HIV-1 superinfection in women broadens and strengthens the neutralizing antibody response.
HIV-1 superinfection in women broadens and strengthens the neutralizing antibody response.
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DOI：
10.1371/journal.ppat.1002611
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发表时间：
2012
期刊：
影响因子：
6.7
通讯作者：
Overbaugh J
中科院分区：
文献类型：
--
作者：
Cortez V;Odem-Davis K;McClelland RS;Jaoko W;Overbaugh J
鉴定对HIV-1所有全球亚型具有交叉反应的自然产生的中和抗体（NAb）是开发疫苗的重要一步。建立宿主和病毒决定因子以诱导这种广泛的nab也是免疫原设计的关键。NAb宽度先前已被证明与病毒多样性呈正相关。因此，我们假设，由于两种不同病毒的抗原刺激增加，超感染个体产生了广泛的NAb反应。为了验证这一假设，在重复感染后（初次感染后~ 5年）的匹配时间点，对12名重复感染妇女的血浆样本进行了检测，这些血浆样本代表了四种不同的HIV-1亚型的八种病毒。我们发现，与单一感染者相比，重复感染个体在重复感染后出现了明显更广泛的NAb反应（RR = 1.68, CI: 1.23-2.30, p = 0.001）。即使在控制了重复感染前形成的NAb宽度、同期CD4+ T细胞计数和病毒载量之后，这也是正确的。同样，未经调整和调整的分析均显示，与对照组相比，超感染病例的效力明显更高。值得注意的是，两名超感染个体能够在血浆稀释度bb1∶300时中和四种不同亚型的变异，这表明他们的nab具有精英活性。交叉亚型宽度在这两个个体的重复感染的一年内被检测到，这是在他们的首次感染的1.5年内。这些数据表明，连续感染导致NAb反应增强，这一过程可能为促进抗体广度发展的潜在机制提供见解。因此，模仿重复感染的成功疫苗接种策略可能导致免疫个体中广泛nab的发展。广泛而有效的抗体反应被认为是有效的HIV-1疫苗的必要条件，这种疫苗将保护人们免受各种流行毒株的侵害。因此，人们对影响自然HIV-1感染中中和抗体（NAb）反应发展的宿主和病毒因素都很感兴趣。感染了来自不同来源伴侣的第二种病毒的hiv感染者是研究抗体反应的独特案例，因为重复感染反映了暴露于不同的HIV-1抗原变体，因此可能为广泛nab的发展提供见解。为了支持这一模型，我们在这里表明，超感染个体比单一感染个体产生更广泛和更有效的NAb反应，这一结果可能是由于来自两种病毒的抗原刺激比一种病毒增加。在控制了其他已被证明影响nab反应的因素（如CD4+ T细胞计数和病毒载量）后，我们的研究结果保持不变。这项研究表明，重复感染产生的抗体具有识别不同循环HIV-1变体的能力。因此，进一步表征这些超感染个体的NAb反应可能会导致对引发广泛NAb的途径的新见解。
Identifying naturally-occurring neutralizing antibodies (NAb) that are cross-reactive against all global subtypes of HIV-1 is an important step toward the development of a vaccine. Establishing the host and viral determinants for eliciting such broadly NAbs is also critical for immunogen design. NAb breadth has previously been shown to be positively associated with viral diversity. Therefore, we hypothesized that superinfected individuals develop a broad NAb response as a result of increased antigenic stimulation by two distinct viruses. To test this hypothesis, plasma samples from 12 superinfected women each assigned to three singly infected women were tested against a panel of eight viruses representing four different HIV-1 subtypes at matched time points post-superinfection (∼5 years post-initial infection). Here we show superinfected individuals develop significantly broader NAb responses post-superinfection when compared to singly infected individuals (RR = 1.68, CI: 1.23–2.30, p = 0.001). This was true even after controlling for NAb breadth developed prior to superinfection, contemporaneous CD4+ T cell count and viral load. Similarly, both unadjusted and adjusted analyses showed significantly greater potency in superinfected cases compared to controls. Notably, two superinfected individuals were able to neutralize variants from four different subtypes at plasma dilutions >1∶300, suggesting that their NAbs exhibit elite activity. Cross-subtype breadth was detected within a year of superinfection in both of these individuals, which was within 1.5 years of their initial infection. These data suggest that sequential infections lead to augmentation of the NAb response, a process that may provide insight into potential mechanisms that contribute to the development of antibody breadth. Therefore, a successful vaccination strategy that mimics superinfection may lead to the development of broad NAbs in immunized individuals. A broad and potent antibody response is considered essential for an effective HIV-1 vaccine that will protect against diverse circulating strains. Consequently, there is great interest in both the host and viral factors that impact the development of the neutralizing antibody (NAb) response in natural HIV-1 infections. HIV-infected individuals who become superinfected with a second virus from a different source partner represent unique cases for studying the antibody response, as superinfection reflects exposure to different HIV-1 antigenic variants, and hence may provide insight into the development of broadly NAbs. In support of this model, we show here that superinfected individuals develop broader and more potent NAb responses than singly infected individuals, a result that is likely due to the increased antigenic stimulation from two viruses compared to one. Our findings remained unchanged after controlling for other factors that have been shown to influence the NAbs response, such as CD4+ T cell count and viral load. This study demonstrates that superinfection yields antibodies that have the capacity to recognize diverse circulating HIV-1 variants. Therefore, further characterization of these superinfected individuals' NAb responses could lead to novel insights into pathways that elicit broadly NAbs.
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