Background
Despite increased availability to antiretroviral therapy, up to 5% of people living with HIV (PLH) still transmit HIV-1 to the infant. Broadly neutralizing antibodies (bNAbs) are the immunologic goal of HIV-1 vaccine candidates; however, in postnatal cohorts, we have reported the presence of bNAbs targeting a single epitope, which contributes to viral escape. We hypothesize that PLH with bNAbs against single epitopes of the HIV envelope are at higher risk of perinatal transmission due to viral escape.
Methods
Plasma was acquired around delivery from 21 perinatal transmitters and 70 non-transmitters with HIV matched 1:3, from the Mother-Infant Cohort Study and the NISDI Perinatal study. Plasma was screened for neutralization breadth against a 10-virus HIV-1 panel. For participants with breadth (neutralizing ≥ 5 viruses with ID50 ≥ 40), plasma was screened against viruses with epitope mutations in the CD4 binding site, V2, V3 Glycan, and the membrane proximal external region of HIV-1 Env. Antibody dependent cellular cytotoxicity (ADCC) was assessed against cells infected with a transmitted/founder subtype B virus (WITO).
Results
Transmitters had higher neutralization breadth (p = 0.0005) and potency (p = 0.0008) compared to non-transmitters (two-sided Fisher’s test). bNAb activity in 6 out of 7 transmitters (87%) were mappable, with 5 out of 7 mapping to the CD4 binding site (71%) and one transmitter mapping to both CD4bs and V3 Glycan. In comparison, 4 out of 14 non-transmitters mapped to a single epitope (29%), while the majority remain unmapped. Overall, a higher proportion of transmitters had epitope-mappable plasma-bNAb activity (p = 0.02, two-sided Fisher’s test). Additionally, regression analysis on pooled data suggests that when adjusted for cohort, transmitters have significantly higher ADCC against subtype B WITO compared to non-transmitters (p = 0.02, ANOVA).
Conclusions
Our findings suggest the existence of increased bNAb activity in transmitters that is primarily specific to a single epitope, which could lead to emergence of bNAb-resistant viral variants that can be transmitted perinatally. While ADCC has been implicated in protection against transmission, our analyses indicates that transmitters have higher ADCC against a subtype B virus, though ADCC breadth analysis could reveal additional details. In conclusion, bNAb-based pediatric HIV prevention and treatments that are synergistic with ART will likely need to be multi-specific to effectively eliminate pediatric HIV.
Table or Figure
