|Chicago D-CFAR: Pilot Project Awardees|
Project Title: Social Network and Geographic Risk Factors for HIV and Hepatitis C among young drug injectors
Project Abstract: In recent years, injection drug use among young adults is a phenomenon increasingly located in non-Hispanic (NH) white suburban and exurban communities rather than in poor, inner city neighborhoods, and NH-whites constitute the predominant racial/ethnic groups initiating drug use in the U.S. today. Despite high levels of injection and sexual risk practices, the new generation of persons who inject drugs (NG-PWID) generally exhibits low to modest levels of HIV and HCV infection. This disjunction between behavior and infection appears to be the product of social network and social geographic characteristics that affect the likelihood of having an infected partner. These protective features are not immutable, however, and our own work with NG-PWID suggests that increasingly their social networks and geographies are evolving toward greater risk. Understanding factors that lead to high-risk partner contact is key to preventing HIV/HCV transmission in this population and likely to include 1) characteristics of the individual (e.g., age, race/ethnicity, drug use status), 2) his/her personal drug-using and sexual networks (e.g. size, connectedness), and 3) elements of the geographic environment (e.g., spaces that promote interaction between the individual and potential partners). Objective: The proposed study will be simultaneously evaluate the relationship between individual level-behavior, social network, and geographic risk factors for HIV and HCV risk among predominantly suburban (estimated >75% of study population) young NG-PWID from Chicago and surrounding areas. Methods: 180 PWID ages 18-30 will be enrolled in a cross-sectional study in Chicago, IL. Recruitment will occur at three community field sites of the Community Outreach Intervention Projects at the University of Illinois at Chicago’s School of Public Health, a center-like group that for 25 years has conducted HIV/HCV research related to substance use. We will collect and integrate quantitative surveys and qualitative interviews. Four types of quantitative data will be collected for the entire sample (n=180): 1) individual demographic, and drug and sexual practices of participants, 2) size and characteristics of participants’ personal drug-use, sexual, and social support networks), 3) HIV and HCV infection status through testing, and 4) geographic data on the locations and characteristics of places where participants and their network members reside, purchase drugs, inject drugs, gain knowledge about and acquire support for injecting drugs, have sex, and meet new risk partners. For a sub-group (n=30), we will also qualitatively explore the role of geographic space on facilitative/retarding HIV/HCV high-risk injection and sexual behaviors and network characteristics using a qualitative interviews and focus groups. Public Health Significance: Study findings are expected to inform the forecasting of trends in HIV and HCV among NG-PWID, improve our understanding of regional variations in infection, and suggest individual-level and structural strategies for HIV/HCV prevention interventions.
Project Title: The role of miRNA in the mechanism of HIV-1-induced impairment of intestinal barrier integrity
Project Abstract: Coming Soon
Sheila Badri is an attending physician in the Division of Infectious Diseases at John Stroger Hospital, and Assistant Professor of Medicine at Rush University. She received her infectious disease fellowship and internal medicine residency training at Rush University Medical Center. She has experience in epidemiology research as the CORE Center site PI for the NIAID-funded Multicenter AIDS Cohort Study (MACS). She also provides primary care to HIV-infected Hispanic/Latino patients in the bilingual clinic at the Ruth M. Rothstein CORE Center for the past 11 years.
Project Title: Racial and Ethnic Disparities in Late Presentation to HIV Care Project
Project Abstract: In 2006, the Centers for Disease Control and Prevention (CDC) estimated that 1 in 5 Americans infected with HIV were unaware of their HIV status, and that half of new HIV infections occurring yearly were transmitted by individuals unaware that they were infected. Many of these individuals present late to care, despite revised CDC guidelines in 2006 advocating routine, universal screening for HIV. Work by us and others have shown high rates of late presentation (defined as AIDS diagnosis at presentation) among racial/ethnic minority groups, with the highest rates among Hispanics/Latinos. There is limited data regarding the social and behavioral factors driving late presentation to care in all racial/ethnic groups, and a paucity of literature on late presentation, barriers to testing, and engagement in care among Hispanics/Latinos. As the Hispanic/Latino population is expected to triple between 2000-2050, it is essential to understand the reasons for late presentation in this group to improve HIV prevention efforts. We propose studying patients presenting for initial care at the CORE Center, a large, urban, safety net HIV clinic, to fully characterize predictors of late presentation to care across racial and ethnic groups. Building upon our previous descriptive data of late presentation, we will explore the demographic, behavioral, and cultural predictors of late presentation using epidemiologic, qualitative, and quantitative survey techniques. In keeping with the goals of the National HIV/AIDS strategy, we believe this approach will provide an opportunity to formulate interventions that can target and tailor testing programs to insure earlier engagement in care.
