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Characterizing intact proviral HIV-1 reservoir size and determinants of reservoir dynamics in African populations by UNIVERSITY OF CAPE TOWN (The Research University TRU)



Project SummaryAntiretroviral treatment is unable to clear HIV-1 infection because a highly stable latent viral reservoirpersists in the host. Key areas of interest with respect to HIV-1 eradication strategies include latentreservoir establishment, size and make-up. A considerable amount is now known about these key areas insubtype B-infected American men, yet there remains limited knowledge in the most affected population,subtype C-infected South African women, or in African populations in general. Population differences mayexist with respect to reservoir characteristics, and eradication strategies would need to take suchdifferences into account. Characterization of the HIV-1 reservoir in the African context therefore representsa much needed area of attention.This project proposes to firstly address the need for implementation of a high-throughput, accurate reservoirsizing method in South Africa through optimization of the newly developed intact proviral DNA assay (IPDA)for subtype C HIV-1. This method will be applied to more than 200 women from KwaZulu Natal. Reservoirsize in these women will be compared to that of individuals from Ugandan and American cohorts using thesame assay to evaulate reservoir differences across populations. This project will also investigate a role forthe viral factors Nef and the long terminal repeat, which are drivers of immune evasion and genetranscription respectively, in reservoir size and make-up in a subset of these women. Finally, we will explorethe contribution of viral variants from the blood and cervix to the long-lived reservoir in these women usingBayesian evolutionary analyses.We hypothesize that Nef-mediated MHC-I downregulation and LTR activity have independent effects onreservoir size and distribution, and these effects differ according to infecting subtype and study population.This project will allow for comparison of reservoir size across populations using a standardized assay andwill evaluate determinants of size and kinetics of establishment.



CombinADO: a combination intervention strategy to improve health outcomes for adolescents living with HIV by COLUMBIA UNIVERSITY HEALTH SCIENCES (The Research University TRU)



UPROJECT ABSTRACT/ SUMMARYAdolescents are at the core of the global HIV epidemic. They are highly vulnerable to HIV acquisitionand?for adolescents living with HIV (ALHIV)?at disproportionate risk for poor health outcomesacross the HIV care continuum. Retention rates, adherence to antiretroviral treatment (ART), and viralsuppression (VS) are alarmingly low among ALHIV, warranting urgent attention. Adolescence is atime of rapid physical and psychological development, when youth move from childhood to adulthoodand experience multiple challenges as well as opportunities for growth, creativity, and learning. Youthwho enter this period under adverse conditions are ill prepared to cope with the impact of living with apotentially fatal, stigmatized, transmissible infection and the need to adopt positive, health-seekingbehaviors, engage with health services, and adhere to daily ART regimens. In high prevalencecountries like Mozambique, the burden of living with HIV during this vulnerable developmental stageis further exacerbated by fragile health systems and nascent ALHIV-specific differentiated servicedelivery (DSD) models. At the same time, few specific interventions have been developed and testedthat address the needs of ALHIV. In response, we propose to develop and test a culturally-appropriate, contextually-relevant, and theoretically-grounded adolescent-focused multicomponentintervention strategy, CombinADO, among ALHIV in Zambézia, Mozambique. Using a human-centered design approach, we will work with ALHIV, caregivers, health care providers, and local andnational stakeholders to develop and pilot this CombinADO intervention strategy consisting of fourcomponents: 1) ALHIV peer navigation and support, 2) adolescent-friendly services, 3) mHealthtechnologies, and 4) health communication messaging (Phase 1). In Phase 2, we propose to evaluatethe effectiveness of the CombinADO strategy on three milestones along the HIV care continuum: (a)retention in HIV care, (b) ART adherence, and (c) VS among ALHIV using a cluster randomizedcontrolled trial design. The study builds on longstanding partnerships between ICAP at ColumbiaUniversity, the Mozambique Ministry of Health and other local stakeholders, all aiming to improve thedisease course as well as outcomes along the continuum of care for this highly vulnerable population,adolescents living with HIV.



