Award Recipients
Research Awards | Newly Hired Investigator Awards
Research Awards: 2010 - 2011
Title:Proteomics of the Host Proteins Associated with HIV-1 Pre-integration Complexes
HIV is capable to infect non-dividing cells and translocate a DNA copy of its RNA genome through the nuclear envelope to the site of integration in the host cell chromatin. This is an essential and vulnerable step of HIV infection which requires participation of a suite of host proteins and other cofactors. Therefore, the nuclear import events represent a promising target for anti-HIV interventions. However, the molecular machinery responsible for intracellular trafficking of the early subviral particles called pre-integration complexes (PICs) has not been fully characterized. Available data indicate that host proteins interacting with the HIV-1 PICs are different in different types of susceptible target cells - T lymphocytes and macrophages. The long-term goal of our studies is to identify the host cell cofactors and pathways which are critical for the successful HIV-1 replication in natural HIV targets. This pilot project represents the first step towards this goal and aims to identify the profiles of host proteins associated with the HIV-1 PICs in the HIV susceptible cells. To attain this objective we will (1) identify the cellular proteins associated with HIV-1 PICs in the T lymphocytes and macrophages using the proteomic approach; and (2) assess expression of PIC-interacting proteins and specificity of their association with HIV-1 PICs in the target cells. A very low abundance of PICs in the cell represents the major challenge for this analysis. We propose to optimize methods of purification of HIV-1 PICs and utilize state of the art molecular techniques for analysis. The high resolution mass spectrometry using the technical base of the new proteomics facility at the Howard University, a proposed part of the DC D-CFAR Basic Science Core, will be utilized for PIC proteomic profiling and subsequent bioinformatic analysis for validation of acquired data. The results of this study will determine the spectra of cell type-specific proteins involved in early stage of HIV-1 infection. Once this study identifies new host proteins associated with PICs, an R21 proposal will be submitted to investigate the mechanism of action of these factors.
Title:The Effects of Antiretroviral Therapy on Energy Metabolism in Children
The drugs used to treat HIV infection (antiretrovirals, or ARV's) are known to be toxic to the mitochondria, the "batteries of the cells." So far, research has focused on the negative effects or ARV's on only one aspect of the mitochondria: oxidative phosphorylation (OXPHOS). An expanded view of the mitochondria suggests that dozens of other metabolic pathways are dependant on OXPHOS and may also be perturbed as a result of ARV's. This disruption of metabolic health is likely to be associated with clinical problems, as is seen in chidren with inborn errors of metabolism (congenital, severe defects in metabolic pathways) and may even be amenable to treatment that is available for children with inborn errors of metabolism. A complete understanding of the adverse effects of ARV's is essential as we enter an era of expanded access to HIV treatment worldwide.
We think that children exposed to ARV's will have a higher rate of dysfunction in the metabolism of fats and protein and that there may be a blood or genetic test that can identify the at-risk patients so they can be helped. The first step is to define the extent of the problem. To do so, we are going to use fresh and frozen samples of blood serum and DNA to perform tests that are usually used in the management of inborn errors of metabolism to define the extent of metabolic dysfunction in ARV-exposed children and analyze the results for a pattern which will tell us which children are at risk and how we might be able to treat them. This is urgent in an era when HIV infection can be controlled with medications, but the long-term health effects of those medications are not completely understood.
Title:Understanding the Negative Impact of Racial Discrimination on HIV Risk Behaviors
Among 20-24 year olds, the rate of HIV/AIDS is 14 times higher for Blacks than it is for other racial groups. Increasing numbers of infections in this population are due to injection drug use, and high-risk sexual contact. These risky sexual behaviors increase with alcohol and drug (substance) use. The negative effects of racial discrimination on HIV-risk behaviors (risky sex and substance use) have been suggested by researchers as a reason for the health disparities, including HIV-risk behaviors, that exist between Blacks and Whites. A study that examines the impact of discrimination over time and through an experiment to see the effects immediately after experiencing discrimination will improve research designed to understand, and eventually help eliminate, the impact of racial discrimination on HIV-risk behaviors among Blacks. The main goals of this project are to examine psychological and social factors that link experiences of racial discrimination to substance use and risky sexual behaviors associated with HIV-risk. Factors that may link the effects of discrimination to HIV-risk behaviors include feelings of hopelessness, feelings of a lack of control over one's environment, and feelings of stress as well as increases in stress-related hormones. We will also test the protective effects of racial and collective socialization for young adults who experience racial discrimination. All of these factors psychological and social factors can be changed, thus are useful to examine for future prevention efforts. Participants will include 260 Black young adults ages 18 to 25 from the Washington D.C. metro area, where rates for HIV and drug use are among the highest in the country and have a more negative impact on the health of Black young adults compared to other populations. This project is consistent with the National Institute of Health's focus on: preventing new cases of HIV, examining both substance use and risky sex as risk factors for HIV, exploring the impact of racial discrimination on the mental and physical health of minority populations, and eventually reducing HIV-related outcomes in Blacks. The proposed study can inform prevention and intervention programs designed to protect young adults from the negative effects of racial discrimination and to reduce HIV-risk behaviors.