Vadim Gaponenko is an Assistant Professor in the Department of Biochemistry and Molecular Genetics at the University of Illinois at Chicago. Dr. Gaponenko's research is aimed at understanding how peptide molecules assemble into nanostructures and how these nanostructures can antagonize membrane receptor function. Using this technology nanoscale devices were developed to inhibit signal transduction initiated by CXCR4 chemokine receptor. CXCR4 is one of the major portals used by HIV viruses for cellular entry. Dr. Gaponenko's investigation of the use of peptide-based nanoparticles to inhibit CXCR4 function in cancer is funded by an R01 grant from the National Cancer Institute. Although CXCR4 can be used by HIV to infect patients, CCR5 chemokine receptor is preferred by the viruses for cell entry. More virulent strains of HIV can even use both CXCR4 and CCR5 portals to initiate infection. This pilot grant will be used develop nanoparticle antagonists of CCR5 that could be employed in conjunction with CXCR4 antagonists as inhibitors of HIV cellular entry through CCR5 and CXCR4 portals.
Project Title: Design of peptide-based nanoscale devices to act as HIV entry inhibitors
Project Abstract: HIV viruses mutate rapidly to change their modes of infectivity and to overcome the effects of drugs that prevent HIV infection. Novel therapeutic strategies are urgently needed to treat HIV infections that evade common modes of treatment. HIV entry inhibitors designed to stop the infection at the virus-host interaction interface hold significant promise as HIV prevention agents and therapeutics for treatment of progressed disease. We propose to interfere with the transmembrane portion of human cellular membrane receptors that facilitate HIV cellular entry. This mode of inhibition would permanently disrupt the structure and function of membrane receptors making them incapable to serve as efficient entry portals for HIV viruses. The use of peptide molecules inserting into the cellular membrane and disrupting cognate receptors can be a viable alternative to drugs interacting with viral surface proteins or with the extracellular portions of host receptors. The most common human receptor utilized by HIV viruses is the chemokine receptor CCR5. CCR5 inactivation in humans by an inherited mutation is not associated with any severe medical condition suggesting that CCR5 inhibition by a membrane fusogenic peptide may be safe. Peptide therapeutic agents are susceptible to degradation in the blood stream and require additional design of cellular delivery mechanisms. Peptide nanoparticles can solve problems with peptide HIV entry inhibitors. In aqueous solutions peptides may exhibit a conformation allowing assembly into spherical nanoparticles that protect peptides from protelysis and recongnize their target proteins. Nanoparticles disassemble in the lipid environment, insert into the plasma membrane, change their conformation, and inhibit target proteins. CXCR4 is an alternative to CCR5 for HIV cellular entry. We designed a transmembrane helix peptide analog x4-2-6 can target CXCR4 receptors for inhibition of HIV entry. Based on what we know about the mode of action of x4-2-6, we designed a peptide analog of the fifth helix in CCR5 (CCR5-5) that can be used in together with x4-2-6 to inhibit dual tropic viruses. We hypothesize that the selected transmembrane peptide analog of helix 5 in CCR5 will display properties similar to x4-2-6. It will assemble into nanoparticles in the aqueous solution, insert into the plasma membrane, acquire a helical conformation in the lipid environment, and inhibit CCR5 mediated HIV entry. In addition to the fifth helix of CCR5, other CCR5 transmembrane analogs will be studied as well. The proposed research is likely to significantly impact the general approach to the development of HIV therapeutics.
Kyle Popovich is currently an Assistant Professor in the Section of Infectious Disease at Rush University. She has experience in epidemiology research in the area of community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) and infection control research for infection prevention. Her research to date from a project funded by the Rush/County Collaborative Grant and her NIAID K23 award has demonstrated the significant impact the CA-MRSA epidemic has had on HIV patients. This pilot grant would be used to expand into HIV/AIDS research to further investigate the disproportionate impact CA-MRSA has had on HIV patients, in particular those who have formerly been incarcerated.