Clinical-Trans-Valid Core by NORTHWESTERN UNIVERSITY (The Research University TRU)



SUMMARY ? CLINICAL TRANSLATION AND VALIDATION COREThe C-THAN Clinical Translation and Validation Core (Clinical Trans Valid Core) will be robust and achievabledue to many years of HIV-focused clinical research and research training with local partners in Nigeria, SouthAfrica, Mali, and Tanzania. In addition to our key academic partners, we will integrate many other international,national, regional and community stakeholders involved in POC development, validation, and implementationacross the partner institutions. Our overarching objective is to develop a pipeline of POC products that meetthe clinical needs of HIV-infected individuals in low and middle-income countries. Investigators will be requiredto demonstrate analytical and clinical performance of technologies as well as suitability and feasibility of use inlow resource settings. The Clinical Trans Valid Core specific aims are: 1. validate and establish best practicesfor innovative POC technologies developed for the diagnosis and management of HIV and HIV related co-morbidities in ?real-world? clinical or public health settings, 2. assess outcomes of implementation processes ofinnovative POC technologies developed for the diagnosis and management of HIV and HIV related co-morbidities in ?real-world? clinical or public health settings, and 3. support translation of innovative POCtechnologies from the Technology Development (Technology Dev) Core into clinical practice though pilotfunding, expertise in validation and implementation science, and providing resources including support todevelop needed trainings, manuals and other tools to ensure effective uptake. Our Clinical Trans Valid Corewill provide a ?clinical laboratory? for innovators that will focus on validation, adoption, and assessment offeasibility and implementation of POC technologies. Depending on the status of a developing POCtechnology, we will work across Cores to select projects to participate in either the Clinical Trans Valid Core orTechnology Dev Core. We will also review projects in the Technology Dev Core in later stages for potentialtransition into the Clinical Trans Valid Core. The primary goal of the Clinical Trans Valid Core is to provideinfrastructure and services dedicated to clinical validation of POC technologies and to evaluate implementationoutcomes including adoption, fidelity, feasibility and acceptability to ensure that POC technology prototypessupported under C-THAN will have a high rate of success for clinical uptake and maximal public health impact.



Dartmouth-Boston University HIV-TB Research Training for the Infectious Disease Institute at Muhimbili University of Health and Allied Sciences by DARTMOUTH COLLEGE (The Research University TRU)



PROJECT SUMMARY/ABSTRACT  The previous three cycles of the Dartmouth-­Boston University-­Muhimbili (DBM) Fogarty HIV training program have resulted in a multi-­faceted research and training collaboration between Dartmouth, BU and Muhimbili University of Health and Allied Sciences (MUHAS). It has produced landmark studies on the epidemiology of HIV, tuberculosis (TB) and HIV-­related TB (HIV-­TB), clinical features of adult and pediatric HIV-­TB, vaccine trials to prevent HIV-­TB, and nutritional supplementation for women with HIV-­TB.     Our current 5-­year award culminated in MUHAS? approval of a TB Research Institute (TRIM-­TB), which is an HIV-­TB research collaboration between the DBM Fogarty program, MUHAS and the Tanzanian National Programme on Tuberculosis and Leprosy (NTLP). Recognizing the benefits of TRIM-­TB, MUHAS leadership endorsed the concept of a broader initiative, designated as the Infectious Disease Institute (IDI). The newly approved IDI will support research and training in all infectious diseases of importance in Tanzania, with an initial focus on HIV and TB. MUHAS, the NTLP and the National AIDS Control Program (NACP) have solicited the DBM Fogarty Program to provide the training needed to achieve the IDI?s goals. To that end, we propose: 1) Train IDI research faculty to conduct HIV and HIV/TB epidemiologic research and clinical trials 2) Establish a mentoring program through IDI to ensure junior faculty are supported and successful in performing research and obtaining independent research funding. 3) Expand the portfolio of funded collaborative HIV and HIV/TB research for MUHAS faculty/trainees. 4) Develop a program of research training for Tanzanian field scientists led by IDI faculty To develop the present proposal, we conducted a comprehensive needs assessment including: 1) discussions with key stakeholders/leadership at MUHAS, NTLP and NACP, 2) interviews with key MUHAS faculty, and 3) a survey of DBM Fogarty alumni. In response, we focused our program on training in epidemiology, biostatistics and clinical trials, developing strong Tanzanian mentors, expanding the research portfolio using NTLP and NACP data, and supporting the IDI to develop its permanent research training program.  At the end of this proposed training program, 5 Tanzanian researchers will have graduated with PhD degrees in epidemiology and/or biostatistics, 1 with a Masters degree in Epidemiology, and 4 with Masters of Public Health degrees;? 18 will have completed short course training outside of Tanzania in epidemiology, biostatistics, TB/HIV/STD research methods;? and over 150 will have attended interactive, hands-­on workshops in Dar es Salaam on HIV-­TB clinical research, monitoring & evaluation, data analysis, and grant and manuscript writing. This training program will provide the expertise to establish IDI as the premiere self-­sustaining research and training institute for HIV and TB in East Africa.






