Due to their diverse functions, antibodies (Abs) can fight viral infections on multiple fronts. For example, neutralizing antibodies (nAbs) can block viral entry into cells, whereas non-neutralizing antibodies can mediate several cytotoxic effector functions, acting as bridges to link infected cells with natural killer (NK) cells and monocytes, which induce cell death in infected cells. During pregnancy in HIV-positive mothers, antibodies, including antibody directed cellular cytotoxicity- (ADCC)-mediating antibodies, are passively transferred to the infant via the placenta. However, due to limited data, the protective capacity of these Abs is not well-defined.
The Overbaugh Lab in the Human Biology Division, has investigated the role of ADCC-mediating antibodies for protection from HIV acquisition and progression in cohorts of mother-to-child transmission cases (MTCT) established prior to the use of antiviral therapy to prevent transmission. In their most recent study, published in Cell Reports Medicine, researchers in the Overbaugh Lab, led by MD/PhD graduate students Zak Yaffe and Nicole Naiman, show that ADCC activity from passively acquired antibodies correlates with improved survival of HIV-infected infants in two independent cohorts. “This study shows that passively-acquired ADCC is associated with improved survival in breastfeeding infants that acquire HIV,” Yaffe added.
Mother-to-child transmission cohorts are a unique setting to investigate the role of ADCC-mediating antibodies in HIV protection and progression. The activity of passively transferred antibodies to HIV-negative at birth infants can be assessed without the interference of de novo responses expected in HIV-positive infants at birth. "The main strength of studying MTCT in infants that are HIV-negative at birth is that they have a circulating HIV-specific antibodies before they acquired HIV. That allows us to directly examine whether these antibodies impact either HIV acquisition or disease progression, much like vaccine studies," explained Yaffe. A previous study from the group did not identify associations between ADCC activity and HIV acquisition risk in the MCTC cohort from the Nairobi Breastfeeding Trial (NBT). However, ADCC activity and survival in infants that eventually became HIV-positive were positively correlated. To determine if ADCC activity and increased survival could also be observed in an independent MTCT cohort, Yaffe and colleagues assessed the ADCC activity of HIV-negative infants at birth in the Cytotoxic T Lymphocyte (CTL) cohort.
The investigators evaluated ADCC activity using two assays: a rapid and fluorometric ADCC (RFADCC) assay – the same assay used in NBT cohort study– and a dimeric FcγR enzyme-linked immunosorbent assay (ELISA), specifically using two different Fc receptors, FcgRIIa and FcgRIIIa, that are found in diverse effector cell types. Results from the RFADCC assay showed that, as in the NBT cohort, HIV-positive infants in the CTL cohort with ADCC activity above median had longer survival times. When the investigators combined the RFADCC data from the NBT and CTL studies, they observed a significant positive correlation between high ADCC activity and longer HIV-positive infant survival times. Importantly, ADCC activity measured by the dimeric FcγR ELISA also showed that high ADCC activity positively correlates with longer survival in HIV-infected infants. Neither study identified significant differences in ADCC activity between infants exposed to HIV who remained uninfected and those that eventually became HIV positive.
“Here, we demonstrate in a second population and using multiple measures of ADCC, that passively-acquired ADCC is associated with improved infant survival. Importantly, we obtained similar results in a combined analysis using data from both breastfeeding cohorts. These findings provide strong evidence for a clinical benefit of antibodies that can mediate ADCC, which leads to killing of infected cells, circulating before the time of infection,” said Yaffe.
Fred Hutch/UW Cancer Consortium member Julie Overbaugh contributed to this study.
This work was supported by grants from the National Institutes of Health and by the Flow Cytometry shared resource of the Fred Hutch/University of Washington Cancer Consortium.
Yaffe, Z. A., Naiman, N. E., Slyker, J., Wines, B. D., Richardson, B. A., Hogarth, P. M., Bosire, R., Farquhar, C., Ngacha, D. M., Nduati, R., John-Stewart, G., & Overbaugh, J. (2021). Improved HIV-positive infant survival is correlated with high levels of HIV-specific ADCC activity in multiple cohorts. Cell reports. Medicine, 2(4), 100254. https://doi.org/10.1016/j.xcrm.2021.100254