Humoral immune responses to HIV clade C isolates

由于在天然病毒粒子上表达的HIV包膜的固有结构特性，广泛有效的HIV-12免疫疗法的发展受到限制。HIV感染涉及一系列env抗原结构和表位呈递的逐步变化，在此过程中病毒展开并暴露中和的表位靠近靶细胞表面结构。我们提出，免疫系统很难在高阶整合中做出反应，其中抗体反应修改包膜以暴露然后识别暴露的中和表位。这种更高的整合必须通过主动或被动免疫强加于免疫系统，其中诱导或包括多种抗体，这些抗体共同介导病毒中和，我们使用了含有初级分离病毒粒子的测定。当对B支系感染者的血清进行IgG抗体检测时，36%的感染者捕获了病毒，但只有7%的感染者捕获了大量病毒。病毒粒子特异性抗体与CD4计数相关，更重要的是，初级分离物中和。与初级分离病毒粒子反应的抗体的低流行率可能与血清一般无法中和初级分离病毒有关。迄今为止，大多数研究都是利用B支分离株，相对而言，关于中和对其他分支分离株的抗体反应的信息很少。由于C枝的感染占全球感染的一半以上，我们建议分离和表征与C枝初级分离病毒粒子反应的人单克隆抗体，以研究这些感染中的中和抗体反应。这些抗体将进一步用于新生猕猴粘膜攻击的被动免疫研究。确定这些抗体用于被动免疫的功效将有助于设计广泛有效的主动疫苗疗法。

Development of a broadly effective HIV-12 immunotherapy has been limited because of the inherent structural properties the HIV envelope expressed on the native virion. HIV infection involves a series of stepwise changes in env antigenic structures and epitope presentation during which the virus unfolds and exposes neutralizing epitopes in close proximity to the target cell surface structure. We propose, that it is difficult for the immune system to respond in a higher order integration in which an antibody response an modify the envelope to expose and then recognize exposed neutralizing epitopes. This higher integration must be imposed on the immune system through active or passive immunization in which multiple classes of antibodies are induced or included which together mediate viral neutralization, we have used an assay incorporating primary isolate virions. When serum from clade B infected individuals was tested for IgG antibodies, 36% of infected individuals captured virus but only 7% of these individuals captured significant quantities of virus. Virion specific antibody correlated with CD4 counts, and of more significance, primary isolate neutralization. The low prevalence of antibodies reactive with primary isolate virions may be related to the general inability of sera to neutralize primary isolates. Most studies to date have utilized clade B isolates with relatively little information as to neutralizing antibody responses to isolates of other clades. Since infection with clade C accounts for over half of the infections wold-wide, we propose to isolate and characterize human monoclonal antibodies reactive with clade C primary isolate virions to study the neutralizing antibody response in these infections. These antibodies will be further studied for passive immunization against mucosal challenge in neonatal macaques. Determinations of the efficacy of the these antibodies for passive immunization will facilitate the design of broadly effective active vaccine therapies.