Wagner Gabriel A, Landais Elise, Caballero Gemma, Phung Pham, Kosakovsky Pond Sergei L, Poignard Pascal, Richman Douglas D, Little Susan J, Smith Davey M
Department of Medicine, University of California San Diego, La Jolla, California, USA
The International AIDS Vaccine Initiative, Neutralizing Antibody Center, La Jolla, California, USA.
J Virol. 2017 Aug 10;91(17). doi: 10.1128/JVI.00475-17. Print 2017 Sep 1.
Understanding whether the neutralizing antibody (NAb) response impacts HIV-1 superinfection and how superinfection subsequently modulates the NAb response can help clarify correlates of protection from HIV exposures and better delineate pathways of NAb development. We examined associations between the development of NAb and the occurrence of superinfection in a well-characterized, antiretroviral therapy (ART)-naive, primary infection cohort of men who have sex with men. Deep sequencing was applied to blood plasma samples from the cohort to detect cases of superinfection. We compared the NAb activity against autologous and heterologous viruses between 10 participants with intrasubtype B superinfection and 19 monoinfected controls, matched to duration of infection and risk behavior. Three to 6 months after primary infection, individuals who would later become superinfected had significantly weaker NAb activity against tier 1 subtype B viruses ( = 0.003 for SF-162 and = 0.017 for NL4-3) and marginally against autologous virus ( = 0.054). Lower presuperinfection NAb responses correlated with weaker gp120 binding and lower plasma total IgG titers. Soon after superinfection, the NAb response remained lower, but between 2 and 3 years after primary infection, NAb levels strengthened and reached those of controls. Superinfecting viruses were typically not susceptible to neutralization by presuperinfection plasma. These observations suggest that recently infected individuals with a delayed NAb response against primary infecting and tier 1 subtype B viruses are more susceptible to superinfection. Our findings suggest that within the first year after HIV infection, a relatively weak neutralizing antibody response against primary and subtype-specific neutralization-sensitive viruses increases susceptibility to superinfection in the face of repeated exposures. As natural infection progresses, the immune response strengthens significantly in some superinfected individuals. These findings will inform HIV vaccine design by providing testable correlates of protection from initial HIV infection.
了解中和抗体（NAb）反应是否会影响HIV-1重复感染，以及重复感染随后如何调节NAb反应，有助于阐明预防HIV暴露的保护相关因素，并更好地描绘NAb的产生途径。我们在一个特征明确、未接受抗逆转录病毒治疗（ART）、处于原发性感染阶段的男男性行为者队列中，研究了NAb产生与重复感染发生之间的关联。对该队列的血浆样本进行深度测序，以检测重复感染病例。我们比较了10例B亚型内重复感染参与者和19例匹配感染持续时间及风险行为的单一感染对照者针对自身和异源病毒的NAb活性。在原发性感染后3至6个月，后来发生重复感染的个体针对1级B亚型病毒的NAb活性显著较弱（针对SF-162，P = 0.003；针对NL4-3，P = 0.017），针对自身病毒的活性略弱（P = 0.054）。感染前较低的NAb反应与较弱gp120结合及较低血浆总IgG滴度相关。重复感染后不久，NAb反应仍较低，但在原发性感染后2至3年，NAb水平增强并达到对照者水平。重复感染病毒通常不易被感染前血浆中和。这些观察结果表明，对原发性感染病毒和1级B亚型病毒的NAb反应延迟的近期感染个体更容易发生重复感染。我们的研究结果表明，在HIV感染后的第一年内，针对原发性和亚型特异性中和敏感病毒的相对较弱的中和抗体反应会增加面对反复暴露时发生重复感染的易感性。随着自然感染的进展，一些重复感染个体的免疫反应会显著增强。这些发现将通过提供预防初始HIV感染的可测试保护相关因素，为HIV疫苗设计提供参考。
