Identifying key determinants of IgG transplacental transfer from HIV-infected mothers to their fetus

Duke University, Durham NC

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Abstract

ABSTRACT With an increase in availability and use antiretroviral prophylaxis to prevent mother to child transmission (MTCT) of HIV, the majority of infants born to HIV-infected mothers do not become infected. In fact, more than 1 million HIV exposed uninfected infants (HEU) are born to HIV-infected mothers each year. Interestingly, HEUs are more susceptible to respiratory and diarrheal diseases and have higher morbidity and mortality rates compared to HIV unexposed infants (HU). The mechanism of the increased susceptibility of HEU infants to these fatal infections remains unknown. Previous studies have shown that maternal HIV infection is associated with poor transplacental transfer of IgG antibodies. As maternal antibodies transferred across the placenta to the fetus are critical in protecting infants against disease in the first few months of life, the low levels of maternal antibodies in HEU infants could contribute to their increased risk of acquiring infectious diseases. In preliminary work, I have measured the levels of maternal and infant IgG to a panel of HIV and non-HIV-specific antigens in two large cohorts of clade B and C HIV-infected mother-HEU infant pairs (n = 167). My results indicate that different IgG specificities are not equally transferred to the fetus and that transplacental IgG transfer efficiency varies between mother infant pairs. I hypothesize that placental IgG transfer efficiency in the setting of HIV infection is dependent on maternal HIV-disease progression factors, characteristics of IgG Fc domain, as well as expression of Fc receptors that shuttle IgG across the placenta (i.e., FcRn). Using HIV- infected mothers, I propose to define the impact of maternal HIV-disease progression clinical factors (CD4+ T cell count, viral load, and hypergammaglobulinemia) and IgG characteristics (IgG subclass, Fc receptor binding, and glycosylation signatures) on antigen-specific IgG transplacental transfer efficiency. Furthermore, I will compare expression levels of FcRn, Fc? receptor, and c-type lectins in placentas from HIV-infected and uninfected mothers to determine if Fc receptor expression predicts IgG transplacental transfer efficiency. Altogether my study will identify key determinants of maternal IgG transplacental transfer in HIV-infected women. These findings will guide the design of interventions to augment the transplacental transfer of antibodies in HEU infants and could inform the development of more effective maternal vaccines to prevent neonatal infections.