Determinants of B-Cell Compartment Hyperactivation in European Adolescents Living With Perinatally Acquired HIV-1 After Over 10 Years of Suppressive Therapy

Abstract

BackgroundDespite a successful antiretroviral therapy (ART), adolescents living with perinatally acquired HIV (PHIV) experience signs of B-cell hyperactivation with expansion of ‘namely’ atypical B-cell phenotypes, including double negative (CD27-IgD-) and termed age associated (ABCs) B-cells (T-bet+CD11c+), which may result in reduced cell functionality, including loss of vaccine-induced immunological memory and higher risk of developing B-cells associated tumors. In this context, perinatally HIV infected children (PHIV) deserve particular attention, given their life-long exposure to chronic immune activation.MethodsWe studied 40 PHIV who started treatment by the 2nd year of life and maintained virological suppression for 13.5 years, with 5/40 patients experiencing transient elevation of the HIV-1 load in the plasma (Spike). We applied a multi-disciplinary approach including immunological B and T cell phenotype, plasma proteomics analysis, and serum level of anti-measles antibodies as functional correlates of vaccine-induced immunity.ResultsPhenotypic signs of B cell hyperactivation were elevated in subjects starting ART later (%DN T-bet+CD11c+ p=0.03; %AM T-bet+CD11c+ p=0.02) and were associated with detectable cell-associated HIV-1 RNA (%AM T-bet+CD11c+ p=0.0003) and transient elevation of the plasma viral load (spike). Furthermore, B-cell hyperactivation appeared to be present in individuals with higher frequency of exhausted T-cells, in particular: %CD4 TIGIT+ were associated with %DN (p=0.008), %DN T-bet+CD11c+ (p=0.0002) and %AM T-bet+CD11c+ (p=0.002) and %CD4 PD-1 were associated with %DN (p=0.048), %DN T-bet+CD11c+ (p=0.039) and %AM T-bet+CD11c+ (p=0.006). The proteomic analysis revealed that subjects with expansion of these atypical B-cells and exhausted T-cells had enrichment of proteins involved in immune inflammation and complement activation pathways. Furthermore, we observed that higher levels of ABCs were associated a reduced capacity to maintain vaccine-induced antibody immunity against measles (%B-cells CD19+CD10- T-bet+, p=0.035).ConclusionWe identified that the levels of hyperactivated B cell subsets were strongly affected by time of ART start and associated with clinical, viral, cellular and plasma soluble markers. Furthermore, the expansion of ABCs also had a direct impact on the capacity to develop antibodies response following routine vaccination.

B-cell immunity and vaccine induced antibody protection reveal the inefficacy of current vaccination schedule in infants with perinatal HIV-infection in Mozambique, Africa

“…This peculiar subset was described as a hallmark of B-cell exhaustion and aging, initially shown in elderly, 28 later in primary immunodeficiency and autoimmune diseases, 29 , 30 , 31 and more recently in people with HIV infection including children with vertical HIV-infection. 5 , 32 In this scenario, our data provide novel information on this B-cell paradoxical perturbation, characterized by a higher frequency in infants with HIV infection of a B-cell subset so far known to be increased in aging or inflamed conditions or in other infectious diseases such as cytomegalovirus or malaria, not tested in the present study. Matching these results at multiple time points we could show that the DN subset is the main driver of B-cell development in HEI with CD38+ and IgG+ DN B-cells inversely contributing to aging.…”

Seroconversion and persistence of neutralizing antibody response after yellow fever vaccination in patients with perinatally acquired HIV infection

“…Patients with pHIV, exposed to early immune activation since birth, may show signs of early aging reflected by the loss of the capacity to maintain postvaccination immune memory [24]. Previous studies have reported a more rapid decline in vaccine-induced antibody response in pHIV subjects compared with HIV-uninfected children and compared with PWH acquired during adulthood [9,20].…”

“…We observed a stability of the rate of YF NAbs above protective threshold with time (91% to 86% after median 7.3 years), although GMT levels decreased sharply after 7 years in pHIV vaccinees. Patients with pHIV, exposed to early immune activation since birth, may show signs of early aging reflected by the loss of the capacity to maintain postvaccination immune memory [24]. Previous studies have reported a more rapid decline in vaccine-induced antibody response in pHIV subjects compared with HIV-uninfected children and compared with PWH acquired during adulthood [9,20].…”