African Female Breast Cancer Epidemiology (AFBRECANE) StudyProject summaryBreast cancer is the commonest cancer in women globally and it is increasingly overtaking cervical cancer asthe commonest female cancer in low and middle income countries (LMIC). The incidence of breast cancerNigeria was 54.3 per 100,000 per year (24,750 new cases per year) in 2014 representing a rise from 20 per100,000 in the 1970s (3,000 new cases per year). It is now a major cancer burden in Nigerian women. Thereare controversies about the epidemiology and molecular subtypes of breast cancer in African women includinglimited knowledge about the incidence of breast cancer and determinants of this incidence such as the role ofdifferent risk factors; incidence and prevalence of molecular subtypes of breast cancer and the contributions ofindigenous African diets to breast cancer incidence. In the absence of prospective cohort studies, we engageinnovative research design and analytic techniques to use data from population based cancer registries(PBCR) to study the epidemiological factors associated with incident breast cancer and molecular subtypes.There has also never been a genome wide association study (GWAS) of breast cancer in general and ofmolecular subtypes of breast cancer in indigenous African women.While many researchers suggest that African diets are associated with reduced risks of breast cancer, therehave been very few systematic studies. We use the nutrition epidemiology tools that we previously developedand validated to study dietary intakes and breast cancer risk in African women. We focus in particular on therole of vitamin D and explore potential associations with breast cancer using nutrition epidemiology andgenomics epidemiology tools.






West African Sustainable Leadership and Innovation Training inBioinformatics Research (WASLITBRe)Training Program Summary. It is evidently clear that NIH has audaciously stimulatedand is supporting research in human health and heredity in Africa, which is further, enhancedwith informatics tools development and short-term training in bioinformatics. However, thelong-term sustainability of the initiatives remain a doubt if effort is not directed to AfricanUniversities to develop innovative, future-looking- oriented data science academic education toperpetuity maintain the scientific research leadership in data science. We therefore proposed hereto develop a West African Sustainable Leadership and Innovation Training in BioinformaticsResearch (WASLITBRe) to support the H3Africa consortium. The proposed WASLITBRe is acollaborative program between Covenant University (CU), Nigeria, University of Bamako (UB),Mali and the University of Ghana/KNUST. The program will have two tracks – a training leadingto award of MSc./ PhD, junior faculty (post doctorate) fellowships, and networking andmentorship training in advanced bioinformatics and data science research. Trainees for theMSc/PhD will be selected from pool of graduates with diverse background (clinician,information Science, computer science, mathematics, data Science, statistics/biostatistics,biology, physics and engineering), junior faculty fellowship will be selected from a pool ofhighly motivated graduates with less than 5 years of research experience post PhD training. Theunifying theme of both tracks is that trainee must express and demonstrate interest inbioinformatics and data science research. Our long-term goal is to produce a sustainable networkof individuals who are well trained in various aspects of advanced bioinformatics and datascience research, ready to assume leadership roles at academic, health care and researchinstitutions in West Africa.



Enhancing HIV Research Training Capacity in University of Rwanda’s Research Office by ALBERT EINSTEIN COLLEGE OF MEDICINE (The Research University TRU)



