HIV Prevention and Treatment Research Program The goals of the HIV Prevention and Treatment Research Program (HPTRP) (Magdalena Sobieszczyk, principal investigator, and Michael Yin, co-investigator) are to set the standards of care for people living with HIV and to help speed the development of an effective vaccine to prevent HIV infection. The program works toward these goals by engaging the community and conducting clinical studies within the Division of Infectious Diseases at the Columbia University Medical Center. The HPTRP participates actively in studies sponsored by three NIH-funded networks: the Adult AIDS Clinical Trials Group (AACTG), and the HIV Vaccine Trials Network (HVTN). The HPTRP also supports pharmaceutical studies. There are opportunities for fellows and residents to participate in all aspects of HIV/AIDS clinical trials.
The AACTG is the largest NIH-sponsored HIV clinical trials organization and plays a major role in defining the standards of care for treatment of HIV infection and opportunistic diseases related to HIV/AIDS around the world. We provide a wide range of treatment studies four areas of focus (1) end organ disease and inflammation, (2) HIV reservoirs and viral eradication (3) hepatitis, (4) tuberculosis.
The HVTN is an NIH-sponsored international network that was designed to facilitate the process of testing preventive vaccines against HIV/AIDS. The New York City HIV Vaccine Trials Unit is a collaboration between the Columbia HPTRP and Project ACHIEVE (AIDS Community Health Initiative En route to a Vaccine Effort) which is part of the New York Blood Center (Beryl Koblin, PhD, principal investigator). The New York City HIV Vaccine Trials Unit supports a large number of HVTN-sponsored preventive vaccine trials, studies investigating combination prevention approaches, as well as a behavioral interventions among high risk individuals. Past and current fellows have conducted HIV prevention research projects with investigators in the Vaccine research unit.
HIV Center for Clinical and Behavioral Studies
Founded in 1987 and continuously supported by a major grant from the National Institute of Mental Health, the HIV Center for Clinical and Behavioral Studies serves as a national and international hub for a network of research activities and community outreach. Research focuses on the intersection of HIV infection, gender, and sexuality; treatment strategies for infected populations; and innovative dissemination of scientific findings. More than one hundred researchers, clinicians, and support staff sustain the work of the center. Affiliated research is conducted through more than two dozen individual studies headed by leading investigators from various disciplines, including psychology, psychiatry, public health, anthropology, sociology, and social work. The center also works with a broad range of HIV-infected and HIV-affected populations and are committed to responding to the needs of underserved populations.
The Division of Infectious Diseases maintains active collaborations with faculty members from the Mailman School of Public Health in the Departments of Epidemiology and Sociomedical Sciences.
HOSPITAL EPIDEMIOLOGY AND INFECTION PREVENTION RESEARCH
Center for Interdisciplinary Research to Prevent Infections (CIRI)
CIRI aims to prepare biomedical researchers and others in interdisciplinary research with a focus on the prevention and control of antimicrobial resistance. Under the leadership of Elaine Larson, PhD, RN and Lisa Saiman, MD, the center has implemented a core program and curriculum to prepare biomedical researchers to conduct interdisciplinary research. The center also funds several demonstration projects designed to rationalize antimicrobial use and reduce antimicrobial resistance. CIRI offers a tremendous resource for pre- and postdoctoral fellows who are interested in true interdisciplinary research. The framework for CIRAR integrates health and risk communication, economics, informatics, epidemiology, and health services with the basic research and disciplinary expertise of its team members.
Hospital Epidemiology and Antimicrobial Utilization, Resistance, and Stewardship
The Division of Infectious Diseases is actively involved in hospital epidemiology and antimicrobial stewardship at NewYork-Presbyterian Hospital. These programs are linked to numerous ongoing clinical research projects focusing on healthcare-associated infections and antimicrobial resistance, as well as outcomes research evaluating the impact of interventions in infection prevention and antimicrobial stewardship. Ongoing research projects include evaluations of specific antimicrobials such as polymyxin B and daptomycin, evaluations of multidrug-resistant gram-negative bacilli including those producing Klebsiella pneumoniae carbapenemase (KPC), and severity criteria and outcomes of patients with Clostridium difficile infections. Past and current fellows have engaged in many of these clinical research projects with mentoring from Drs. Yoko Furuya, Christine Kubin, and Lisa Saiman.
