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HUMAN GENETIC SUSCEPTIBILITY to MOTHER to CHILD TRANSMISSION of HIV: a Study of Mother-Infant Pairs in Malawi by Bonnie Rachel J

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HUMAN GENETIC SUSCEPTIBILITY to MOTHER to CHILD TRANSMISSION of HIV: a Study of Mother-Infant Pairs in Malawi by Bonnie Rachel J HUMAN GENETIC SUSCEPTIBILITY TO MOTHER TO CHILD TRANSMISSION OF HIV: A Study of Mother-Infant Pairs in Malawi by Bonnie Rachel Joubert A dissertation submitted to the faculty of the University of North Carolina at Chapel Hill in partial fulfillment of the requirements of the degree of Doctor of Philosophy in the Department of Epidemiology Chapel Hill 2009 Approved by: Steven R Meshnick Kari E. North Ethan M. Lange Nora Franceschini Jian Liu Andrew F. Olshan Copyright 2009 by Bonnie Rachel Joubert All rights reserved ii ABSTRACT BONNIE RACHEL JOUBERT: Human Genetic Susceptibility to Mother-To-Child- Transmission of HIV: A Study of Mother-Infant Pairs in Malawi (Under the direction of Steven Meshnick, M.D., Ph.D.) Mother-To-Child Transmission of HIV (HIV MTCT) is a worldwide public health problem and particularly burdens mothers and children in Sub-Saharan Africa, where in 2006, over 500,000 infants were newly infected with HIV 1. To more clearly understand the mechanisms of transmission, we studied genetic exposures and HIV MTCT in consenting mother-infant pairs receiving antenatal care in Blantyre, Malawi. We first examined infant genetic susceptibility to maternal infection through a genome wide association (GWA) scan of 655,000 SNPs. Top associations with HIV MTCT were found for 20 SNPs within 7 genes (p<5 x 10 -5, Bonferroni p=1), including rs8069770, located within the gene, HS3ST3A1, which facilitates the biosynthesis of a subtype of Heparan Sulfate that plays a role in viral infection. We then applied our GWA data to determine how genetic variation in our Malawi population compares to that of African ancestry (AFA) populations from the International HapMap Project. Allele frequency in the Malawian population was highly correlated to that of AFA populations (r2>0.90) but not with other ancestry populations (r 2<0.51). Similar findings were observed for adjacent linkage disequilibrium (AFA r2>0.80, other ancestry r 2<0.54). Frequencies of 4 SNPs in the lactase gene ( LCT ) varied greatly between the Malawi population and Maasai in Kenyawa, Kenya (Bonferroni p<1x10 -33 ). The Malawi population was genetically homogenous but distinct from other populations. iii Finally, we examined the regulation of chemokine co-receptor 5 ( CCR5 ) expression in human placenta by infant polymorphisms and maternal infection. The CCR5 promoter polymorphisms CCR5 -2554T (rs2734648, β= -0.67, 95% CI= -1.23, - 0.11) and -2132T (β=-0.75, 95% CI=-0.131, -0.18) were significantly associated with reduced placental expression of CCR5 . An incremental increase in CCR5 expression by expression of HS3ST3A1 (β=0.27, 95% CI=0.18, 0.35) and HS3ST3B1 (β=0.11, 95% CI=0.06, 0.18) was observed. CCR5 expression was up-regulated for higher maternal HIV viral load (β=0.76, 95% CI=0.12, 1.39; p=0.020) and malaria infection (β=0.37, 95% CI=-0.43, 1.18, p=0.362), with variable statistical significance. This cumulative body of work provides a fresh look at genetic factors involved in the risk of HIV MTCT as well as how such findings can be generalized to other populations in Africa. iv ACKNOWLEDGEMENTS This body of work was in many ways a collaborative effort and would not have gone farther than one day if the individuals involved were not creative, giving, and patient people. I would like to sincerely thank my committee chair and advisor, Steven Meshnick, who taught me the practicalities of research, good and bad, and instilled a sense of realism into my graduate studies. His “sink or swim” approach to mentoring made me a stronger student and researcher. I hope this swimmer made you proud. I have enormous gratitude to Kari North, who I always perceived as a co-advisor. Your patience and selfless support made it easy to talk to you about anything and pursue what I was most passionate about without regret. Your methodological teaching also served very much as a base for this work. I am very grateful for the statistical knowledge and creativity of Ethan Lange, which played a large role in the methodological nature of this work, especially when analyses increased in complexity. I also want to thank Nora Franceschini for your friendship and insight, Jian Liu, who was willing to take a chance on this by crossing fields from pharmacy to genetic epidemiology, and Andy Olshan, for helping to keep this project grounded on sound epidemiology. I am enormously grateful to the Meshnick Laboratory, especially Jon Juliano, Anne Purfield, and Carla Hand, who helped me with the nuts and bolts of lab work and who made my time in the lab so much more fun. v I would like to acknowledge Victor Mwapasa, who shared his office space with me