Role of Fc Receptor Polymorphisms in Antibody-Mediated Protection

描述（由研究者提供）：最近的研究表明，体内有效中和艾滋病病毒远远超出了抗体对病毒的空间抑制。有效的中和还取决于额外的功能活动，如Fc？受体介导的病毒失活。在人类中已充分确立，抗体的作用取决于增强其靶标的有效杀灭的多种途径。然而，由于抗体的全部潜力需要宿主免疫系统的额外组分，因此抗体介导的免疫控制变得更加复杂。事实上，根据宿主免疫系统内的特定多态性，相同的有效单克隆抗体可能显示出不同的体内功效。这已被证明是详细的Fc？受体多态性，其中特定抗体治疗在某些肿瘤患者中导致临床成功的可能性较低，因为由于患者之间的遗传变异，抗体的下游功能活性效率较低。 在HIV感染中，有限的研究表明，作为Fc？受体多态性也可能影响艾滋病的进展。然而，到目前为止，还没有公布的信息，是否作为Fc？受体多态性可能影响恒河猴中的SIV感染，恒河猴是研究非人灵长类动物中AIDS样疾病最常用的动物模型。我们最近确定为Fc？受体多态性的恒河猴，并已获得统计学证据表明，作为Fc？受体多态性也影响 抗体在这种非人灵长类动物中的体内效力。我们的初步数据还表明，作为Fc？受体多态性可能与不同的抑制SIV设定点病毒血症的能力相关。 虽然这些初步数据非常令人鼓舞，但这些观察结果需要进一步审查。在这里，我们提出的研究，（目的1）将确定不同的多态性形式的功能活性的Fc？恒河猴体内的受体。我们将进行（目的2）一项前瞻性低剂量中和抗体给药和低剂量粘膜激发研究，以研究是否作为Fc？受体多态性可能影响中和抗体B12在保护动物免受阴道攻击中的效力。

DESCRIPTION (provided by investigator): Recent investigations have suggested that efficient neutralization of AIDS viruses in vivo goes well beyond steric inhibition of the virus by antibodies. Efficient neutralization also depends on additional functional activities such as Fc? receptor-mediated deactivation of the virus. It is well established in humans that the action of antibodies depends on multiple pathways that enhance efficient extermination of its target. However, as the full potential of antibodies requires additional components of the host's immune system, antibody-mediated immune control gets more complex. In fact, the same potent monoclonal antibody may show a different in vivo efficacy depending on specific polymorphisms within the host's immune system. This has been demonstrated in detail for as Fc? receptor polymorphisms where a particular antibody treatment in some tumor patients has resulted in an inferior likelihood of clinical success because the downstream functional activities for the antibody were less efficient due to genetic variation between patients. In HIV infection, limited research has suggested that as Fc? receptor polymorphisms may also affect the progression to AIDS. However, until to date there is no published information available whether as Fc? receptor polymorphisms may affect SIV infection in rhesus macaques that are the most utilized animal model to study an AIDS-like disease in nonhuman primates. We have recently determined as Fc? receptor polymorphisms in rhesus macaques and have gained statistical evidence that as Fc? receptor polymorphisms also affect the in vivo efficacy of antibodies in this nonhuman primate species. Our preliminary data also suggest that as Fc? receptor polymorphisms may be correlated with a differential ability to contain SIV setpoint viremia. While these preliminary data are very encouraging, these observations need more scrutiny. Here we propose studies that (Aim 1) will determine the functional activity of different polymorphic forms of the as Fc? receptors in rhesus macaques. We will conduct (Aim 2) a prospective low dose neutralizing antibody administration and low dose mucosal challenge study to investigate whether as Fc? receptor polymorphisms may impact the efficacy of the neutralizing antibody b12 in protecting the animals from vaginal challenges.