ABSTRACTRwanda’s strategic vision includes improving the people’s health by becoming a regional center of excellencein performing high-quality biomedical research to inform evidence-based policy and program decision-making.In pursuit of this mission, the University of Rwanda (UR) has partnered with Albert Einstein College of Medicineto develop high quality research infrastructure and develop capacity in individual investigators both to becomescientifically productive researchers and to be able to independently apply for, obtain and manage externalgrant funding. The two institutions have collaborated successfully in obtaining large multi-year researchfunding, including the International Epidemiologic Database to Evaluate AIDS and the HIV/HPV MalignancyResearch Consortium to develop research and scientific capacity in Rwanda. Critical to the development ofindividual investigators’ ability to obtain independent grant funding is the support of an institution’s dedicatedresearch office in all components of grant-funded research. The 2014 assessment of research capacity needsat the College of Medicine and Health Sciences (CMHS) highlighted several gaps, including the need toimprove institutional and faculty capacity in several areas related to effective implementation of researchactivities, compliance requirements and management of research funding. To address these gaps, UR-CMHSand Einstein will, through this grant, develop a sustainable research administrative capacity through adedicated research office to facilitate research activities at all phases of the grant cycle including pre-awardand post award processes, ensuring research integrity, financial oversight, regulatory compliance,management and accounting for revenue, through three specific aims: 1.) develop leadership in researchadministration, 2.) enhance UR-CMHS capacity in administrative research support infrastructure, and 3.)develop UR-CMHS to serve as a grant resource center hub in Rwanda. The aims of this application will lead toan effective centralized administrative structure to facilitate the implementation of Einstein and URs fundedjoint research activities as well as the capacity of a robust and dedicated Grants and Research Support andTraining Center (GRSTC) at UR-CMHS.



Project 1: Mechanisms of Disease Progression by SEATTLE CHILDREN’S HOSPITAL (The Research University TRU)



Abstract ? Project 1Human Mtb infection results in a large variety of clinical outcomes, ranging from bacterial eradication, to controland latent infection, to progression and active disease with a range of clinical phenotypes. We recentlydiscovered a blood transcriptional signature that predicts TB risk in Mtb-exposed individuals up to 18 monthsbefore they exhibit clinical symptoms, a landmark contribution to the field. Still, the mechanisms that underlieTB disease progression remain poorly understood, in large part because the key immune responses within thehuman lung cannot be readily monitored. Furthermore, TB is a highly heterogeneous disease in whichindividuals progress to active disease due to a variety of mechanisms. In this project, we will conduct acomprehensive, multi-scale integration of transcriptomic, cytokine, chemokine and eicosanoid profiles fromlung and blood during Mtb infection in order to identify and model molecular mechanisms and pathways thatdetermine the outcome of infection. First, we will use multiple experimental strategies to recapitulate theheterogeneity of human Mtb infection in the mouse. These include a novel ?ultra low dose? (ULD) infectionmodel that we have pioneered in which mice are infected with 1-3 bacteria and subsequently exhibit a broadrange of outcomes, ranging from immune control to progression. We will also employ mice from theCollaborative Cross project that have demonstrated extreme TB phenotypes and Mtb strains that span a rangeof pathogenicity. Second, we will interrogate and model the host-Mtb interaction in these mouse models usinga variety of systems biology approaches in order to uncover the molecular regulators, pathways, and networksin pulmonary innate and adaptive immune cells. We will test the predicted role of critical regulatory moleculesby genetically perturbing them in vivo and examining the impact on control of Mtb infection. We will also applymachine-learning approaches to define multi-omic blood based signatures in mice that predict TB progression.In our preliminary work, we have defined an early blood-based signature that predicts the late-time bacterialburdens in ULD-infected mice. We will correlate this signature with systems-level measurements of immunefunction in the lung to uncover mechanisms of Mtb control. Third, we will translate these findings to humandisease. Through the Africa Health Research Institute, we will leverage a large-scale program that will obtaingenomic sequence data as well as associated epidemiological and clinical metadata on 50,000 individualsliving in a TB-endemic region. We will conduct a candidate gene genetic association analysis to validateregulatory molecules identified in mice to determine whether mutations in human orthologs are associated withaltered risk of TB. In addition, we will use several existing non-human primate and human datasets to refinethe blood based multi-omic progression signatures defined in mice and test their ability to predict TBprogression in humans.



