Natural IgM antilymphocyte autoantibodies inhibit HIV-1

描述（由申请人提供）：从感染HIV-1到艾滋病发作之间的潜伏期存在显着差异。潜伏期由控制病毒感染性的宿主因素决定。 趋化因子受体（CCR5 和 CXCR4）作为 HIV-1 进入细胞的辅助受体。流行病学数据清楚地表明，表达突变型 CCR5 受体的个体的 HIV-1 感染进展较慢，从而认识到 HIV-1 和趋化因子受体之间相互作用的关键作用。 我们提供的初步数据表明，正常人血清中存在与淋巴细胞上的 CCR5 和 CXCR4 结合的 IgM 自身抗体。 此外，我们的初步研究表明，从正常个体或无症状HIV-1感染个体获得的IgM抗淋巴细胞抗体可显着抑制HIV-1感染细胞。 我们已经证明，具有 HIV-1 抑制活性的 IgM 抗淋巴细胞自身抗体的这一子集在 AIDS 患者中被耗尽。 现阶段，尚不清楚具有 HIV-1 抑制活性的 IgM 抗淋巴细胞抗体亚群是否主要是与淋巴细胞上的趋化因子受体结合的抗体，或者该 HIV-1 抑制亚群是否另外由与非趋化因子受体结合的其他抗体组成，例如到CD4。 这些 IgM 抗 CCR5 和 CXCR4 自身抗体不会显着抑制趋化性，尽管它们部分抑制趋化因子与受体的结合。 在拟议的体外研究中，我们计划重点关注人类 IgM 抗淋巴细胞自身抗体，以更好地表征防止 HIV-1 感染易感细胞的抗淋巴细胞抗体子集。 (i) 人类 B 淋巴细胞将被 EBV 病毒转化，以寻找分泌 IgM 的 B 细胞克隆，这些 IgM 能与淋巴细胞结合并抑制 HIV-1 感染性。将评估每个克隆对一组特定的不同 HIV-1 毒株的抑制活性范围。 一些具有 HIV-1 抑制活性的单克隆 IgM 克隆将进一步评估其与趋化因子受体和 CD4 受体的结合特异性和亲和力及其对趋化性的影响。 (ii) 我们还将确定是否存在分泌与趋化因子受体没有结合活性的 IgM 的 HIV-1 抑制性克隆。 拟议研究的成功结果可以更好地了解 H1V-1 感染的发病机制，并可能提供延长 HIV-1 感染后无症状状态的策略。

DESCRIPTION (provided by applicant): There is a marked variability in the period of latency between infection by HIV- l and the onset of AIDS. The latency period is determined by host factors that control viral infectivity. Chemokine receptors (CCR5 and CXCR4) serve as co-receptors for HIV-1 entry into cells. The pivotal role of the interactions between HIV-1 and chemokine receptor was realized with epidemiological data clearly demonstrating that individuals expressing mutant CCR5 receptors had a slower progression of their HIV-1 infection. We provide preliminary data indicating that IgM autoantibodies that bind to CCR5 and CXCR4 on lymphocytes are present in normal human serum. Futhermore, our preliminary studies show that IgM anti-lymphocyte antibodies obtained from normal individuals or asymptomatic HIV-1 infected individuals significantly inhibits HIV-1 from infecting cells. We have shown that this subset of IgM antilymphocyte autoantibodies with HIV-1 inhibitory activity is depleted in patients with AIDS. At this stage, it is unclear whether the subset of IgM anti-lymphocyte antibody with HIV-1 inhibitory activity is predominantly the antibody that binds to chemokine receptors on the lymphocyte or whether this HIV-1 inhibitory subset in addition consists of other antibodies binding to non-chemokine receptors, e.g. to CD4. These IgM anti-CCR5 and CXCR4 autoantibodies do not significantly inhibit chemotaxis even though they partially inhibit chemokines from binding to the receptors. In the proposed in-vitro studies, we plan to focus on human IgM anti-lymphocyte autoantibodies to better characterize the subset of anti-lymphocyte antibodies that prevent HIV-1 from infecting susceptible cells. (i) Human B lymphocytes will be transformed with EBV virus in an effort to find B cell clones secreting IgM that bind to lymphocytes and inhibit HIV-1 infectivity. Each clone will be evaluated for their range of inhibitory activity towards a defined panel of different HIV-1 strains. Several of the monoclonal IgM clones with HIV-1 inhibitory activity will be further evaluated for their binding specificity and affinity to chemokine receptors and CD4 receptors and their effect on chemotaxis. (ii) We will also determine if there are HIV-1 inhibitory clones secreting IgM that has no binding activity to chemokine receptors. A successful outcome with the proposed studies could better our understanding on pathogenesis of H1V-1 infection and may provide strategies to prolong the asymptomatic state after HIV-1 infection.