胞导致HIV-1感染性增加2- 15倍。受体和辅助受体表达，HTV-长末端重复序列（LTR）的反式激活，并与嗜热假型小鼠白血病病毒（MLV）为基础的载体转导的分析表明，感染性的增加是不是人为的。在这些条件下感染性增加似乎是由于HIV-1和MLV颗粒在晚期内体和溶酶体中免于降解时通过内吞途径进入的能力。这些结果可能有显着的影响，目前和未来的溶动剂的管理，艾滋病毒疾病的患者。
Productive entry of human immunodeficiency virus type 1 (HIV-1) into a host cell is believed to proceed via fusion of the viral envelope with the host cell's plasma membrane. Interestingly, the majority of HIV-1 particles that bind to the cell surface are taken up by the host cell via endocytosis; however, this mode of internalization generally does not result in infection. Presumably, virus particles remain trapped in the endocytic pathway and are eventually. degraded. Here, we demonstrate that treatment of cells with various pharmacological agents known to elevate the pH of endosomes and lysosomes allows HIV-1 to efficiently enter and infect the host cell. Pretreatment of cells with bafilomycin Al results in up to a 50-fold increase in the infectivity of HIV-1(SF2). Similarly, pretreatment of target cells with amantadine, concanamycin A, concanamycin B, chloroquine, and ammonium chloride resulted in increases in HIV-1 infectivity ranging between 2- and 15-fold. Analysis of receptor and coreceptor expression, HTV-long terminal repeat (LTR) transactivation, and transduction with amphotropic-pseudotyped murine leukemia virus (MLV)-based vectors suggests that the increase in infectivity is not artifactual. The increased infectivity under these conditions appears to be due to the ability of HIV-1 and MLV particles to enter via the endocytic pathway when spared from degradation in the late endosomes and lysosomes. These results could have significant implications for the administration of current and future lysosmotropic agents to patients with, HIV disease.