Natural IgM antilymphocyte autoantibodies inhibit HIV-1

描述（由申请人提供）：在HIV-1感染和AIDS发作之间的潜伏期有明显的变化。潜伏期由控制病毒感染性的宿主因素决定。 趋化因子受体（CCR 5和CXCR 4）作为HIV-1进入细胞的共受体。HIV-1和趋化因子受体之间相互作用的关键作用是通过流行病学数据实现的，这些数据清楚地表明表达突变型CCR 5受体的个体的HIV-1感染进展较慢。 我们提供的初步数据表明，IgM自身抗体结合到淋巴细胞上的CCR 5和CXCR 4存在于正常人血清中。 此外，我们的初步研究表明，从正常个体或无症状HIV-1感染者中获得的IgM抗淋巴细胞抗体显著抑制HIV-1感染细胞。 我们已经表明，这一子集的IgM抗淋巴细胞自身抗体与HIV-1抑制活性耗尽艾滋病患者。 在此阶段，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（例如与CD 4）结合的其他抗体组成。 这些IgM抗CCR 5和CXCR 4自身抗体不显著抑制趋化性，即使它们部分抑制趋化因子与受体的结合。 在拟定的体外研究中，我们计划重点关注人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亚群。(i)将用EB病毒转化人类B淋巴细胞，以寻找分泌与淋巴细胞结合并抑制HIV-1传染性的IgM的B细胞克隆。将评价每个克隆对一组定义的不同HIV-1毒株的抑制活性范围。 将进一步评价几种具有HIV-1抑制活性的单克隆IgM克隆对趋化因子受体和CD 4受体的结合特异性和亲和力及其对趋化性的影响。(ii)我们还将确定是否有HIV-1抑制克隆分泌IgM，没有结合活性的趋化因子受体。 本研究的成功结果将有助于我们更好地理解H1 V-1感染的发病机制，并可能为延长HIV-1感染后的无症状状态提供策略。

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.