Characteristics of the earliest cross-neutralizing antibody response to HIV-1.

Characteristics of the earliest cross-neutralizing antibody response to HIV-1.

Recent cross-sectional analyses of HIV-1+ plasmas have indicated that broadly cross-reactive neutralizing antibody responses are developed by 10%–30% of HIV-1+ subjects. The timing of the initial development of such anti-viral responses is unknown. It is also unknown whether the emergence of these responses coincides with the appearance of antibody specificities to a single or multiple regions of the viral envelope glycoprotein (Env). Here we analyzed the cross-neutralizing antibody responses in longitudinal plasmas collected soon after and up to seven years after HIV-1 infection. We find that anti-HIV-1 cross-neutralizing antibody responses first become evident on average at 2.5 years and, in rare cases, as early as 1 year following infection. If cross-neutralizing antibody responses do not develop during the first 2–3 years of infection, they most likely will not do so subsequently. Our results indicate a potential link between the development of cross-neutralizing antibody responses and specific activation markers on T cells, and with plasma viremia levels. The earliest cross-neutralizing antibody response targets a limited number of Env regions, primarily the CD4-binding site and epitopes that are not present on monomeric Env, but on the virion-associated trimeric Env form. In contrast, the neutralizing activities of plasmas from subjects that did not develop cross-neutralizing antibody responses target epitopes on monomeric gp120 other than the CD4-BS. Our study provides information that is not only relevant to better understanding the interaction of the human immune system with HIV but may guide the development of effective immunization protocols. Since antibodies to complex epitopes that are present on the virion-associated envelope spike appear to be key components of earliest cross-neutralizing activities of HIV-1+ plasmas, then emphasis should be made to elicit similar antibodies by vaccination. A fraction of those infected with HIV develop broadly neutralizing antibodies (bNAbs) capable of preventing cell-infection by diverse HIV isolates; the type of antibodies we wish to elicit by vaccination. Identifying factors associated with the natural development of bNabs, and defining the timing of their emergence and their epitope specificities, will assist the development of more effective immunogens and vaccination protocols. Here we performed a neutralization screen of plasma samples collected longitudinally from HIV-1-infected subjects and determined that on average, cross-neutralizing antibody responses emerge 2–3 years, but as early as one year, following infection. A significant portion of the earliest cross-neutralizing antibody response to HIV targets epitopes that are present on the virion-associated trimeric Env spike, but not the corresponding soluble monomeric versions of that viral protein. Our study highlights the importance of eliciting by vaccination antibodies with this type of complex epitope specificities.

对HIV - 1阳性血浆的近期横断面分析表明，10% - 30%的HIV - 1阳性受试者产生了广泛交叉反应的中和抗体反应。这种抗病毒反应最初产生的时间尚不清楚。也不清楚这些反应的出现是否与针对病毒包膜糖蛋白（Env）单个或多个区域的抗体特异性的出现相一致。在此，我们分析了在HIV - 1感染后不久直至7年期间收集的纵向血浆中的交叉中和抗体反应。我们发现抗HIV - 1交叉中和抗体反应平均在感染后2.5年首次明显出现，在极少数情况下，早在感染后1年就出现。如果在感染的前2 - 3年没有产生交叉中和抗体反应，那么随后很可能也不会产生。我们的结果表明交叉中和抗体反应的产生与T细胞上的特定激活标志物以及血浆病毒血症水平之间存在潜在联系。最早的交叉中和抗体反应针对有限数量的Env区域，主要是CD4结合位点以及单体Env上不存在但在病毒体相关三聚体Env形式上存在的表位。相比之下，未产生交叉中和抗体反应的受试者的血浆中和活性针对单体gp120上除CD4 - BS之外的表位。我们的研究提供的信息不仅有助于更好地理解人类免疫系统与HIV的相互作用，还可能指导有效免疫方案的制定。由于针对病毒体相关包膜刺突上存在的复杂表位的抗体似乎是HIV - 1阳性血浆最早交叉中和活性的关键成分，因此应强调通过接种疫苗来诱导类似抗体。 一部分HIV感染者会产生广泛中和抗体（bNAbs），能够阻止多种HIV分离株对细胞的感染；这是我们希望通过接种疫苗诱导产生的抗体类型。确定与bNAbs自然产生相关的因素，并明确它们出现的时间及其表位特异性，将有助于开发更有效的免疫原和疫苗接种方案。在此，我们对从HIV - 1感染受试者纵向收集的血浆样本进行了中和筛选，并确定交叉中和抗体反应平均在感染后2 - 3年出现，但最早可在感染后1年出现。对HIV最早的交叉中和抗体反应的很大一部分针对病毒体相关三聚体Env刺突上存在的表位，而不是该病毒蛋白相应的可溶性单体形式。我们的研究强调了通过接种疫苗诱导具有这种复杂表位特异性的抗体的重要性。