Ranasinghe Srinika, Soghoian Damien Z, Lindqvist Madelene, Ghebremichael Musie, Donaghey Faith, Carrington Mary, Seaman Michael S, Kaufmann Daniel E, Walker Bruce D, Porichis Filippos
Ragon Institute of MGH, MIT, and Harvard, Massachusetts General Hospital and Harvard Medical School, Cambridge, Massachusetts, USA Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, California, USA
Ragon Institute of MGH, MIT, and Harvard, Massachusetts General Hospital and Harvard Medical School, Cambridge, Massachusetts, USA.
J Virol. 2015 Dec 9;90(5):2208-20. doi: 10.1128/JVI.02278-15.
Antigen-specific CD4(+) T helper cell responses have long been recognized to be a critical component of effective vaccine immunity. CD4(+) T cells are necessary to generate and maintain humoral immune responses by providing help to antigen-specific B cells for the production of antibodies. In HIV infection, CD4(+) T cells are thought to be necessary for the induction of Env-specific broadly neutralizing antibodies. However, few studies have investigated the role of HIV-specific CD4(+) T cells in association with HIV neutralizing antibody activity in vaccination or natural infection settings. Here, we conducted a comprehensive analysis of HIV-specific CD4(+) T cell responses in a cohort of 34 untreated HIV-infected controllers matched for viral load, with and without neutralizing antibody breadth to a panel of viral strains. Our results show that the breadth and magnitude of Gag-specific CD4(+) T cell responses were significantly higher in individuals with neutralizing antibodies than in those without neutralizing antibodies. The breadth of Gag-specific CD4(+) T cell responses was positively correlated with the breadth of neutralizing antibody activity. Furthermore, the breadth and magnitude of gp41-specific, but not gp120-specific, CD4(+) T cell responses were significantly elevated in individuals with neutralizing antibodies. Together, these data suggest that robust Gag-specific CD4(+) T cells and, to a lesser extent, gp41-specific CD4(+) T cells may provide important intermolecular help to Env-specific B cells that promote the generation or maintenance of Env-specific neutralizing antibodies.
One of the earliest discoveries related to CD4(+) T cell function was their provision of help to B cells in the development of antibody responses. Yet little is known about the role of CD4(+) T helper responses in the setting of HIV infection, and no studies to date have evaluated the impact of HIV-specific CD4(+) T cells on the generation of antibodies that can neutralize multiple different strains of HIV. Here, we addressed this question by analyzing HIV-specific CD4(+) T cell responses in untreated HIV-infected persons with and without neutralizing antibodies. Our results indicate that HIV-infected persons with neutralizing antibodies have significantly more robust CD4(+) T cell responses targeting Gag and gp41 proteins than individuals who lack neutralizing antibodies. These associations suggest that Gag- and gp41-specific CD4(+) T cell responses may provide robust help to B cells for the generation or maintenance of neutralizing antibodies in natural HIV-infection.
长期以来，抗原特异性CD4(+)辅助性T细胞反应一直被认为是有效疫苗免疫的关键组成部分。CD4(+) T细胞通过为抗原特异性B细胞提供帮助以产生抗体，对于产生和维持体液免疫反应是必需的。在HIV感染中，CD4(+) T细胞被认为是诱导Env特异性广泛中和抗体所必需的。然而，很少有研究调查HIV特异性CD4(+) T细胞在疫苗接种或自然感染情况下与HIV中和抗体活性相关的作用。在此，我们对34名未经治疗的HIV感染控制者队列中的HIV特异性CD4(+) T细胞反应进行了全面分析，这些患者的病毒载量相匹配，且对一组病毒株具有或不具有中和抗体广度。我们的结果表明，具有中和抗体的个体中，Gag特异性CD4(+) T细胞反应的广度和强度显著高于没有中和抗体的个体。Gag特异性CD4(+) T细胞反应的广度与中和抗体活性的广度呈正相关。此外，具有中和抗体的个体中，gp41特异性而非gp120特异性CD4(+) T细胞反应的广度和强度显著升高。总之，这些数据表明，强大地Gag特异性CD4(+) T细胞以及在较小程度上gp41特异性CD4(+) T细胞可能为Env特异性B细胞提供重要的分子间帮助，从而促进Env特异性中和抗体的产生或维持。
与CD4(+) T细胞功能相关的最早发现之一是它们在抗体反应发展过程中为B细胞提供帮助。然而，对于CD4(+)辅助性T细胞反应在HIV感染背景下的作用知之甚少，并且迄今为止没有研究评估HIV特异性CD4(+) T细胞对能够中和多种不同HIV毒株的抗体产生的影响。在此，我们通过分析有和没有中和抗体的未经治疗的HIV感染者中的HIV特异性CD4(+) T细胞反应来解决这个问题。我们的数据表明，与缺乏中和抗体的个体相比，具有中和抗体的HIV感染者针对Gag和gp41蛋白的CD4(+) T细胞反应明显更强。这些关联表明，在自然HIV感染中，Gag和gp41特异性CD4(+) T细胞反应可能为B细胞产生或维持中和抗体提供强大帮助。
