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

Abstract

Background: Despite a successful antiretroviral therapy (ART), adolescence living with perinatally acquired HIV (PHIV) experience B-cells dysfunction, 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. Methods: Here, we studied 40 PHIV who started treatment by 2nd year of life and maintain 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-omics 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. Findings: Elevated levels of aging B-cells (T-bet+CD11c+) were associated with later start of treatment, detectable cell-associated HIV-1 RNA, Spikes, higher frequency of exhausted T-cells (PD-1+, LAG3+, TIGIT+). The proteomic analysis revealed that subjects with expansion of aging B-cells and exhausted T-cells had enrichment of proteins involved in immune inflammation and complement activation pathways. Signs of precocious aging were associated with a reduced capacity to maintain virological memory against measles vaccination. Interpretation: To our knowledge, this is the first study focusing on precocious B-cell aging and dysfunctionality in PHIV with long-term virological suppression. We identified clinical, viral, cellular and plasma soluble markers associated with B-cells aging. Our results pave the way to further define risk of disease progression or lymphoproliferative disorders in PHIV. Funding Information: PENTA-ID Foundation (http://penta-id.org/); NIH; CFAR. Declaration of Interests: The authors have declared that no conflict of interest exists. Ethics Approval Statement: This is a multi-center study which include the following institutions: Bambino Gesu Children’s Hospital (OPBG, Rome, Italy), University of Padua (Padova, Italy), University Hospital 12 de Octubre (Madrid, Spain), Hospital Gregorio Maranon (Madrid, Spain), Imperial College Healthcare NHS Trust (London, UK), Great Ormond Street Hospital (London, UK), Brighton and Sussex University Hospitals (Brighton, UK). Each recruiting sites received approval by local ethic committees (Foster, Dominguez-Rodriguez et al. 2020). Study participants or their legal guardians gave written informed consent in accordance with the Declaration of Helsinki.