Antibody Neutralization and Escape of Subtype C HIV-1

描述（由申请人提供）：HIV-1的遗传多样性亚型和重组形式在地球仪的不同地区传播，是当前艾滋病流行的基础。这种病毒多样性的生物学后果知之甚少，并对疫苗接种构成了重大挑战。在HIV-1感染的患者中，免疫系统产生针对HIV-1包膜糖蛋白的中和抗体，但这些蛋白质在序列上高度可变，特别是在亚型之间，并且它们利用复杂的机制来避免免疫识别。因此，对携带全球流行的HIV-1基因亚型的患者中病毒中和和逃逸的研究具有重大意义。拟议研究的目标是更好地了解抗体如何中和在撒哈拉以南非洲占主导地位的C亚型HIV-1，并确定病毒如何逃脱免疫识别。这些研究将使用病毒包膜克隆进行，这些病毒包膜克隆来源于赞比亚不一致夫妇队列中最近感染的未经治疗受试者的纵向收集材料（血细胞DNA和血浆），其中C亚型HIV-1占主导地位。将使用单轮感染试验评价患者血浆中抗体中和自体病毒包膜克隆的能力，并使用分子方法分离患者源性抗体，鉴定中和靶点并重建病毒逃逸途径。突变模式发生在一个螺旋结构域的信封和周边相关的中和逃逸也将进行调查。的假设是，（i）在早期亚型C感染的主要逃逸途径不同的报道占主导地位的亚型B感染，（ii）这些逃逸途径进行健身成本，并依赖于辅助的变化？2螺旋，和（iii）C亚型感染中的B细胞应答靶向Env的菌株特异性和共享区域，其不同于亚型B感染所定义的那些。 公共卫生相关性：HIV-1感染中的中和抗体针对包膜（Env）糖蛋白gp 120和gp 41。然而，HIV-1 Env利用高度有效但定义不明确的重叠机制来逃避抗体介导的中和。我们缺乏关于B细胞反应、自体中和靶点和C亚型感染中病毒逃逸机制的信息，这表明我们对全球最主要的HIV-1变异体的理解存在重大差距。因此，这些研究的目的是确定B细胞靶点，并确定新感染的C亚型患者中病毒中和和逃逸的机制。

DESCRIPTION (provided by applicant): Genetically diverse subtypes and recombinant forms of HIV-1 circulate in different regions of the globe and are the basis of the current AIDS pandemic. The biological consequences of this viral diversity are poorly understood and pose a substantial challenge for vaccination. In HIV-1 infected patients, the immune system makes neutralizing antibodies against the HIV-1 envelope glycoproteins, but these proteins are highly variable in sequence, especially between subtypes, and they utilize sophisticated mechanisms to avoid immune recognition. The study of virus neutralization and escape in patients that harbor globally prevalent genetic subtypes of HIV-1 is therefore of substantial interest. The goal of the proposed studies is to better understand how antibodies neutralize subtype C HIV-1, which predominates in sub-Saharan Africa, and to determine how the virus escapes from immune recognition. The studies will be performed using viral envelope clones derived from longitudinally collected material (blood cell DNA and plasma) from recently infected, treatment-naive subjects in a discordant couple cohort in Zambia, where subtype C HIV-1 predominates. The ability of antibodies in patient plasma to neutralize autologous viral envelope clones will be evaluated for a panel of 15 seroconvertors using a single round infection assay, and molecular approaches will be used to isolate patient-derived antibodies, identify neutralization targets, and reconstruct pathways of viral escape. Mutational patterns that occur in a helical domain of the envelope and are peripherally associated with neutralization escape will also be investigated. The hypotheses are that (i) the major escape pathways operative in early subtype C infection differ from those reported to dominate in subtype B infection, (ii) these escape pathways carry a fitness cost and are dependent on ancillary changes in the ?2 helix, and (iii) B cell responses in subtype C infection target strain-specific and shared regions of Env that are distinct from those defined for subtype B infection. PUBLIC HEALTH RELEVANCE: Neutralizing antibodies in HIV-1 infection are directed against the envelope (Env) glycoproteins gp120 and gp41. However, HIV-1 Env utilizes highly effective, but poorly defined, overlapping mechanisms to evade antibody-mediated neutralization. Our lack of information about the B cell responses, targets of autologous neutralization, and mechanisms of viral escape in subtype C infection represents a significant gap in our understanding of the most predominant HIV-1 variants worldwide. The goal of these studies is therefore to identify B cell targets and define mechanisms of virus neutralization and escape in newly infected subtype C patients.