Doctor of Philosophy, The Ohio State University, 2019, Public Health

Introduction: Lifelong treatment for HIV-infected women offers profound benefits in terms of the prevention of mother-to-child transmission of HIV (PMTCT) and disease management, though poor adherence to antiretroviral drugs (ARV) and disengagement from PMTCT care can jeopardize these benefits. Insights from the field of behavioral economics reveal that high temporal discounting can lead to risky health behaviors, and these findings have informed the development of interventions, such conditional cash transfers (CCT), to mitigate these effects. Few studies, however, have directly assessed the effects of temporal discounting on behaviors relating to HIV prevention and treatment, and none have evaluated these effects among pregnant and breastfeeding women. Further, few studies have assessed the role of temporal discounting on the effect CCT or other similar interventions providing conditional economic incentives to improve behaviors relating to HIV treatment and prevention. Methods: We conducted a secondary analysis of data from a randomized controlled trial (RCT) conducted in Kinshasa, the Democratic Republic of Congo, which assessed the effect of a CCT intervention on retention in PMTCT care, adherence to ARV and viral suppression among newly-diagnosed HIV-infected pregnant women. We identified correlates of temporal discounting from health and demographic information collected at baseline. We then assessed the association between temporal discounting and retention in care at 6 weeks postpartum, uptake of available PMTCT services, and viral suppression at 6 weeks postpartum using log-binomial models to calculate unadjusted and adjusted RRs for high vs. low discounting for each outcome. We also evaluated possible interaction between temporal discounting and CCT for each outcome (retention, uptake of available PMTCT services and viral suppression). Results: High temporal discounting was associated with incomplete uptake of PMTCT services, and this effect was mitiga (open full item for complete abstract)

Committee: Abigail Norris Turner PhD (Advisor); Maria Gallo PhD (Committee Member); Abigail Shoben PhD (Committee Member); Marcel Yotebieng PhD, MD (Committee Member) Subjects: Economics; Epidemiology; Psychology; Public Health

PHD, Kent State University, 2016, College of Arts and Sciences / Department of Psychological Sciences

Adolescent mothers are at risk for poor parenting adjustment and their children are at risk for behavior and learning problems. These young mothers' own mothers (the children's grandmothers), are a key presence in their lives, but the contribution of grandmother childcare involvement to mother-child interactions is mixed in the literature. Research is needed to better understand the conditions under which grandmother involvement in childcare can be beneficial for mother-child interactional styles like dyadic synchrony, which is characterized by mutual engagement, reciprocity, and warmth. Recent findings suggest that the quality of the mother-grandmother relationship is one of the factors that may determine whether grandmother childcare is beneficial for parenting adjustment. The current study investigated mother-grandmother relationship quality as well as other conditions (e.g., grandmother coresidency with mother, mother nativity status, child gender) that may foster higher levels of dyadic synchrony in a sample of primarily Puerto Rican young mothers (N= 160; Mage=19.5 years) and their toddlers (Mage=18.2 months). Descriptive information on dyadic synchrony measures in this sample, including mutual positive affect, dyadic reciprocity, and a dyadic synchrony composite, is presented. Hierarchical linear regressions examined grandmother coresidency, mother nativity, and child gender as demographic and contextual factors that may qualify how grandmother childcare relates to dyadic synchrony. Findings indicated that higher levels of grandmother childcare involvement related to displays of more dyadic reciprocity for mother-daughter dyads but not mother-son dyads. For the main research question, grandmother supportiveness and acceptance did not moderate the association between grandmother childcare involvement and dyadic synchrony, even after taking into account child and maternal characteristics. However, group differences by gender remained significant, above and beyo (open full item for complete abstract)

Committee: Josefina Grau PhD (Committee Chair); Beth Wildman PhD (Committee Member); Manfred van Dulmen PhD (Committee Member); Susan Roxburgh PhD (Committee Member); Carla Goar PhD (Committee Member) Subjects: Developmental Psychology; Minority and Ethnic Groups; Psychology

