Role of gp-340 in HIV Infection and Transmission

描述（由申请方提供）：HIV-1进入靶细胞需要病毒包膜（Env）蛋白、CD 4和趋化因子受体辅助受体之间的相互作用。病毒附着于细胞表面，这可能是感染的限速步骤，可以通过与多种分子的相互作用来介导，其中只有一些分子已经被很好地表征。GP-340是清道夫受体富含半胱氨酸家族的成员。它存在于肺泡巨噬细胞上，并结合表面活性剂蛋白以清除细菌，作为肺先天免疫系统的一部分。我们先前证明gp-340以高亲和力结合HIV Env，并且以其可溶形式抑制HIV感染。某些针对gp-340的特异性抗体抑制Env与gp-340的结合，并且用这种抗体处理表达细胞表面gp-340的单核细胞衍生的巨噬细胞减少了急性HIV-1感染;这表明可溶性和细胞表面gp-340对病毒感染具有相反的作用。GP-340也由上皮细胞表达，包括排列在生殖道上的上皮细胞。我们观察到用HIV脉冲表达gp-340的生殖器上皮细胞导致感染有效结合并转移至CD 4 + T细胞（反式感染）。gp-340的结合增加了病毒的感染性和半衰期，并且可以被抗gp-340抗体和显示与gp-340结合的Env肽抑制。与不介导融合但促进结合Env碳水化合物的跨感染的其他HIV Env结合分子（DC-SIGN、多配体聚糖和甘露糖受体）不同，gp-340和Env之间的相互作用似乎涉及Env上的蛋白质。该假说是通过gp-340和HIV Env之间的特异性相互作用; gp-340介导反式HIV感染。我们将从四个方面来验证这一假设：1）确定gp-340-Tm与HIV Env结合的表位和氨基酸残基，2）分析与gp-340-Tm结合的重要Env决定簇，3）研究gp-340-Tm在HIV传播中的作用，4）研究gp-340-Tm在HIV感染中的作用。和4）HIV与表达内源性gp-340的生殖道上皮细胞结合后的运输研究。由于gp-340在HIV免疫发病机制（肺、脑、淋巴组织）和传播（生殖器上皮细胞）的许多领域中表达，这些研究对于进一步了解HIV传播和发病机制以及制定干扰HIV传播、感染和复制的潜在途径将非常重要。

DESCRIPTION (provided by applicant): The entry of HIV-1 into target cells requires interactions between the viral envelope (Env) protein, CD4, and a chemokine receptor coreceptor. Attachment of virus to the cell surface, which may be the rate limiting step to infection, can be mediated by interactions with a variety of molecules, only some of which have been well characterized. Gp-340 is a member of the scavenger receptor cysteine-rich family. It is found on alveolar macrophages and binds surfactant proteins to clear bacteria as part of the lung innate immune system. We previously demonstrated that gp-340 binds HIV Env with high affinity and, in its soluble form, inhibits HIV infection. Certain specific antibodies against gp-340 inhibit binding of Env to gp-340 and treatment of monocyte derived macrophages expressing cell surface gp-340 with such antibodies diminishes acute HIV-1 infection; suggesting that soluble and cell surface gp-340 have opposite effects on viral infection. Gp-340 is also expressed by epithelial cells including ones that line the genital tract. We observed that pulsing of genital epithelial cells expressing gp-340 with HIV results in efficient binding and transfer of infection to CD4+ T cells trans-infection). The binding by gp-340 increases the infectivity and half-life of virus and can be inhibited by anti-gp-340 antibodies and Env peptides shown to bind to gp-340. Unlike other HIV Env binding molecules that do not mediate fusion but promote trans-infection (DC-SIGN, syndecan, and mannose receptor) that bind Env carbohydrate, the interaction between gp-340 and Env appears to involve protein on Env. The hypothesis is that through specific interactions between gp-340 and HIV Env; gp-340 mediates trans- HIV infection. We will test this hypothesis in four specific aims: 1) the Identification of the epitope and amino acid residues of gp-340-Tm used in binding to HIV Env; 2) the analysis of Env determinants important in binding to gp-340-Tm; 3) the investigation of the role of gp-340-Tm in transmission of HIV; and 4) studies of the trafficking of HIV after binding to genital tract epithelial cells expressing endogenous gp-340. As gp-340 is expressed in many areas of HIV immunopathogenesis (lung, brain, lymphoid tissue) and transmission (genital epithelial cells), these studies will be important in further understanding HIV transmission and pathogenesis and for formulating potential avenues of interference in HIV transmission, infection, and replication.