Liver Disease and HIV-HBV Coinfection in the HAART era

Chronic hepatitis B (CH-B) is common in HIV-infected persons, and HIV accelerates the rate of hepatitis B-related liver disease progression. In the Multicenter AIDS Cohort Study (MACS), the risk of liver-related death was nearly 18 times higher in those coinfected with HIV-HBV compared to those with CH-B alone. Furthermore, the rate was two times higher after compared to before 1996, the time of the introduction of highly active antiretroviral therapy (HAART). These data support the need to study the effects of HAART on liver disease progression in HIV-HBV coinfected persons. This proposal investigates CH-B in HIV-infected persons receiving HAART in a cohort of HIV-HBV coinfected patients from the MACS and two well-characterized Australian cohorts, one in Melbourne and one in Sydney. The first aim will test the hypothesis that long-term HAART active against HBV will alter the rate of HAART-related hepatotoxicity in HIV-HBV coinfected persons. We will determine the rates of hepatotoxicity over a five-year period following HAART initiation. In the second aim the magnitude and durability of HBV DNA suppression with a HBV active HAART regimen will be determined by prospectively following HBV DNA levels. The third aim is designed to study the evolution of resistance mutations that occur in persons who do not have a durable suppression of their HBV DNA with HBV-active HAART. The entire HBV genome will be sequenced at the time of relapse and then followed subsequently for the development of compensatory mutations. These mutant viruses will be tested for anti-viral drug sensitivity and replication competence. These aims are integrated in the fourth aim, which tests the hypothesis that an effective HBV active HAART regimen will slow the rate of liver disease progression. In this aim, paired liver biopsies will be examined to determine the rates of liver disease progression and analyzed with respect to the ability to maintain a durable HBV DNA response, to the development of drug-resistant mutants, and to intrahepatic levels of HBV DNA and ccc DNA. Given the experience of the investigative team and the well-characterized cohorts involved, the results from this proposal will yield insights into the management of HIV-HBV co-infected patients.

Researchers
Chloe Thio

Minority Global Health Disparities Research Training Program

The Overarching goal of the "Minority Global Health Disparities Research Training Program" is to provide international health disparity research opportunities for undergraduate and graduate/medical students who are from health disparities populations. The program is also directed at increasing the students'' ability to function effectively in a global environment as well as gain insights into different cultures and ethical aspects of research. Inherent in this objective is for the trainees to realize the universality of requirements for critical thinking and quantitative thought in the global human health research arena, as well as the cultural and ethical aspects of conducting research abroad. The ultimate goal of this program is to meet the nation''''s need for increasing the number of highly motivated minority researchers who pursue biomedical, biobehavioral, and clinical research careers. In essence, our plan has four components: 1) planning, assessment and student selection; 2) student preparation for foreign research experience; 3) research experience in a foreign country; and 4) evaluation. Even though the research at foreign sites will be at different institutions, the research and other components are united by their focus on health disparities of underserved populations. A consortium of U.S., (Johns Hopkins University, Winston-Salem State University, North Carolina A&T State University, and The Leadership Alliance at Brown University) and foreign faculty (Goteborgs University, Gothenburg Sweden; University of New Castle, Australia; University of KwaZulu Natal, Durban, South Africa; Medical Research Council, Cape Town, South Africa; and Kung Hee University, Seoul, South Korea) will further develop, implement and evaluate the program. The program will accommodate 27 undergraduate and 5 graduate/medical students over a four year period. Our capabilities to contribute to the pool of highly motivated and competitive baccalaureates from health disparities populations who enter graduate/doctoral degree programs in the biomedical, biobehavioral and clinical sciences will be greatly enhanced. Such participation will have both short-term and long-term positive effects. The program plans include evaluation and strategic recruitment with special emphasis on underrepresented minorities, as well as training in the ethical conduct of research, scientific integrity and cultural competence.