Doctor of Philosophy, The Ohio State University, 2014, Microbiology

By the end of 2011, there were approximately 34 million HIV-infected individuals and more than 25 million AIDS-related deaths worldwide. The lack of successful prevention strategies and economic constraints of antiretroviral regimens highlight the importance of HIV-1 research. Current research goals aim to understand molecular mechanisms of transmission and infection so preventative measures and superior treatment regimens can be devised. This dissertation has two major foci: determining how viral genetic diversity contributes to transcriptional regulation within in utero mother-to-child transmission and understanding how pharmacological modulation of epigenetic pathways regulates HIV latency. Without intervention, mother-to-child transmission accounts for approximately 30% of all HIV infections; however, MTCT is responsible for 90% of pediatric HIV infections. Approximately 20% of all HIV-1 mother-to-child transmission (MTCT) occurs in utero (IU), with little understanding of the molecular mechanism underlying this event. During IU MTCT, viral variants must traverse an intact placental barrier to reach fetal circulation, creating a genetic bottleneck. As a model of transmission, we hypothesize that viral genetic diversity within the U3R is associated with selection for gestational transmission. To this end, we used single template amplification to isolate 517 U3R sequences from maternal, placental, and infant plasma derived from seventeen HIV-infected Malawian women. Specific TF sequence polymorphisms were not significantly associated with IU MTCT; thus, we were unable to detect a promoter genotype associated with gestational transmission. We then tested the hypothesis that genetic variability of the HIV-1 U3R associates with a transcriptional phenotype. To test this hypothesis, we cloned 90 U3R sequences and assayed promoter activity in multiple cell lines. Although we observed significant, yet highly variable promoter activity, there was no association between me (open full item for complete abstract)

Committee: Jesse Kwiek PhD (Advisor); Chad Rappleye PhD (Committee Member); Li Wu PhD (Committee Member); Marshall Williams PhD (Committee Member) Subjects: Microbiology; Molecular Biology; Virology

Doctor of Philosophy, The Ohio State University, 2012, Comparative and Veterinary Medicine

The complex retrovirus Human T-lymphotropic virus type-1 (HTLV-1) is the causative agent of adult T-cell leukemia/lymphoma and other lymphocyte-mediated inflammatory disorders. In endemic regions, HTLV-1 is primarily spread from mother to child through infected breast milk. The establishment of persistent HTLV-1 infection following the ingestion of infected lymphocytes is determined by the delicate balance between viral spread and the host immune response. The immunopathogenesis of these early events is not completely understood, and advances in this area have been hindered by the lack of an appropriate animal model. This thesis describes a novel rabbit model of HTLV-1 milk-borne infections, and provides data to understand the early immunological and virological events following oral mucosal exposure to HTLV-1. Herein, we performed an extensive examination of the rabbit gut-associated lymphoid tissue. Using two quantitative methods to exam lymphocyte subsets within the major inductive sites our data revealed similarities between rabbits and humans. This information validates this species as a model for mucosal immunology studies following oral exposure to HTLV-1 and establishes reference ranges for future studies. Our data provides important knowledge of the immune response against HTLV-1 infection following oral exposure to infected lymphocytes. We established a protocol for infection via the oral mucosal route using a method that mimics infant exposure to repeated doses of comparable numbers of infected lymphocytes. We further characterized this model of infection through evaluation of humoral and cellular immune responses and viral parameters. We determined that rabbits exposed orally to HTLV-1 infected lymphocytes develop a persistent infection characterized by a delayed and variable humoral immune response similar to infected infants. Rabbits exposed by this route also displayed a variable, decreased and delayed peripheral cellular immune response with lower (open full item for complete abstract)

Committee: Stefan Neiweisk DVM/PhD (Advisor); Michael Lairmore DVM/PhD (Committee Member); Burkhard Mary Jo DVM/PhD (Committee Member); Wellman Maxey DVM/PhD (Committee Member) Subjects: Immunology; Virology

