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持续的HIV-1逃逸自体内中和作用以及交叉反应性抗体反应的发展是儿童疾病进展缓慢的特征。

Continuous HIV-1 Escape from Autologous Neutralization and Development of Cross-Reactive Antibody Responses Characterizes Slow Disease Progression of Children.

作者信息

Dispinseri Stefania, Cavarelli Mariangela, Tolazzi Monica, Plebani Anna Maria, Jansson Marianne, Scarlatti Gabriella

机构信息

Viral Evolution and Transmission Unit, Division of Immunology, Transplantation and Infectious Diseases, IRCCS Ospedale San Raffaele, 20132 Milan, Italy.

Inserm, CEA, Center for Immunology of Viral, Auto-Immune, Hematological and Bacterial Diseases (IMVA-HB/IDMIT), University Paris-Saclay, 92265 Fontenay-aux-Roses & Le Kremlin-Bicêtre, France.

出版信息

Vaccines (Basel). 2021 Mar 14;9(3):260. doi: 10.3390/vaccines9030260.

Abstract

The antibodies with different effector functions evoked by Human Immunodeficiency Virus type 1 (HIV-1) transmitted from mother to child, and their role in the pathogenesis of infected children remain unresolved. So, too, the kinetics and breadth of these responses remain to be clearly defined, compared to those developing in adults. Here, we studied the kinetics of the autologous and heterologous neutralizing antibody (Nab) responses, in addition to antibody-dependent cellular cytotoxicity (ADCC), in HIV-1 infected children with different disease progression rates followed from close after birth and five years on. Autologous and heterologous neutralization were determined by Peripheral blood mononuclear cells (PBMC)- and TZMbl-based assays, and ADCC was assessed with the GranToxiLux assay. The reactivity to an immunodominant HIV-1 gp41 epitope, and childhood vaccine antigens, was assessed by ELISA. Newborns displayed antibodies directed towards the HIV-1 gp41 epitope. However, antibodies neutralizing the transmitted virus were undetectable. Nabs directed against the transmitted virus developed usually within 12 months of age in children with slow progression, but rarely in rapid progressors. Thereafter, autologous Nabs persisted throughout the follow-up of the slow progressors and induced a continuous emergence of escape variants. Heterologous cross-Nabs were detected within two years, but their subsequent increase in potency and breadth was mainly a trait of slow progressors. Analogously, titers of antibodies mediating ADCC to gp120 BaL pulsed target cells increased in slow progressors during follow-up. The kinetics of antibody responses to the immunodominant viral antigen and the vaccine antigens were sustained and independent of disease progression. Persistent autologous Nabs triggering viral escape and an increase in the breadth and potency of cross-Nabs are exclusive to HIV-1 infected slowly progressing children.

摘要

1型人类免疫缺陷病毒(HIV-1)母婴传播所引发的具有不同效应功能的抗体及其在受感染儿童发病机制中的作用仍未明确。与成人相比,这些反应的动力学和广度也有待明确界定。在此,我们研究了从出生后不久直至五年内随访的不同疾病进展速率的HIV-1感染儿童的自体和异源中和抗体(Nab)反应动力学,以及抗体依赖性细胞毒性(ADCC)。通过基于外周血单核细胞(PBMC)和TZMbl的检测来确定自体和异源中和作用,并用GranToxiLux检测评估ADCC。通过酶联免疫吸附测定(ELISA)评估对免疫显性HIV-1 gp41表位和儿童疫苗抗原的反应性。新生儿表现出针对HIV-1 gp41表位的抗体。然而,未检测到中和传播病毒的抗体。针对传播病毒的Nab通常在疾病进展缓慢的儿童12个月龄内产生,但在疾病进展迅速的儿童中很少出现。此后,自体Nab在疾病进展缓慢的儿童整个随访期间持续存在,并诱导逃逸变体不断出现。在两年内检测到异源交叉Nab,但其随后效力和广度的增加主要是疾病进展缓慢儿童的特征。类似地,在随访期间,介导对gp120 BaL脉冲靶细胞的ADCC的抗体滴度在疾病进展缓慢的儿童中有所增加。对免疫显性病毒抗原和疫苗抗原的抗体反应动力学持续存在,且与疾病进展无关。持续的自体Nab引发病毒逃逸以及交叉Nab的广度和效力增加是HIV-1感染的疾病进展缓慢儿童所特有的。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dd6a/7999787/ee1ded43b10e/vaccines-09-00260-g001.jpg

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