Project Title: Impact of HIV status and Incarceration on MRSA Infection
Project Abstract: The CA-MRSA epidemic has disproportionately impacted certain patient groups, in particular HIV patients. Individuals with a history of incarceration may also be at increased risk for CA-MRSA. The goal of this project is to further understand the extent to which incarceration exposure and factors within the jail are associated with CA-MRSA among HIV-infected patients.
Dr. Abrams and Dr. Patil are assistant professors in the Anthropology Department at the University of Illinois at Chicago. They have both worked in East Africa on women's health issues since 2000. Dr. Abrams, a biomedical anthropologist, focuses on social and ecological determinants of health, particularly pregnancy and birth outcomes. Dr. Patil, an applied medical anthropologist, employs a biocultural approach to health and specializes in using mixed methods research to promote health equities. Drs. Patil and Abrams have collaborated since 2008 on a project investigating the complexities of the choices around place of birth in rural Tanzania. Because antenatal care (ANC) was shown to play such an important role in shaping pregnancy behavior and birth outcomes, the focus on quality ANC that incorporates locally-important content, particularly HIV education for all women, is a natural extension of this research.
Project Title: Integrating HIV Prevention Into Innovative Group Antenatal Care
Project Abstract: For this project, Drs. Abrams and Patil will adapt a successful and innovative model of group ANC, CenteringPregnancy, to sub-Saharan African healthcare contexts. Current ANC in sub-Saharan Africa reflects the situation of many developing countries: providers are constrained by low resources, overcrowding, understaffing and the burden of intensive one-on-one counseling of HIV positive women at ANC. CenteringPregnancy offers an opportunity to shift the ANC paradigm to be in line with the goals of the World Health Organization’s primary health care initiative by offering comprehensive, continuous and person-centered ANC without increasing staff or budgets. For this pilot project, the team will develop and integrate HIV-related content into CenteringPregnancy ANC manuals. We will then test the feasibility and acceptability of the CenteringPregnancy model in sub-Saharan Africa. The specific aims of this pilot study are to 1) develop the CenteringPregnancy model to integrate preconceptual, antenatal, and postnatal HIV-related health promotion content; and 2) establish the acceptability of the adapted CenteringPregnancy model to healthcare administrators, staff and women attending ANC and establish its feasibility within the current constraints of sub-Saharan African healthcare and ANC contexts. This innovative group ANC approach will allow providers to offer high quality and comprehensive ANC that will retain women in care, improve health outcomes and reduce HIV stigma within current time and budgetary constraints; it is a powerful tool for meeting maternal, infant, and community health goals.
As the Principal Investigator of the application, I have the expertise, leadership and motivation necessary to successfully carry out the proposed work. I have a broad background and training in molecular virology. I have more than 15 years of research experience in studying the entry mechanism and viral replication of several viruses including retroviruses (Rous sarcoma virus and HIV), filoviruses, influenza viruses, and HCV, leading to publications of more than 35 peer reviewed papers in molecular virology. Recently, in collaborations with other groups, we have identified several antiviral (including HIV) inhibitors, some of which have potentials to become therapeutic agents. In addition, I have successfully administered the projects (e.g. staffing, research protections, budget), collaborated with other researchers. As a result of these previous experiences, I am aware of the importance of frequent communication among project members and of constructing a realistic research plan, timeline, and budget. In summary, I have a demonstrated record of successful and productive research projects in an area of high relevance for HIV entry and infection, and my expertise and experience have prepared me to lead the proposed project.
Project Title: Identification of the Host Proteins that Restrict HIV Replication
Project Abstract: Acquired immunodeficiency syndrome (AIDS) was first report in the United States in 1981 and it is estimated that over 25 million people have died from AIDS and that roughly 33 million people are infected with human immunodeficiency virus (HIV), the causative agent of AIDS. There is no effective vaccine or a cure for the virus. Thus mechanistic insights on HIV replication and pathogenesis are important for us to understand the nature of HIV persistent infection and to develop novel therapeutics against HIV/AIDS. This application is based on our exciting preliminary results that HIV replication was enhanced when expression of some human genes was interrupted by siRNAs. Based on these results, we hypothesize that the proteins encoded by these genes can restrict HIV replication in the host cells. Because little is known about the roles of restrictive host genes of HIV replication in the literature, we believe that characterization of these proteins may provide insights on HIV replication, and potentially become novel therapeutic targets in HIV/AIDS disease. Two specific aims are proposed here: (1) Analysis and validation of “hit” genes, and (2) the ability of the “hit” genes to restrict replication- competent HIV strains in vitro.