Research Awards (Co-Morbidities): 2011 - 2012
Priscilla Dass-Brailsford, Ed.D.
Title: Traumatic Life Experiences among Women with HIV and PTSD Comorbidity
The District of Columbia (DC) has one of the highest HIV prevalence rates (3%) in the U.S. and women accounted for 29% of all new HIV infections in 2009; 91% of them were African American women. Although 58% of HIV+ women in DC are linked to care within 3 months of diagnosis, they are 40% less likely than men to be in care during the 12-month period following diagnosis. Most of them are also at high risk of trauma exposure, which frequently lead to psychiatric conditions such as Post-Traumatic Stress Disorder (PTSD). When HIV and PTSD diagnoses co-occur, both psychological (eg. Risk-taking, substance use, poor eating habits, depression, social isolation) and physical functioning (eg. Diminished functioning of the immune system and increased susceptibility to infections) can be affected. Although trauma histories are a major risk factor in HIV care little is known about the relationship between these co-morbidities. Given the serious (public) health implications of this risk factor often associated with undiagnosed trauma history/PTSD, there is a critical need to better understand the co-morbidity between HIV/AIDS and PTSD among low-income minority women in Washington DC. Our objective in this pilot study is to identify most common forms of trauma exposure among HIV+ women in Washington DC and to explore their differential relationship to HIV-risk behaviors, health behaviors and health care utilization.
David Leitenberg, M.D., Ph.D.
Title: Regulation of the immune response to Toxoplasma gondii by the CD45 phosphatase
Infection with Toxoplasma gondii can cause significant morbidity and mortality in patients with HIV/AIDS-associated immunosuppression. As factors that regulate immune cell function are becoming increasingly well defined, there is considerable potential for the development of novel approaches to augment immune system function in immunodeficient HIV patients. Attractive targets for these therapeutic approaches are molecules that regulate immune cell receptors that detect signals from the environment and translate that information into patterns of gene transcription that regulate the development of both beneficial and harmful immune and inflammatory responses. The CD45 protein tyrosine phosphatase is the predominant transmembrane tyrosine phosphatase in all leukocytes and plays a critical role in both positively and negatively regulating many of these signaling events mediated by immune cell receptors. Over the last 15 years, my laboratory has largely focused on the role and regulation of CD45 in the regulation of antigen receptor signaling in T lymphocytes. Using biochemical, genetic and cell biology-based approaches we have helped to define the role of CD45 in regulating specific aspects of T lymphocyte activation and development and identified important factors that regulate CD45 activity. In order to develop new research areas relevant to HIV/AIDs, we are beginning to evaluate the role of CD45 in chronic infectious disease settings, and have recently developed a collaboration with Dr. Imtiaz Khan in the Dept. of Microbiology, Immunology and Tropical Medicine at George Washington University, who is an internationally recognized expert on the host-immune response to Toxoplasma gondii infection. The main goal of this project is to develop preliminary data that characterize the changes in immune responses during the acute and chronic phases of the immune response to Toxoplasma in mice that express decreased levels of CD45. Then, using adoptive transfer approaches, we will determine how changes in CD45 activity affect specific aspects of innate and adaptive immune cell function, and identify the critical factors affected by CD45 that promote disease protection from Toxoplasma.
Magali Moretto, Ph.D.
Title: Early CD8 T cell response to microsporidia
In recent years, microsporidia species have rapidly emerged as human enteric pathogens in HIV infected individuals. Using E. cuniculi as a model of microsporidial infection, our laboratory has demonstrated the critical rol of T cell for protection against these pathogens. Since E. cuniculi is a zoonotic infection, in depth study of gut mucosal immune response against this pathogen is essential. Reports from our laboratory have demonstrated that per-oral infection with E. cuniculi generates an early and strong intraepithelial lymphocytes (IEL) response and CD8+ population plays a central role in protection against the pathogen. Lately, the use of tetramer technology has allowed in depth study of systemic CD8+ T cell immune response to a number of viral and bacterial infections. As antigen(s) involved in the elicitation of CD8+ T cell immunity have not been identified, reagents needed to determine the magnitude and quantum of this response against the infection cannot be generated. Recent study and preliminary data presented in this proposal strongly suggest that polar tube protein 1 (PTP1) from E. cuniculi contains at least one immunodominant CD8+ specific epitope. Thus, this protein is an obvious candidate for further screening to identify CD8+ T cell epitopes which can ultimately lead to the generation of much needed tetramers. Furthermore, these tools will allow us to focus on CD8+ IEL in response against this important gut pathogen, which according to recent studies poses a major problem for HIV infected subjects.
