The history of previous immune exposures shapes an individual's response to current exposures, a phenomenon termed heterologous immunity. Infants represent a unique population for evaluation of heterologous immunity because limited in utero antigenic exposure creates a cleaner 'slate'from which antigenic perturbations ofthe T-cell receptor repertoire can be read. The effect of in utero HIV-1 exposure on the infant's ability to respond to vaccines and other infections is unknown and may be important to strategically refine vaccine schedules. The long-term objective of this project is to define the effects of in utero exposure to HIV-1 on the immune status ofthe infant at birth and during early vaccination. We hypothesize that Exposed Uninfected (EU) infants respond differently to routine vaccinations than unexposed infants as a result of heterologous immunity induced by maternal persistent viral infection and chronic immune activation.
We aim to test this by 1) TCR repertoire analysis at birth and one month of age, 2) examination of HIV-1 EU TCR repertoire diversity and mortality risk during the first year of life, 3) evaluation of vaccine responses in HIV EU and unexposed infants, and 4) correlation of maternal plasma cytokine levels with infant cytokines in HIV-1 infected and uninfected women and their uninfected infants. CDR3 spectratyping, a molecular tool designed to analyze size distributions within the TCR 3-chain variable gene (BV) families, allows for quantification of TCR repertoire size and diversity, which will be conducted on umbilical cord blood (CB) and peripheral blood collected at one month of age from HIV-1 exposed and unexposed infants. Additionally, CB TCR repertoire from HIV-1 EU infants who died before 1 year of life will be compared with EU infants alive at 1 year, to identify repertoire changes associated with mortality. Maternal and infant cytokine profiles will be assessed using Luminex multiplex technology. Poliovirus vaccine responses will be measured using a poliovirus antibody neutralization assay. This study is significant because it is the first to explore heterologous immunity as a mechanism of increased morbidity and mortality in HIV-1 EU infants, a growing population in developing countries.

Public Health Relevance

The history of previous immune exposures shapes an individual's response to current exposures, a phenomenon termed heterologous immunity. Infants represent a unique population for evaluation of heterologous immunity because limited in utero antigenic exposure creates a cleaner 'slate'from which antigenic perturbations ofthe T-cell receptor repertoire can be read. The effect of in utero HIV-1 exposure on the infant's ability to respond to vaccines and other infections is unknown and may be important to strategically refine vaccine schedules. The long-term objective of this project is to define the effects of in utero exposure to HIV-1 on the immune status ofthe infant at birth and during early vaccination. We hypothesize that Exposed Uninfected (EU) infants respond differently to routine vaccinations than unexposed infants as a result of heterologous immunity induced by maternal persistent viral infection and chronic immune activation. We aim to test this by 1) TCR repertoire analysis at birth and one month of age, 2) examination of HIV-1 EU TCR repertoire diversity and mortality risk during the first year of life, 3) evaluation of vaccine responses in HIV EU and unexposed infants, and 4) correlation of maternal plasma cytokine levels with infant cytokines in HIV-1 infected and uninfected women and their uninfected infants. CDR3 spectratyping, a molecular tool designed to analyze size distributions within the TCR 3-chain variable gene (BV) families, allows for quantification of TCR repertoire size and diversity, which will be conducted on umbilical cord blood (CB) and peripheral blood collected at one month of age from HIV-1 exposed and unexposed infants. Additionally, CB TCR repertoire from HIV-1 EU infants who died before 1 year of life will be compared with EU infants alive at 1 year, to identify repertoire changes associated with mortality. Maternal and infant cytokine profiles will be assessed using Luminex multiplex technology. Poliovirus vaccine responses will be measured using a poliovirus antibody neutralization assay. This study is significant because it is the first to explore heterologous immunity as a mechanism of increased morbidity and mortality in HIV-1 EU infants, a growing population in developing countries.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Exploratory Grants (P20)
Project #
1P20GM104317-01
Application #
8465984
Study Section
Special Emphasis Panel (ZGM1-TWD-A (CB))
Project Start
Project End
Budget Start
2013-09-01
Budget End
2014-05-31
Support Year
1
Fiscal Year
2013
Total Cost
$269,078
Indirect Cost
$93,783
Name
University of Rhode Island
Department
Type
DUNS #
144017188
City
Kingston
State
RI
Country
United States
Zip Code
02881
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