Dr. Rubin received her PhD from the UIC Department of Psychology, and completed a NIMH-funded predoctoral fellowship under the mentorship of Drs. Pauline M. Maki and C. Sue Carter. She is currently a Building Interdisciplinary Research Careers in Women’s Health (BIRCWH) scholar (K12 awardee). Dr. Rubin has built a research program in the field of psychoneuroendocrinology to understand the impact of sex steroids, neurohormones, and glucocorticoids on cognition and brain function in healthy women and female psychiatric patients. She has recently started to extend this line of work to better understand the impact of stress on cognition and brain structure in HIV-infected women.
Project Title: Effects of Stress on Memory and Hippocampal Volume in HIV-infected women
Project Abstract: This application requests funding to support an early career investigator in a psychoneuroendocrine research project aimed at defining the role of stress and stress hormones as risk factors for memory dysfunction in HIV+ women. The candidate aims to apply and extend her experience examining hormonal effects on cognition in healthy and psychiatric populations to HIV. The applicant will integrate two CFAR emphasis areas (aging and women) for this project and receive mentorship from the two CFAR emphasis area leaders (Maki, Weber). The applicant has approval to use stored specimens and WIHS data to accomplish the proposed study aims quickly and cost effectively. The general aims are: 1) to characterize the relationship between stress and memory performance in HIV+ versus HIV- women and 2) to use structural magnetic resonance imaging (MRI) to better understand the impact of stress on hippocampal volume in HIV+ versus HIV- women. The motivation for examining this relationship is that HIV+ women report high rates of life stressors and childhood trauma and these factors are believed to have deleterious effects on hippocampally dependent memory tasks which are impaired in HIV and which are a strong predictor of cognitive impairment. Aim 1 includes 75 women (50 HIV+) from the Chicago Core Center WIHS site who completed initial cognitive testing (stressor) and provided saliva pre- and post testing. Aim 2 includes 50 women (30 HIV+) from Chicago WIHS site who will undergo brain MRI (stressor) and provide saliva pre- and post-imaging between Dec 2010-May 2011. We propose to analyze the saliva specimens (65% already collected) to assess stress responsivity (cortisol and DHEA) on verbal memory and hippocampal volume. We predict that greater perceived stress and stress responsivity will predict worse memory and smaller hippocampal volumes and these effects will be greater for HIV+ versus HIV- women. Findings will provide insight into the impact of stress on memory and brain structure in women living with HIV and will identify risk factors that may compound memory deficits. Future studies could identify coping strategies and other stress-reduction interventions to help maintain memory function in HIV+ women especially as they age.
Dr. Bin He earned his PhD in molecular microbiology from Purdue University in 1993. He received his postdoctoral training in the laboratory of Dr. Bernard Roizman at the University of Chicago, where he worked on human herpes simplex viruses. Dr. He joined the University of Illinois at Chicago (UIC) as faculty in 1998. He is an Associate Professor of Microbiology and Immunology, College of Medicine at UIC. He studies virus-host interactions in viral pathogenesis, with a focus on innate immunity.
Project Title: Mechanisms of HIV-HSV coninfection
Project Abstract: Human immunodeficiency virus type 1 (HIV-1) infection is one of the leading causes of mortality in the world. It is commonly associated with infection of other pathogens, such as herpes simplex viruses (HSV) which may facilitate HIV-1 replication and transmission, thereby affecting the clinical course of HIV-1 diseases. Emerging evidence suggests that HSV replication or reactivation results in increased HIV-1 infection. Notably, while inducing localized inflammatory foci containing CD4+T cells and dendritic cells in the genital mucosa, HSV profoundly suppresses type I IFN expression. In this respect, it is notable that an HSV virulence factor suppresses type IFN expression by targeting TANK-binding kinase 1, a key component of Toll-like receptor (TLR) pathways. In addition, this viral factor confers viral resistance to type I IFN by inhibiting double-stranded DNA dependent protein kinase PKR. Therefore, a central hypothesis underlying this proposal is that HSV may augment HIV-1 replication or acquisition by modulating type I IFN responses in TLR pathways during confections. The objectives of this exploratory project are: (i) To establish an ex vivo tissue culture model which retains tissue architecture, including major lymphocyte subtypes and follicular-dendritic cell network. This model will be used to optimize and define key elements in HSV-HIV-1 confections. (ii) To explore the mechanism through which HSV facilitates HIV-1 replication or acquisition. As such, multifaceted approaches will be employed to investigate type I IFN production, TANK-binding kinase 1, and double-stranded DNA dependent protein kinase PKR in relation to HIV-1 infection. The proposed studies are designed to provide an insight into the mechanism of HSV-HIV co-infections, which may help in developing novel antiviral therapeutics.