Joint CFAR-CTSI Awards (Mental Health, Substance Use, Behavioral Science): 2011 - 2012
Title: SmAART: A Novel mHealth Approach to Promote HIV Management with Substance Abusing Adolescents
The issue of non-adherence to antiretroviral (ARV) medication presents a considerable barrier to treatment for adolescents preparing to transition to adult care. This can cause significant public health implications given the increasing rates of adolescents suffering from HIV in the United States. Despite some promising signs, most interventions designed to improve adherence are limited in their ability to transfer newly acquired skills and behaviors from the clinic setting to real life in sustainable ways. Additionally, clinics with limited resources often find implementation of tailored and developmentally appropriate interventions challenging given the additional staff requirements. A more effective means for addressing this problem may include developing and testing an HIV adherence protocol for patients that integrates evidence-based strategies with adolescent friendly technology in an intervention that is clinically efficient and practical. Among many advantages, using mobile technology to implement an ecological momentary intervention has the potential to engage challenging populations, such as substance abusing youth, in care. The proposed investigation is designed to be a feasibility study to develop an innovative HIV adherence intervention known as SmAART (Supportive mHealth Adherence to Antiretroviral Therapy) for substance abusing youth using a multimedia, cellular phone-based platform that is interactive and tailored to meet individual participant needs.
Title: HIV-associated neurocognitive disorders and cognitive control among HIV-infected older adults: a pilot study using fMRI among a high risk, community-based sample in DC
The prevalence of HIV among individuals in the United States 50 years and older has grown substantially with increased antiretroviral availability and improved care. With this changing demographic, a significant public health concern has emerged: older adults have heightened vulnerability to cognitive dysfunction (HIV –associated neurocognitive disorders, HAND) when compared to younger adults. Despite the elevated prevalence of HAND, its neural bases are largely uncharacterized – it is unclear how HIV affects neuronal function, and how changes at the neuronal level give rise to behavioral deficits. Neuroimaging techniques such as magnetic resonance imaging are non-invasive ways to examine pathological changes caused by HIV. Despite their attractiveness as a diagnostic or measurement approach, few studies apply stateof-the-art brain imaging to examine cognitive processing deficits associated with HIV. A root cause of this missed opportunity is the challenge in forming multidisciplinary teams connecting experts with access to community based patient pools to cognitive neuroscientists with expertise in probing the neural bases of complex behaviors. This proposal represents collaboration between epidemiologists in the GWU School of Public Health and Health Services, with expertise in recruitment of at risk populations, with cognitive neuroscientists in the department of Neuroscience at GUMC, experienced in the use of advanced MRI techniques. This team is in a unique position to recruit participants from the DC community and conduct and analyze cutting edge functional MRI (fMRI) experiments. This study not only will characterize the relationship between HAND and behavioral deficits among HIV-infected persons 50 years of age and older and their uninfected counterparts, it will provide proof of concept towards the multidisciplinary collaboration between GWU SPHHS and GUMC investigators within the DC DCFAR.
Jennifer Huang, M.D., Ph.D., M.P.H.
Title: Drug use and their associations with HIV risks among female streetwalkers and their clients in Shanghai, China
Although conventional wisdom ties drug use and sexual risks to younger populations, the incidence of both HIV and drug abuse have reportedly shown the greatest increase among China’s growing middle-aged population (40-60 years old). Several studies have documented indications of high sexual risks among these target populations from different perspectives. For example, a cross-sectional study of 11,461 STI patients in China found that 46% of patients at least 50 years old acknowledged purchasing commercial sex, while less than 4% acknowledged using condoms.9 Older clients are more likely to frequent streetwalkers, who compared to other
types of sex workers are at the bottom of the sex work hierarchy, tend to be older, less educated, lower-paid, less likely to use protection during sexual transactions, and have a higher prevalence of syphilis (ranging from 10-38%) and other STIs. Strategies to prevent HIV/STI
infection and drug use are generally ineffective among this population since they are primarily designed to target younger populations and traditional injection drug users. Thus, appropriate intervention strategies must be developed to target this high-risk population. To do so, it is critical to establish reliable and valid data regarding their determinants of risk and the context in
which these determinants occur. The proposed 12-month pilot study will build upon our current R21 study (funded by NICHD/NIH) characterizing peer social networks and sexual health among female streetwalkers in Shanghai, China. Our multi-institutional and interdisciplinary
team is based upon collaboration among experts from behavioral epidemiology, psychology, anthropology, community participatory research, and clinical medicine, and has been prolific in conducting and publishing HIV behavioral research among both male and female sex workers in Shanghai. These projects particularly benefit from collaboration between academic institutes in China (Fudan University) and the US (Georgetown and George Washington University), and US and Chinese government agencies (US CDC and China CDC). This new application will allow us to broaden our research from a specific focus on sexual health to include patterns and determinants of substance abuse. We will apply the tried-and-tested model of International Rapid Assessment, Response and Evaluation (I-RARE) to describe the sexual and drug-use HIV risk behaviors of streetwalkers and their clients in Shanghai within a short period.
