Fredericksen Brenda L, Wei Bangdong L, Yao Jian, Luo Tianci, Garcia J Victor
Department of Internal Medicine, Division of Infectious Diseases, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390, USA.
J Virol. 2002 Nov;76(22):11440-6. doi: 10.1128/jvi.76.22.11440-11446.2002.
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 A1 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, HIV-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.
人们认为，人类免疫缺陷病毒1型（HIV-1）有效进入宿主细胞是通过病毒包膜与宿主细胞质膜融合来实现的。有趣的是，大多数与细胞表面结合的HIV-1颗粒会被宿主细胞通过内吞作用摄取；然而，这种内化模式通常不会导致感染。据推测，病毒颗粒被困在内吞途径中，最终被降解。在此，我们证明，用已知可提高内体和溶酶体pH值的各种药理试剂处理细胞，可使HIV-1有效进入并感染宿主细胞。用巴弗洛霉素A1预处理细胞可使HIV-1（SF2）的感染性提高多达50倍。同样，用金刚烷胺、抗霉素A、抗霉素B、氯喹和氯化铵预处理靶细胞可使HIV-1感染性提高2至15倍。对受体和共受体表达、HIV长末端重复序列（LTR）反式激活以及用基于双嗜性假型鼠白血病病毒（MLV）的载体进行转导的分析表明，感染性的增加并非人为造成。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能够通过内吞途径进入。这些结果可能对向HIV疾病患者施用当前和未来的溶酶体促渗剂具有重要意义。