Dr. Zhang has more than 20 years of research experience in the isolation, identification, structure elucidation, analysis, synthesis and biological evaluation of natural products and other small molecules, leading to publication of more than 100 peer reviewed papers and several patents. His research group is focused on drug discovery from natural products. Specifically, he is interested in finding natural lead compounds from plant and microbial organisms against different disease targets including HIV. It is anticipated that novel potent bioactive compounds will be discovered from natural products through direct separation from natural resources and chemical synthesis. We have isolated over 1,000 compounds including more than 200 new ones. Many of these compounds showed biological activities against cancer, tuberculosis, malaria and viruses, and some of them have been evaluated in in vivo studies. We expect that our continued comprehensive study combining natural products and synthetic chemistry in concert with biology will lead to the discovery of novel potent active compounds.
Project Title: Discovery of Potent Anti-HIV Natural Product Inhibitors
Project Abstract: HIV/AIDS has killed more than 25 million people since its first report 30 years ago, and more than 30 million people are still living with HIV/AIDS. Although a number of treatments are available for HIV infected patients, there is no cure for AIDS nor is there an effective vaccine to prevent HIV infection, and the efficacy of the current drugs available on the market is diminishing due to drug resistance and side effects. Thus, development of new therapeutic drugs against HIV is urgently needed. In a search for new anti-HIV active lead compounds from over 3,500 plant extracts, we have identified a potent active plant lead. Bioassay-guided fractionation of the plant extract led to the identification of an anti-HIV active compound. The compound displayed potent activity against four HIV strains (Bal: M-tropic, 89.6:Dual-tropic, SF162:M-tropic and Lav.04:T-tropic) with IC50 values in the range of 14-37 nM (AZT: IC50 77-95 nM) with no apparent toxicity against several cell lines at high concentrations. Thus, we have discovered a potent anti-HIV natural lead compound, and more in depth chemical and biological studies are then needed to determine its therapeutic potentials. The current project is designed to establish a de novo synthetic method for the resupply of the compound for furture studies as well as to isolate yet to be discovered new natural active compounds with more potent anti-HIV activity by chemical-directed fractionation of this plant. The promising anti-HIV inhibitors synthesized/isolated in this study will be validated by a battery of assays using a broad spectrum of HIV-1 strains in tissue culture.
Project Title: Intra-axonal Regulation of Fast Axonal Transport by The HIV Glycoprotein gp120
Principle Investigator: Scott Brady, University of Illinois at Chicago
Project Title: Microbial Diversity of Genital Ulcers: Potential Causes and Mediators
Principle Investigator: Supriya Mehta, University of Illinois at Chicago
Project Title: Feasibility of ACASI Intimate Partner Violence Screening, Referral and Intervention for Women Infected with HIV and at Risk for Infection with HIV
Principle Investigator: Romina Kee, John H. Stroger Hospital of Cook County/Collaborative Research Unit
Project Title: Role for IL-7 and IL-15 in T cell Trafficking to Mucosal Tissues
Principle Investigator: Dr. Amanda Marzo; Dept. of Immunology/Microbiology, Rush University Medical Center
Project Title: Project Chicago Area Transmission Clustering in HIV (CATCH)
Principle Investigator: Dr. Ronald Lubelchek, Ruth M. Rothstein CORE Center, Cook Count Bureau of Health Services
Project Title: Updating intervention and outcome measures for Share the Care, a group intervention for female family AIDS caregivers in Malawi
Principle Investigator: Dr. Linda McCreary, University of Illinois at Chicago, College of Nursing
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