during my time in Malawi and who played a key role in the implementation of the Malawi and HIV in Pregnancy (MHP) Cohort Study. To the nurses at the University of Malawi who are responsible for much of the data collected, without which, this work would not have been possible. I express great gratitude to the mothers and infants enrolled in the MHP study. I hope that this work in some way contributes towards better circumstances for mothers living with HIV in Malawi. I am very grateful to the funding resources that have helped me through my graduate training, including the Centers for HIV/AIDS Vaccine Initiative (CHAVI), the NIEHS training grant, the Virology training grant, and the CDC Dissertation Award. These have encouraged my confidence in the value of research. I owe a great deal to my parents, siblings, and close friends, whose encouragement, love, and comedy gave me perspective and happiness. And a special thank you to my husband, J.P., who reminds me what truly matters, provides comic relief, and encourages my confidence when faced with any task. vi TABLE OF CONTENTS ABSTRACT .................................................................................................................................... iii ACKNOWLEDGEMENTS ............................................................................................................. v TABLE OF CONTENTS ............................................................................................................... vii LIST OF TABLES ........................................................................................................................ xiv LIST OF FIGURES ..................................................................................................................... xvii LIST OF ABBREVIATIONS ..................................................................................................... xviii CHAPTER 1 REVIEW OF THE LITERATURE ........................................................................... 1 1.1 Summary ............................................................................................................................. 1 1.2 Types of Mother-to-Child Transmission of HIV ................................................................ 1 1.2.1 Intrauterine Transmission ...................................................................................... 2 1.2.2 Intrapartum Transmission ...................................................................................... 2 1.2.3 Postpartum Transmission ....................................................................................... 3 1.3 Epidemiology of HIV MTCT and High Risk Populations ................................................. 4 1.4 Environmental and Behavioral Risk Factors for HIV MTCT ............................................ 5 1.5 Genetic Risk Factors for HIV MTCT ................................................................................. 7 1.5.1 Chemokines and Chemokine Receptors ................................................................ 8 1.5.2 CCR5 ...................................................................................................................... 9 1.5.3 CXCR4 ................................................................................................................. 10 1.5.4 CCR2 .................................................................................................................... 11 1.5.5 CX3CR1 ............................................................................................................... 12 1.5.6 DCSIGN ............................................................................................................... 13 vii 1.5.7 HLA Class I .......................................................................................................... 14 1.5.8 KIR -HLA Interactions .......................................................................................... 15 1.5.9 IL-4 ...................................................................................................................... 17 1.5.10 MBL2 ................................................................................................................... 17 1.5.11 APOBEC3G ......................................................................................................... 18 1.6 Syndecans ......................................................................................................................... 25 1.7 Heparan Sulfate and Viral Infection ................................................................................. 26 1.7.1 Heparan Sulfate Structure and Function .............................................................. 26 1.7.2 Heparan Sulfate and HSV .................................................................................... 29 1.7.3 Heparan Sulfate and HIV ....................................................................................
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