Department of Experimental Immunology, Sanquin Research, Landsteiner Laboratory, Center for Infection and Immunity Amsterdam, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
J Virol. 2012 Feb;86(4):2045-55. doi: 10.1128/JVI.06091-11. Epub 2011 Dec 7.
We previously established that at 3 years postseroconversion, ~30% of HIV-infected individuals have cross-reactive neutralizing activity (CrNA) in their sera. Here we studied the kinetics with which CrNA develops and how these relate to the development of autologous neutralizing activity as well as viral escape and diversification. For this purpose, sera from five individuals with CrNA and one elite neutralizer that were obtained at three monthly intervals in the first year after seroconversion and at multiple intervals over the disease course were tested for neutralizing activity against an established multiclade panel of six viruses. The same serum samples, as well as sera from three individuals who lacked CrNA, were tested for their neutralizing activities against autologous clonal HIV-1 variants from multiple time points covering the disease course from seroconversion onward. The elite neutralizer already had CrNA at 9.8 months postseroconversion, in contrast with the findings for the other five patients, in whom CrNA was first detected at 20 to 35 months postseroconversion and peaked around 35 months postseroconversion. In all patients, CrNA coincided with neutralizing activity against autologous viruses that were isolated <12 months postseroconversion, while viruses from later time points had already escaped autologous neutralizing activity. Also, the peak in gp160 sequence diversity coincided with the peak of CrNA titers. Individuals who lacked CrNA had lower peak autologous neutralizing titers, viral escape, and sequence diversity than individuals with CrNA. A better understanding of the underlying factors that determine the presence of CrNA or even an elite neutralizer phenotype may aid in the design of an HIV-1 vaccine.
我们之前已经证实，在感染 HIV 3 年后，约 30%的感染者的血清中存在交叉中和抗体（CrNA）。在这里，我们研究了 CrNA 产生的动力学及其与同源中和抗体产生、病毒逃逸和多样化的关系。为此，我们在感染后第一年每三个月、此后在病程中每隔一段时间收集了 5 名具有 CrNA 的个体和 1 名精英中和抗体个体的血清，用建立的多基因型 6 种病毒的面板检测其对这些血清的中和活性。我们用同样的血清样本，以及缺乏 CrNA 的 3 名个体的血清，在病程中从感染后开始的多个时间点检测其对同源克隆 HIV-1 变体的中和活性。该精英中和抗体个体在感染后 9.8 个月就已经具有 CrNA，而其他 5 名个体的情况则不同，他们的 CrNA 是在感染后 20 至 35 个月才首次检测到，并在感染后 35 个月左右达到峰值。在所有个体中，CrNA 与感染后 <12 个月分离的同源病毒的中和活性一致，而来自后续时间点的病毒已经逃逸了同源中和活性。此外，gp160 序列多样性的峰值与 CrNA 滴度的峰值一致。缺乏 CrNA 的个体的峰值同源中和抗体滴度、病毒逃逸和序列多样性均低于具有 CrNA 的个体。更好地了解决定 CrNA 甚至精英中和抗体表型存在的潜在因素，可能有助于 HIV-1 疫苗的设计。
