ART-Naïve Children Living with HIV-1 Can Produce Polyfunctional Antibodies Against HIV-1
Zeynep Bahadir, Kenneth Vuong, Maria Dennis, Ashley Nelson, Genevieve G FoudaAbstract
Background
Globally ~1.5 million children are living with HIV-1, while current prevention and treatment strategies rely on antiretroviral therapy (ART), it cannot effectively eliminate HIV. Immune-based interventions that induce non-neutralizing and broadly neutralizing antibodies (bnAbs) are needed to complement ART-based regimens. We previously showed an earlier bnAb response in a cross-sectional cohort of 212 ART-naïve children living with HIV-1 (CLWH) (age 1-3) compared to adults living with chronic HIV-1 (ALWH). While bnAbs target conserved binding sites on the HIV envelope (env) to prevent entry of multiple HIV strains, they also demonstrate non-neutralizing effector functions such as antibody-dependent cellular phagocytosis (ADCP). These functions play a significant role in decreasing the viral load and protecting against viral transmission. We aim to show the association between neutralization breadth and non-neutralizing antibody functions to better understand polyfunctional antibody responses in CLWH.
Methods
We obtained plasma samples from ART-naive CLWH (n=33, age 4-5) from the International Maternal, Pediatric, Adolescent AIDS Clinical Trials (IMPAACT) repository. These children were born to women living with HIV in the United States acquired HIV-1 either at birth or in utero. A two-phase screening approach was implemented to assess neutralization breadth and potency. Plasma neutralization was assessed against a panel of 10 viruses representing global HIV-1 isolates. Samples that neutralized ≥5 of 10 viruses in the panel were defined as having neutralization breadth. Plasma ADCP was assessed using antigen conjugated fluorescent NeutrAvidin beads, to which controls and plasma samples were added to form immune complexes. A human leukemia monocytic cell line (THP-1 cells) was added to the plate to observe phagocytosis. Flow-cytometry was utilized for the analysis. The phagocytosis scores were formulated by multiplying the mean fluorescence intensity (MFI) and frequency of positive cells and divided by the negative control’s MFI and frequency of positive cells.
Results
Majority of children screened at 4 (n=12/13) and 5 years (n=14/20) neutralized ≥3 of 5 viruses in the first screening phase. Samples from 77% of children at 4 years (n=10/13) and 60% at 5 years (n=12/20) of age neutralized ≥5 of 10 viruses. Of 33 samples tested, 6 developed antibodies with ADCP activity. Of 6 samples, 5 belonged to children that developed broad plasma neutralization.
Conclusion
CLWH might be capable of developing polyfunctional antibodies against HIV-1. Thus, early life immune system might possess distinct immune characteristics that could provide valuable insight into future immune-based therapeutic interventions and HIV vaccine studies.