Our laboratory focuses on immune preotection against mother-to-child transmission of neonatal viral pathogens, namely HIV-1 and cytomegalovirus. We utilize nonhuman primate models and human cohort studies to understand and elicit immune responses that can prevent vertical virus transmission.
Immune protection against mother to child transmission (MTCT) of HIV-1
Nearly a quarter million infants contius to becaome infected iwth HIV-1 annually. Interestingly, in the absence of prophylactic interventions over half of infants are protected against virus acquisition. Thus, we are interested in defining the virus-specific immune responses that naturally protect infants against HIV-1 acquisition. We have studied this question by comparing the immune responses and virus variants present in HIV-infected transmitting and nontransmitting women, defining maternal and infant immune correlates of protection against MTCT. We have identified specific Envelope-specific antibody responses that are associated with protection against virus transmission in human cohorts. Moreover, using the nonhuman primate model of HIV/AIDS, simian immunodeficiency virus (SIV) infection of rhesus monkeys, we have defined the maternal immune responses and virus characteristics that are associated with protection of the infant. We have also studied the maternal immune responses and virus variant phenotypes natural primate hosts that evolved with SIV for tens of thousands of years, as they evolved mechanisms to largely protect their infants against SIV acquisition. Finally, we have utilized the nonhuman primate model as a platform for testing the effectiveness of maternal HIV vaccination for passive protection of the infant against HIV-1 acquisition.
Mucosal immunity and protection against mother to child virus transmission
Breast milk provides important immunity against neonatal pathogens to the developing infant. Antibody, and primarily secretory IgA, is present in high concentration in breast milk. Therefore, we are interested in understanding the role of breast milk antibody in protecting the infant against viral pathogens. T and B lymphocytes are also present in breast milk, but their role in neonatal immunity is less clear. We have identified antiviral properties of these specialized breast milk lymphocyte populations and related their function to virus transmission. Moreover, we have identified an innate factors in breast milk, such as Tenascin-C, that neutralizes HIV-1 and may contribute to the inherently low rate of virus transmission via this route. We have devised ways to study these innate and adaptive immune responses in both humans and nonhuman primates. Moreover, we developed a model induced lactation in nonhuman primates so that this work does not rely on breeding cycles. Finally, we have utilized the nonhuman primate models to define ways in which we can target immune responses that will be passively transferred to the infant and could effectively block virus transmission. We hope to design strategies of maternal vaccination that will allow safe breastfeeding for all infants.
Maternal immune protection against perinatal cytomegalovirus transmission
Cytomegalovirus (CMV) complicates 1% of all pregnancies and results in 8,000 severe infections in U.S. children annually, resulting in brain damage, seizures, and vision and hearing loss. It is the leading nongenetic cause of infant hearing loss, accounting for 25% of all hearing loss, and causes more permanent disabilities in U.S. children then spina bifida or Down syndrome. Much like the rubella vaccine eliminated congenital rubella syndrome in this country, a vaccine that induces protection maternal immune responses in needed to protect against congenital CMV. Thus, our laboratory is working to identify the maternal immune responses that are required to protect against placental transmission of CMV in mother-infant cohort studies. Moreover, we have developed a nonhuman primate model of placental CMV transmission that can be employed to define the arms of the maternal immune response that is most necessary for protection of the fetus, as well as testing the efficacy of maternal CMV vaccines. We are also using this model to define the virologic determinants of placental virus transmission. Finally, as CMV can be pathogenic in very low birth weight preterm infants who acquire infection via breast milk feeding, we are also interested in harnessing the innate and adaptive maternal immune response to safely provide breast milk to this highly vulnerable population.