Master of Science in Biomedical Sciences (MSBS), University of Toledo, 2008, College of Graduate Studies

The objective of this study is to determine the phenotype of lymphoma associated with temperature sensitive Moloney Murine Leukemia Virus (Mo-MuLV-ts1) retrovirus and the alteration in specific genes of mRNA expression in these lymphomas. MoMuLV-ts1 infection in BALB/c mice mimics HIV infection in humans. In previous work, we have demonstrated breast milk transmitted Mo-MuLV-ts1 infection and subsequent lymphoma development in offspring. In this experiment, a total of 146 pups from BALB/c mice were divided into 5 groups; one control and 4 experimental. Splenic tissues were used for immunohisto-chemistry, Inverse-PCR and quantitative real-time PCR (RT-PCR). Through studying viral integration sites, twenty-seven genes were identified as candidate genes in lymphoma development. mRNA expression levels for each of 27 genes were determined using a standard curve method, normalized for GAPDH gene expression. A total of 13 pups developed lymphoma of which 7 suckled either from their infected biological or surrogate mothers and developed T-cell lymphoma (Group #1 and #2). Six pups from control mother that suckled from infected surrogate mother (Group #3) developed T-cell lymphoma and B-cell lymphoma. The cells of these lymphomas expressed significantly higher levels of mRNA for two genes (Gfi1 and Ncor2). Two other genes (Ahi1 and Tacc3) were found to be generally significantly upregulated in all lymphomas. Our results indicated that ts1 integration activates the expression of four cellular genes including Ahi1, Ncor2, Tacc3, and Gfi1 that may contribute to lymphomagenesis.

Committee: Joana Chakraborty PhD (Committee Chair); Joan Duggan MD (Committee Member); Sonia Najjar PhD (Committee Member) Subjects: Molecular Biology; Virology

Doctor of Philosophy, Case Western Reserve University, 2011, Pathology

Mother-to-child-transmission of HIV (MTCT) remains a significant cause of new HIV infections in many countries. Maternal risk factors such as high viral load, maternal immune status, vaginal delivery and presence of cervicovaginal infections increase the rate of HIV transmission to the newborn. However, all risk factors for MTCT during the in utero and perinatal periods, especially in developing countries, are not fully understood. To examine whether fetal immune activation as a consequence of prenatal exposure to parasitic antigens increases risk of MTCT, cord blood mononuclear cells (CBMC) from Kenyan versus North American newborns were examined for relative susceptibility to HIV infection in vitro. Kenyan CBMC were 3-fold more likely to be infected with HIV compared to North American CBMC (p=0.03). Fetal sensitization to malaria antigens further enhanced susceptibility to HIV when compared to Kenyan CBMC not sensitized to malaria (p=0.03). CD4+ T cells from malaria sensitized newborns expressed higher levels of CD25 and HLA-DR ex vivo, consistent with increased immune activation. CD4+ T cells were the primary reservoir of infection at day four following virus exposure.To explore mechanisms for this selective susceptibility, we examined subpopulations of CBMC infected and molecular pathways involved. Effector memory CD3+CD4+ T cells (TEM) were the exclusive initial targets of HIV infection with rapid spread to central memory cells (TCM). HIV susceptibility correlated with increased expression of CD25 and HLA-DR on TEM. Virus entered all samples equally, however gag/pol RNA was only detected in HIV susceptible samples, suggesting regulation of proviral gene transcription. Targeted analysis of human genes in memory T cells showed greater expression of IFNG, NFATc1, IRF1, FOS, and PPIA and decreased expression of YY1 and TFCP2 in HIV susceptible samples.Thus prenatal exposure and in utero priming to malaria increases the susceptibility of fetal cells to HIV infection (open full item for complete abstract)

Committee: Christopher L. King MD, PhD (Advisor); Alan D. Levine PhD (Committee Chair); Eric J. Arts PhD (Committee Member); James W. Kazura MD (Committee Member); Zahra Toossi MD (Committee Member) Subjects: Biomedical Research; Immunology; Virology