Researchers
Fannie Gaston-Johansson

International Epidemiologic Databases to Evaluate AIDS (IEDEA)

Initiative to establish international regional centers for the collection and harmonization of data and the establishment of an international research consortium to address unique and evolving research questions in HIV/AIDS currently unanswerable by single cohorts. More than 200,000 HIV-infected persons from 38 different countries are included. Questions regarding utilization and effectiveness of ARV therapy, toxicities, opportunistic disease and other co-morbidities (e.g., TB, hepatitis) and other topics will be addressed. For more information visit, http://www.iedea-hiv.org/about/

Researchers
Richard Moore

Small Molecule Protein-Glycan Inhibitors as Malaria Transmission-Blocking Therapeutics

Malaria transmission entails development of the Plasmodium parasite in the mosquito. We have identified a critical interaction between an unknown ookinete lectin-like protein and a chondroitin sulfate glycosaminoglycan ligand on the mosquito midgut lumenal surface. We hypothesize that by disrupting this interaction through the use of small molecule inhibitors we can prevent parasite establishment in the mosquito and, subsequently, completely abrogate malaria transmission. This is a translational research grant proposal with the goal of taking our basic research understanding of Plasmodium-mosquito host interactions toward the development of novel highly potent malaria transmission-blocking therapeutics. Our first aim, the Complete molecular characterization of Plasmodium ookinete protein-midgut glycosaminoglycan interactions involves (1) identifying novel lectin-like ookinete molecules by glycan-affinity chromatography and mass spectrometry, (2) characterizing their functional role in vivo through the production of gene knockout parasites, (3) assessing their binding affinity for mosquito chondroitin glycosaminoglycans by protein array-surface plasmon resonance, and (3) gaining insight into the structure-function of the molecule(s) in complex with chondroitin glycosaminoglycan fragments and structural analogues by molecular modeling and x-ray crystallography. The second aim of the project, the Development of lead Plasmodium transmission-blocking glycan-mimetic compounds and assessment of their transmission-blocking potential involves identification of novel derivatives and analogues of our lead transmission-blocking compound, VS1 (a non-peptidyl polyvinylsulfonated polymer), which is a structural mimic of midgut chondroitin glycosaminoglycans and inhibits >95% of parasite development in the mosquito. To develop more potent structural analogs, we propose a four-tiered approach: (1) isolation of varying chain-lengths of the VS1 polymer, (2) derivitization of VS1 to enhance inhibitory activity and bioavailability, (3) derivitization of (+)-usnic acid, a polyphenolic compound from lichens, and (4) assessment of the utility of peptide mimotopes of mosquito chondroitin sulfate glycosaminoglycans as transmission-blocking vaccine targets. To help progress toward preclinical studies, the top candidate compounds from each approach will be analyzed for their pharmacokinetic and pharmacodynamic properties in animal and human serum models.

Researchers
Rhoel Dinglasan

Cochrane Eyes and Vision Group

The Cochrane Eyes and Vision Group aims to prepare, maintain and promote access to systematic reviews of interventions used to prevent or treat eye diseases and/or visual impairment. The work of the CEVG is carried out by over 300 members in more than 30 countries. The CEVG editorial team is located in London, UK and the CEVG US Project (CEVG@US) is a US-based satellite at the Johns Hopkins Bloomberg School of Public Health. The CEVG@US is funded by the National Eye Institute. The overall objective of CEVG@US is to develop a critical mass of US-based vision researchers and practitioners who are trained in preparing and using systematic reviews. The CEVG@US aims to accomplish four main goals: 1) Expand awareness of evidence-based health care in general and in eyes and vision specifically, 2) Develop a critical mass of vision researchers who are able to perform and interpret systematic reviews, and train others to do the same; 3) Develop a critical mass of clinicians who use the results of systematic reviews as an evidence base to guide their practice, and to train others to do the same; 4) Generate an increased number of systematic reviews in priority vision research areas, published in The Cochrane Library and in the traditional vision research literature.

Researchers
Kay Dickersin
Ann-Margret Ervin
Barbara Hawkins
Roberta W. Scherer