H3Africa Kidney Disease Research Network- Collaborative Centers by COLLEGE OF HEALTH SCIENCES, UNIVERSITY OF GHANA (The Research University TRU)



Chronic kidney disease (CKD) including end stage renal disease (CKD stage 5) is a major health problem insub-Saharan Africa (SSA) affecting more than 50 million individuals but there is lamentable lack of research dataand there is no promise of urgently needed preventative strategies. The lack of data on CKD in SSA are in partdue to the absence of population-based epidemiologic studies of CKD and a scarcity of physician scientistsconducting genetic, clinical and translational research on CKD according to local priorities. Herein, we proposeto leverage the H3Africa Kidney Disease Research Network (H3A-KDRN) to (i) conduct genomics, clinical andtranslational research on the most prevalent forms of CKD; (ii) expand and support a well-trained cadre of Africanresearchers and physician scientists to conduct CKD research according to regional priorities; (iii) engage SSAcommunities and research participants in the initiation, governance, implementation and dissemination of CKDresearch and (iv) foster collaboration with U.S.-based basic, clinical and translational researchers (includingAfricans in the diaspora) to elucidate etiologies and mechanisms and discover effective therapeutic andpreventative strategies to combat the extraordinary burden of CKD in people of African ancestry globally TheH3A-KDRN is organized as a research consortium initially composed of: (a) 15 academic medicalcenters/university teaching hospitals in five African countries- Cameroon – 1, Ghana ? 4, Nigeria ? 8, South Africa- 1 and Tanzania ? 1; (b) 9 North American/Israeli research intensive academic medical institutions; (c) 3 sharedcores ? Training and Career Development, Data Management and Biostatistics and Genotyping Laboratories.At the end of the five-year funding requested in this application, The H3AKDRN will have accomplished thefollowing:1. Completion of three research projects on: (i) CKD in HIV-infected patients; and (ii) childhood and adolescent onset nephrotic syndrome and (iii) sickle cell disease nephropathy. These three prospective cohort studies will have a total sample size of 5800 participants.2. Completion of training of four African-based research scientists toward PhD (n=2) and MSc (n=1) in Clinical and Translational Science (CTS) awarded by the University of Arizona3. Completion of certificate training in clinical research methods for 45 African-based research personnel4. Establish a high functioning regional Clinical and Translational Research Coordinating Center to support multicenter research in CKD and other non-communicable chronic diseases in SSA.With these foundational objectives, the H3Africa Kidney Disease Research Network will a transformative impacton CKD research in SSA and thence move us closer to the goal of reducing the burden of CKD in the 352 millionAfricans living in the five H3A-KDRN countries and in the 1.2 billion people of African descent globally.






ABSTRACTParasitic protist Trypanosoma brucei causes African human and animal trypanosomiasis, a spectrum of diseasesaffecting the population and economy in sub-Saharan Africa. These digenetic hemoflagellates belong toKinetoplastea, a taxonomic class distinguished by possession of a kinetoplast. This nucleoprotein body containsmitochondrial DNA (kDNA) of two kinds: ~25 maxicircles (each ~23 kb) encoding rRNAs, ribosomal proteins andsubunits of respiratory complexes, and approximately 5000 of ~1 kb minicircles bearing guide RNA genes.Relaxed maxicircles and minicircles are interlinked and packed into a dense disc-shaped network by associationwith histone-like proteins. Decades of kDNA studies have unraveled fascinating phenomena of general biologicalsignificance, such as DNA bending and mRNA editing, and revealed exquisite details of replication and RNAprocessing. However, the molecular mechanisms of transcription remain virtually unexplored and arguablyconstitute the most critical gap in understanding mitochondrial gene expression. The historically enduring viewof polycistronic RNA synthesis has abridged efforts to investigate transcription’s contribution to regulatinggenome activity. In contrast, this proposal presents evidence that maxicircle and minicircle genes are individuallytranscribed into 3? extended precursors. The transcription start site defines pre-mRNA 5? terminus, which issubsequently converted into monophosphorylated state by a pyrophosphohydrolase complex, termed thePPsome. Most guide RNAs lack PPsome recognition sites and remain triphosphorylated. Furthermore, weestablish that antisense transcripts delimit the 3? boundaries of mature RNAs by blocking 3?-5? degradation ofprecursors by the 3? processome (MPsome). It follows that transcription start sites on sense and antisensestrands define 5? and 3? mRNA termini, respectively. These findings support a concept of mitochondrial gene-specific transcriptional control with broad implications in parasite development and pathogenesis. We posit thatelucidating transcription complex composition, DNA template requirements and functions of specific factors willbuild a foundation for this nascent research area. We propose to: 1) Characterize RNA polymerase complexfrom bloodstream and insect parasite forms, and assess transcription factors’ contributions to RNA synthesis; 2)Map maxicircle and minicircle promoters; and 3) Reconstitute the active transcription complex.


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