Alterations in B Cell Compartment Correlate with Poor Neutralization Response and Disease Progression in HIV-1 Infected Children

Abstract

Several B cell defects are reported in HIV-1 infected individuals including variation in B cell subsets, polyclonal B cell activation and exhaustion, with broadly neutralizing antibodies elicited in less than 10–20% of the infected population. HIV-1 disease progression is faster in children than adults. B Lymphocyte Stimulator (BLyS), expressed on dendritic cells (DCs), is a key regulator of B cell homeostasis. Understanding how DCs influence B cell phenotype and functionality (viral neutralization), thereby HIV-1 disease outcome in infected children, is important to develop interventional strategies for restoration of B cell function. In this study, a total of 38 vertically transmitted HIV-1 infected antiretroviral therapy (ART) naïve children and 25 seronegative controls were recruited. Based on the CD4 counts and years post-infection, infected children were categorized as long-term non-progressors (LTNPs) (n = 20) and progressors (n = 18). Eight of these progressors were followed up at 6–12 months post-ART. Percentages (%) of DCs, B cell subsets, and expression of BLyS on DCs were analyzed by flow-cytometry. Plasma levels of B cell growth factors were measured by ELISA and viral neutralization activity was determined using TZM-bl assay. Lower (%) of myeloid DCs (mDCs), plasmacytoid DCs, and high expression of BLyS on mDCs were observed in HIV-1 infected progressors than seronegative controls. Progressors showed lower % of naive B cells, resting memory B cells and higher % of mature activated, tissue-like memory B cells as compared to seronegative controls. Higher plasma levels of IL-4, IL-6, IL-10, and IgA were observed in progressors vs. seronegative controls. Plasma levels of IgG were high in progressors and in LTNPs than seronegative controls, suggesting persistence of hypergammaglobulinemia at all stages of disease. High plasma levels of BLyS in progressors positively correlated with poor viral neutralizing activity. Interestingly on follow up, treatment naïve progressors, post-ART showed increase in resting memory B cells along with reduction in plasma BLyS levels that correlated with improvement in viral neutralization. This is the first study to demonstrate that reduction in plasma BLyS levels correlates with restoration of B cell function, in terms of viral neutralization in HIV-1-infected children.

An HIV-1 broadly neutralizing antibody from a clade C infected pediatric elite neutralizer potently neutralizes the contemporaneous and autologous evolving viruses

“…At the time of sampling (2015), he was antiretroviral (ART) naïve, the CD4 T cell counts and plasma viral loads were 1033 cells/µl and 85,400 RNA copies/ml respectively. The plasma antibody neutralization activity of AIIMS_330 donor against a few HIV-1 viruses has been previously documented (37, 39, 40). In order to assess the evolution of antibody response in this donor, we further characterized AIIMS_330 (2015) plasma against a large panel of heterologous HIV-1 tier 1, 2 and 3 pseudoviruses (n=33) (Figure 1A, Table S1).…”

“…Few longitudinal studies, including ours, conducted on pediatric HIV-1 directed humoral immune response showed that plasma bNAbs develop in select chronically infected children and slow progressors, with diverse epitope specificities, (24, 34–37), and with higher breadth and potency than infected adults (35). Further, the bNAbs present in the plasma of infected children demonstrated similar epitope specificities as that observed for the adult bNAbs (24).…”

“…This study describes for the first time, a pediatric bNAb AIIMS-P01 IgG1, isolated from single B cell of an ART naïve HIV-1C chronically infected pediatric LTNP AIIMS_330, and identified as an elite neutralizer in this study, based on plasma mapping analysis. This AIIMS_330 donor belonged to a rare cohort of vertically transmitted ART naïve HIV-1C infected children that have been followed up for more than a decade (37–40). The AIIMS-P01 bNAb isolated from this elite neutralizer showed comparable neutralization efficiency against clade C and B HIV-1 viruses thereby suggesting that this bNAb may neutralize major viral clades responsible for infection globally.…”

Viral characteristics associated with sustenance of elite neutralizing activity in chronically HIV-1C infected monozygotic pediatric twins

“…Chronically infected children have been shown to have potent plasma bnAbs with diverse epitope specificities (5,6). In our pediatric cohort of antiretroviral naïve HIV-1C infected long term non-progressors (LTNPs) characterized for plasma antibody responses (6,13–18), we identified a pair of antiretroviral naive HIV-1C infected children AIIMS_329 and AIIMS_330, defined herein as genetically identical twins by their identical HLA haplotypes, who had acquired the infection at birth by vertical transmission. Both twins AIIMS_329 and AIIMS_330 developed potent plasma neutralizing antibodies, with the latter showing elite neutralizing activity since first sampling.…”

A study of viral tissue tropism and cytokine expression in Bovine Ephemeral Fever

“…Besides the pyrogenic properties, IL-6 promotes innate and adaptive immune mechanisms (Kishimoto et al, 1992;Yang et al, 2016) properties of IL-6 and IL-10 in B-cell activation and differentiation (Aggarwal et al, 2017;Houssiau et al, 1988;Kishimoto et al, 1992;Yang et al, 2016), and if interpreted in the context of the present study, the two cytokines most likely played some role(s) in pre-seroconversion cellular events that may have ultimately paved the way to the antibody production in the BEFV-infected cattle.…”