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Newly Hired Investigator Awards: 2010-2011
Title:Probing alterations of neuronal selectivity in middle-age HIV+ individuals
Due to decreases in mortality rates and increased rates of HIV infection among older adults, the prevalence of older adults (>50 years old) living with HIV has increased substantially. This poses a significant public health concern, as older adults with HIV infection are more vulnerable to cognitive dysfunction (HIV-associated neurocognitive disorders, HAND) than their younger counterparts. It has been suggested that this increased vulnerability might be due to HIV-induced premature cognitive aging. Recently, magnetic resonance imaging (MRI) has provided a non-invasive way to examine pathological changes. Diffusion tensor imaging (DTI) has provided evidence for changes in brain white matter in HIV (see Bakshi & Ketonen, 2006 for a review). However, changes in grey matter have proven to be difficult to detect using both anatomical MRI and conventional functional MRI (fMRI), especially at the early stage of HAND. Here we propose, to conduct a pilot study to use fMRI-Rapid adaptation (fMRI-RA) to probe differences in neuronal selectivity between HIV+ middle age (45-55 years) adults and age-matched HIV- controls. Neuronal selectivity in occipital and temporal cortex as well as prefrontal cortex will be estimated while subjects perform a face odd-ball task, in hope to identify the neural causes of accelerated aging by quantitatively linking decline in behavioral performance to decline in neuronal specificity, to provide a general index of broad cognitive decline in HAND that can aid HAND diagnosis, to identify neural targets for therapeutic interventions.
Title:Synthesis of betulinic acid analogs as entry and maturation inhibitors of HIV-1
Betulinic acid (BA) has been shown to be maturation and entry inhibitor of various HIV-1 strains. Because of its novel mode of action and relatively low toxicity, there has been a great interest in the elaboration of the BA core in search of highly active analogs. As a result, various betulinic acid derivatives have been synthesized to date. The derivatization so far has been restricted to C3 and C28 positions. This is primarily due to the utilization of commercially available betulinic acid as a starting material for the synthesis of these analogs. As a result, the unnatural analogs bearing a novel carboskeletal framework have remained inaccessible to date. The aforementioned analogs could only be furnished via total synthesis of the core of betulinic acid. It is hypothesized that the alternations in the BA backbone would furnish analogs with a potent, selective antiretroviral activity.
This proposal describes two major modifications to the BA core. The first set of modifications is based on the working hypothesis that the inclusion of heteroatoms in the BA core will render analogs with potent, subtype specific anti-HIV activity. One of the major problems associated with BA analogs is their poor water solubility. To address this issue, the second set modifications are proposed. These novel analogs are expected to display improved aqueous solubility and thus, improved pharmacokinetic or "drug-like" properties.
From the synthetic perspective, the reaction protocols are designed to provide a facile, convergent synthesis of the desired analogs. They offer significant improvements to the previously established synthetic procedures. Lastly, the modular approach will permit the extension of this methodology for the synthesis of a small focused library of analogous derivatives.
Title:Epigenetic and inflammatory profile of HIV positive African American patients with chronic kidney disease compared to HIV positive African American patients without chronic kidney disease: A pilot study
There is a high rate of HIV infection in the District of Columbia. This is very disturbing since there is still no cure for HIV. However, with the medications we have available for treating HIV, patients are living longer and fuller lives. Unfortunately, because patients are living longer, they are now developing other medical conditions that were not usually seen in HIV patients about 15 years ago. One of these medical conditions is chronic kidney disease. Chronic kidney disease in HIV patients results from many factors including genetic factors (condition passed from parent to child) as well as medications used to treat HIV.
There is a higher rate of HIV/AIDS in African Americans who also have a higher rate of chronic kidney disease. Genetic factors play a part in the higher rate of chronic kidney disease seen in African American patients compared to Caucasian patients. However, genetics alone cannot explain the difference in rates of chronic kidney disease between the races. Environment has an effect on chronic kidney disease development. In fact, the environment can affect the genetic make-up of people making them more likely to develop problems like kidney disease and heart disease. The talk between the genetic make-up and the environment is called epigenetics. This field of epigenetics is a new and exciting area of medicine and there are a number of tests developed or being developed to measure epigenetic changes in people due to different factors in the environment. This study is created to discover epigenetic patterns seen in HIV positive African American patients without chronic kidney disease. We ultimately want to study differences in epigenetic pattern based on race.
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