Developing an efficient vaccine against HIV-1 includes the identification of a target (antigen) that will elicit an antibody response mediating antibody-dependent cellular cytotoxicity (ADCC) because such responses have been linked to protection from HIV-1 infection. Among strategies to access this information is the analysis of cases of mother-to-child transmission (MTCT). MTCT represents an interesting setting to study antibody protection because maternal antibodies cross the placental barrier during pregnancy and remain in the infant’s circulation for months after birth, but the ones carried in breast milk do not cross the gut barrier. Thus, in the case of HIV-1 infected mothers, antibodies against HIV-1 will be transferred from the mother to the child during pregnancy and for infants who are born uninfected at birth, the unique HIV-1 targeted antibodies present in the child’s circulation after birth will be those inherited from the parent, until infection occurs through breast feeding. Delayed disease for the child can be representative of a more efficient HIV-1 related ADCC. The Overbaugh lab (Human Biology Division) has been studying mother-to-child transmission for a long time and have previously demonstrated that ADCC potential of antibodies from infant blood is associated with better survival. However, the nature of the epitopes involved in the ADCC related to the improved survival is unknown.
One of the common antigens for naturally occurring ADCC antibodies is a conformational epitope of gp120 (a subunit of the viral envelope) induced by the binding to the CD4 receptor. Overbaugh and her team hypothesized that passively transferred antibodies targeting these CD4-inducible (CD4i) epitopes were responsible for the improved survival of HIV-infected infants. The authors analyzed plasma samples from participants of the Nairobi Breastfeeding Clinical Trial conducted in Kenya between 1992 and 1998, prior to the use of anti-retroviral therapy (ART). In the original trial, blood from mothers at the third trimester and from child at regular intervals were collected to determine infection status. These data and the stored samples were critical for conducting the current study. The results of these studies were published in EBioMedicine this summer.
A Rapid and Fluometric ADCC assay was used on these plasma samples, in the presence or absence of engineered antibodies that compete for binding CD4i epitopes but do not elicit ADCC. Quantification of the inhibition of ADCC by the competing antibodies reveals the proportion of ADCC antibodies that target specific CD4i epitopes. As expected, the authors observed a drastic inhibition of ADCC in most plasma samples by the competing antibodies. However, they were surprised to see that the level of ADCC related to CD4i epitopes was the same in HIV-exposed uninfected (HEU) vs infected infants, suggesting that targeting CD4i epitopes is not related to prevention of infection. Moreover, maternal plasma from non transmitting and transmitting mothers also displayed the same level of ADCC related to CD4i epitopes. Dr. Nicole Naiman, former graduate student and first author of the study, and her colleagues analyzed patient survival depending on the level of ADCC related to CD4i epitopes. Unexpectedly, infants with the lowest level of this specific ADCC lived longer than those with high level of CD4i epitope-related ADCC.
This study marks the start of a new research axis for the Overbaugh lab: “As with many studies, this one raises more questions than it answers”, says Dr. Overbaugh. “We set out to find an antibody specificity that is associated with better outcomes in HIV infected infants. Instead, we found one that is associated with worse outcomes. This is clearly important in thinking about vaccine design and suggest we need to understand these type of responses and how they may be acting in more details.”
This work was supported by the National Institutes of Health.
Fred Hutch/UW Cancer Consortium member Dr. Overbaugh contributed to this research.
Naiman NE, Slyker J, Richardson BA, John-Stewart G, Nduati R, Overbaugh JM. 2019. Antibody-dependent cellular cytotoxicity targeting CD4-inducible epitopes predicts mortality in HIV-infected infants. EBioMedicine. 47:257-268. doi: 10.1016/j.ebiom.2019.08.072.