Aging B-cells (ABC) and anti-Env humoral responses are associated with T-bet expression in B-cells of perinatally HIV infected children (PHIV) treated within 24 months (m) of life (the CARMA cohort)

Authors: Ruggiero A, Cotugno N, Domínguez-Rodríguez S,  Zicari S, Rinaldi S, Zangari P, Tagarro A, Foster C, De Rossi A, Nastouli E, Luzuriaga K, Giaquinto C, Rossi P, Pawha S, Palma P, on behalf of the EPIICAL consortium.


This poster was presented at the 23rd Virtual International AIDS Conference

Background The role of T-bet, an immune factor involved in adaptative and innate response, has been poorly explored in B-cells. Previous studies concentrated on HIV+ and HIV- adults and T-bet was found to be associated with ABC. This work characterizes T-bet expression in B-cell (CD19+CD10-) subsets associated with aging (activated memory AM CD21-CD27+, Tissue Like Memory TLM CD21-CD27- and Double Negative DN CD27-IgD-) and with immunological memory (Resting Memory, RM CD27+CD21+IgD-) in PHIV.

Methods We studied 40 PHIV starting ART at median 4m of age (min 0m, max 22m) and ART-suppressed for >5 years (median 14 years (y) (min 5y, max 22y). Flow Cytometry was used to define B-cell phenotype and intracellular T-bet (MFI) in PHIV and in 20 age and gender-matched controls (HC). Anti-HIV serology was measured using Western blot and ELISA. Comparisons were analysed using Mann-Whitney test (MW). Associations were explored using Spearman test (rho, p) and multivariable ridge Poisson Regression model including baseline CD4, gender, and age at ART as confounders.

Results DN were expanded in PHIV compared with HC (p=0.01 MW). T-bet levels were elevated in AM, TLM and marginally DN compared to the others.  The models demonstrated a strong association between T-bet levels and time of ART start: for each month without ART T-bet increased by 3% and 2% in DN and AM, respectively (Fig.1a). Anti-Env responses were positively associated and were identified as predictors of T-bet levels in IgG+ B-cells (rho=0.35, p=0.03, Fig 1b), IgM+ B-cells (rho=0.39, p=0.01), RM IgM+ (rho=0.33, p=0.042).

Conclusions ABC are expanded in PHIV compared with HC, despite suppressive ART. Earlier ART-start preserves from premature aging of B-cell compartment. Furthermore, elevated levels of T-bet in memory B-cells was associated with anti-Env responses. Our findings add onto the previous literature by suggesting a role of T-bet in the anti-HIV B-cell response that warrant further investigation.