Laboratory of Neonatal Viral Pathogen Immunity

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Sallie Permar, MD, PhD
Associate Professor of Pediatrics
Assistant Professor in Immunology
Assistant Professor in Molecular Genetics and Microbiology
 
Our laboratory focuses on immune responses at the maternal-fetal interface that protect against neonatal viral pathogens, namely HIV-1 and cytomegalovirus.  We utilize nonhuman primate models and human cohort studies understand and elicit immune responses that can prevent vertical virus transmission.
 
Immune protection against mother to child transmission (MTCT) of HIV-1
 
In the absence of prophylactic interventions, up to 40% of HIV-exposed infants become infected with HIV-1, either during the pregnancy, during delivery,  or via breastfeeding.  But interestingly, 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 identified specific Envelope-specific antibody responses that may be associated with protection against virus transmission.  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 populations 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
 
We are interested in identifying and inducing maternal immune responses that will effectively block virus transmission via breastfeeding.  It is well known that 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 unclear.  We have identified antiviral properties of these specialized breast milk lymphocyte populations.  Moreover, we recently identified an innate factor in breast milk, Tenascin-C, that neutralizes HIV-1 and likely contributes 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 hepatitis, neutropenia, 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.