Master of Sciences, Case Western Reserve University, 2009, Epidemiology and Biostatistics

Understanding sexual behaviors of persons on Antiretroviral therapy(ART) is critical designing and implementation of positive prevention programs. 559 HIV infected adults were enrolled in clinic based prospective observational study and sexual behaviors ascertained at ART initiation and semi-annually thereafter. Using Logistic regression with generalized estimating equations, factors associated with sexual activity and unprotected sex were examined. Over the first three years of ART, the proportion sexually active did not change at ~52% (χ2 Trend, p=0.94) while the proportion reporting unprotected sex decreased (χ2 Trend, p<0.0001). Men reported unprotected sex less often than women (p<0.0001). In all analyses, having no children and female gender (controlling for any other factors) was associated with the practice of unprotected sex. The interventional effect of comprehensive HIV care resulted in marked reductions in unprotected sex particularly among men. Strengthening of positive prevention interventions, especially among females are needed in ART programs in this setting.

Committee: Ajay Sethi Phd,MHS (Committee Chair); Christopher Whalen MD, MS (Committee Member); Jeffrey Albert Phd (Committee Member) Subjects: Biostatistics; Epidemiology; Health; Health Care; Virology

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

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, EDU Policy and Leadership

The use of a measure of HIV transmission risk which incorporates seroadaptive behaviors is needed in order to assess the complex effects of disclosure on HIV transmission. The purpose of this study was to explore the use of a modified version of the ordinal scale of HIV risk behavior proposed by Osmond, Pollack, Paul, and Catania (2007) to operationalize the risk of HIV transmission among HIV-positive MSM and to establish the strength of the empirical evidence supporting the use of these scores for inference about HIV transmission. The original measure was modified to include the full potential for seropositioning (i.e., with and without 100% condom use) as a potential preventive strategy used by MSM to reduce the risk of HIV transmission. Additionally, the measure was applied to individual sexual encounters rather than globally so that the frequency of risk behaviors can be accurately modeled. The appropriateness of these methods was explored using data from a study involving the disclosure of serostatus to sexual partners in a sample of HIV-positive MSM. Results of the study are promising for the refinement of measurements of HIV transmission risk, and for the understanding of seroadaptive behavior in MSM. For researchers who are seeking to demonstrate the effectiveness of interventions designed to reduce HIV transmission risk, the ordinal measure provides a means for detecting qualitative shifts in sexual activity which can be critical to the question of effectiveness.

Committee: Ann A. O'Connell Ed.D. (Advisor); Julianne M. Serovich Ph.D. (Committee Member); Dorinda J. Gallant Ph.D. (Committee Member) Subjects: Educational Evaluation; Educational Tests and Measurements

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

Doctor of Philosophy, Case Western Reserve University, 2008, Epidemiology and Biostatistics

The Effect of HIV-1 Subtypes on HIV Transmission and Disease Progression in Rakai District, Uganda Objectives: To determine whether HIV transmission and disease progression differ by HIV-1 subtype. Methods: The effect of HIV-1 subtypes on HIV transmission and disease progression was investigated using data from community-based cohort studies in Rakai district, Uganda. HIV-1 subtype was determined by genomic sequencing of the gag and gp41 viral regions and by the Multi-region Hybridization Assay (MHA). HIV viral loads were determined by Roche Amplicor v1.5, and CD4+ T cell counts by BD Facscalibur system. Adjusted measures of association were estimated using Poisson regression model, linear mixed effects model, and Cox proportional hazards model. Results: Adjusting for age, viral load, and genital ulcers (GUD), HIV transmission was higher for subtype A relative subtype D (Rate ratio, 1.98; 95% CI, 1.17 - 3.34). Age (<30 years) of the positive partner (RR, 3.98; 95%CI, 1.90 - 8.35), GUD (RR, 1.83; 95% CI, 1.16 - 2.89), and viral load (RR, 2.17; 95% CI, 1.60 - 2.94) were significant risk factors for HIV transmission. Regardless of subtype, the rate of CD4+ T cell loss (cells/μL per year) was -31.6 (95%CI; -44.6, -18.6), adjusted for age, baseline CD4 counts, and viral load. Adjusted rate of CD4+ cell loss was -8.8 (95%CI; -35.1, 17.4) for subtype A, -34.3 (95%CI; -64.0, -4.6) for R, -37.5 (95%CI; -54.1, -20.8) for subtype D, and -77.5 (95%CI; -136.6, -18.4) for M. The median time from seroconversion to AIDS was shorter for subtypes D, R and M (6.5, 5.6, and 5.8 years, respectively), compared with A (8.0 years; p =0.022). Relative to subtype A, adjusted hazard ratios (95% CI) of progression to AIDS were 2.13 (1.10 - 4.11) for subtype D, 2.16 (1.05 - 4.45) for recombinants, and 4.40 (1.71-11.3) for infection with multiple HIV strains. Conclusions: In Rakai, subtype A has a higher rate of HIV transmission than subtype D or inter-subtype recombinants. However, subtype (open full item for complete abstract)

Committee: Christopher Whalen MD (Committee Chair); Ajay Sethi PhD (Committee Member); Jeffery Albert PhD (Committee Member); Catherine Stein PhD (Committee Member); Peter Zimmerman PhD (Committee Member) Subjects: Biomedical Research; Epidemiology