Laboratory of Immunoregulation, National Institutes of Health, Bethesda, MD 20814;
Instituto Nacional de Câncer, Rio de Janeiro, 20231-050, Brazil.
Proc Natl Acad Sci U S A. 2020 Dec 22;117(51):32566-32573. doi: 10.1073/pnas.2011501117. Epub 2020 Dec 7.
Acute HIV infection is characterized by rapid viral seeding of immunologic inductive sites in the gut followed by the severe depletion of gut CD4 T cells. Trafficking of αβ-expressing lymphocytes to the gut is mediated by MAdCAM, the natural ligand of αβ that is expressed on gut endothelial cells. MAdCAM signaling through αβ costimulates CD4 T cells and promotes HIV replication. Similar to MAdCAM, the V2 domain of the gp120 HIV envelope protein binds to αβ In this study, we report that gp120 V2 shares with MAdCAM the capacity to signal through αβ resulting in CD4 T cell activation and proliferation. As with MAdCAM-mediated costimulation, cellular activation induced by gp120 V2 is inhibited by anti-αβ monoclonal antibodies (mAbs). It is also inhibited by anti-V2 domain antibodies including nonneutralizing mAbs that recognize an epitope in V2 that has been linked to reduced risk of acquisition in the RV144 vaccine trial. The capacity of the V2 domain of gp120 to mediate signaling through αβ likely impacts early events in HIV infection. The capacity of nonneutralizing V2 antibodies to block this activity reveals a previously unrecognized mechanism whereby such antibodies might impact HIV transmission and pathogenesis.
急性 HIV 感染的特征是病毒迅速在肠道的免疫诱导部位定植，随后肠道 CD4 T 细胞严重耗竭。αβ 表达淋巴细胞向肠道的迁移是由 MAdCAM 介导的，MAdCAM 是肠道内皮细胞表达的 αβ 的天然配体。MAdCAM 通过 αβ 共刺激 CD4 T 细胞并促进 HIV 复制。类似于 MAdCAM，HIV 包膜蛋白的 gp120 V2 结构域与 αβ 结合。在这项研究中，我们报告 gp120 V2 与 MAdCAM 具有相同的信号转导能力，导致 CD4 T 细胞活化和增殖。与 MAdCAM 介导的共刺激一样，gp120 V2 诱导的细胞活化被抗 αβ 单克隆抗体（mAbs）抑制。它也被抗 V2 结构域抗体抑制，包括非中和 mAbs，这些 mAbs 识别 V2 中的一个表位，该表位与 RV144 疫苗试验中获得风险降低有关。gp120 V2 结构域介导信号转导通过 αβ 的能力可能会影响 HIV 感染的早期事件。非中和 V2 抗体阻断这种活性的能力揭示了一种以前未被认识的机制，通过这种机制，这种抗体可能会影响 HIV 的传播和发病机制。
