Exploring the Tolerogenic Fetal Immune Response to in utero Exposure to HIV and/or Malaria
Outside the Box AIDS Vaccine Award
The developing human immune system is distinct from that of the adult immune system. In particular, it is endowed with a relatively large compartment of regulatory T cells (TReg). These fetal-type TReg have a unique gene-expression pattern, and may normally serve to suppress immune responses against self and/or against unshared maternal antigens. Each of these functions could be construed as beneficial. If, in this setting, maternal to child transmission of HIV or malaria were to occur, it is not clear whether enhanced TReg activity would be beneficial or detrimental. The experiments of this proposal are designed to better understand the pathogenesis of these infections of the fetus and newborn. We hypothesize that many if not all neonates born to HIV-infected mothers are exposed to infectious HIV. Such exposure might occur before, during, and/or after birth. We further hypothesize that the exposed human neonatal immune system can mount immune responses capable of limiting viral replication and spread. Inter-individual variations in the strength and/or type of these responses may then determine disease outcome, ranging from effective protection to different rates of disease progression. Finally, we hypothesize that these variations in protective immunity are related to the balance between HIV-specific T cell responses (limiting viral spread) and non-specific inflammation (enhancing viral replication), a balance that itself is determined by the frequency and function of TReg.
Given these considerations, the general objective of this proposal is to explore the disposition and function of the TReg compartment in mothers and their newborns when the mothers are infected with HIV and/or malaria during pregnancy. Given preliminary data from these studies, a larger, prospective study could potentially be developed to relate these findings to outcome, e.g., to mother-to-child transmission of HIV or to signs or symptoms of malaria in the newborn. The specific research objectives of this proposal are as follow:
- (1) To determine if TReg (which are known suppressors of the immune response) in the umbilical cord blood of HIV EU infants suppress specific anti-HIV responses, and whether these TReg are less effective in the setting of co-infection with malaria.
- (2) To determine whether HIV specific TReg in EU neonates have a signature gene-expression pattern that is similar to fetal TReg cells, which are known to induce tolerance, and whether this pattern is altered by co-infection with malaria.