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

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

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.

Highlights

The rational design of an effective vaccine against Human Immunodeficiency Virus type 1 (HIV-1) requires an understanding the functional characteristics of antibodies capable of preventing transmission of the virus or providing a benefit to the disease in terms of severity of symptoms and/or progression to a fatal outcome
To analyze the development of neutralizing antibody (Nab) responses in relation to disease progression, we tested the autologous neutralizing activity of plasma from 15 infected children, seven ware used for calculation was GraphPad Prism Version 8 (San Diego, California, USA)
To analyze the development of Nab responses in relation to disease progression,6 of we tested the autologous neutralizing activity of plasma from 15 infected children, seven rapid and eight slow progressors, against their own viruses obtained throughout disease rapid and eight slow progressors, against their own viruses obtained throughout disease progression, using a Peripheral blood mononuclear cells (PBMC)-based assay

Summary

Introduction

The rational design of an effective vaccine against Human Immunodeficiency Virus type 1 (HIV-1) requires an understanding the functional characteristics of antibodies capable of preventing transmission of the virus or providing a benefit to the disease in terms of severity of symptoms and/or progression to a fatal outcome. In specific, during motherto-child transmission (MTCT) of HIV-1 different specificities and effector function of the antibodies may impact the risk of transmission according to the route of infection, i.e., during pregnancy, at delivery or via breast feeding. AIDS slowly over several years, in contrast to adults approximately one-quarter of them has a rapidly progressing disease, and develops features characteristic of AIDS within the first year of life [2,3,4]. Knowledge on the immunological mechanisms underlying the different patterns of disease progression in HIV-1 infected children is still lacking

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Conclusion