TRANSPLANT INFECTIOUS DISEASES RESEARCH
Transplant Infectious Diseases Program
The active transplant infectious diseases service presents many opportunities for collaborative and multidisciplinary research projects. Past and ongoing clinical research projects aim to, for example, develop new tools for diagnosis and treatment of multi-drug resistant infections in immunocompromised adults in the pre and post-transplantation period.
Past and current fellows have engaged in mentored research in the area of transplantation infectious diseases: Jennifer Horan, Stephanie Pouch and Claire Gordon.
The Columbia Center for Translational Immunology (CCTI) at Columbia University Medical Center is a multi-departmental, multidisciplinary research center aimed at optimizing translation of advances in basic immunology from the laboratory to the clinic, understanding immunological diseases and events in humans and optimizing transfer of information and methodologies to achieve synergy between different disciplines of applied immunology. The CCTI currently consists of three laboratories and three cores, including a Sample Repository, a Human Studies Core and a Flow Cytometry Core. CCTI investigators have expertise at all levels of immunology and transplantation, from molecular biology to large animal and clinical transplantation studies. Extensive collaborations are carried out among these laboratories and between clinicians and basic scientists, including close interactions with the transplant physicians and surgeons in the Columbia Transplant Initiative.
The mission of the CCTI is to accelerate translation of basic advances in immunology into new clinical therapies for immune diseases by creating a center that: 1) Fosters “horizontal” integration of information and advances between immunological disciplines and "vertical" integration between scientists and clinicians; 2) Trains a new generation of scientists and clinicians with the skills to lead the translation of future advances in immunology into clinical therapies.
University of KwaZulu-Natal, IACTU, and CAPRISA in South Africa
The division maintains a strong collaborative relationship with the Mandela School of Medicine, University of KwaZulu-Natal in Durban, South Africa. The projects currently in place include the establishment of an International AIDS Clinical Trials Unit (IACTU) (Professor Umesh Lalloo, principal investigator) and the Centre for the AIDS Program of Research in South Africa, CAPRISA (Professor Salim Abdool Karim, principal investigator). CAPRISA's goal is to develop and undertake research that contributes to the understanding of HIV pathogenesis and epidemiology, as well as to build local research infrastructure and to provide training through research fellowships for young investigators from South Africa and the United States. One of the projects initiated by the CAPRISA research team is an NIH-funded acute infection study evaluating the clinical, immunological, and viral factors during acute and early HIV-1 subtype C infection. A large cohort of HIV-1 negative high risk women has been enrolled into this observational study.
The International Center for AIDS Care and Treatment Programs (ICAP)
Bringing together diverse initiatives aimed at addressing the HIV/AIDS epidemic, the International Center for AIDS Care and Treatment Programs (ICAP) focuses on service delivery, research, and training/education in resource-limited settings. Faculty and staff provide support in program development, clinical issues, administration, training, monitoring and evaluation, and research endeavors. The program draws upon the broader resources of the Mailman School of Public Health, as well as those of Columbia University, to fulfill its mission. As a center within the school, and as part of the Columbia health sciences campus, ICAP is committed to participating in the life of the academic medical institution and to providing training opportunities for students, house staff, and fellows. ICAP offers postdoctoral trainees access to large databases in order to develop, conduct, and analyze cohort studies while addressing infectious disease epidemiology issues of global importance.
ICAP provides support and assistance to international partners and clinical facilities through these programs and initiatives:
The Columbia University International Family AIDS Program (IFAP), La Romana, Dominican Republic
IFAP is a non-profit organization that supports clinical services, and research, education and training. Program activities focus on improving direct care and treatment as well as preventive health education and services for TB and HIV-infected women, children and families and other vulnerable populations in the Dominican Republic.
Fogarty and Profamilia in the Dominican Republic
Dr Karen Brudney, the director of the Infectious Diseases Clinic, which has treated hundreds of Dominican patients over the past 15 years, received a Fogarty Research Training Award, which is currently being implemented in Santo Domingo. A pilot treatment project has been established at Profamilia, a nongovernmental organization with seven clinics throughout the country which has provided women's health care for more than thirty years. Dr Brudney and Catherine Vaughan, who was the head nurse and coordinator in the clinic at Columbia for 14 years and now resides in Santo Domingo, have trained a team of health care workers at Profamilia including physicians, nurses, and educators to counsel, educate, and treat patients with HIV in Santo Domingo.
As part of the Fogarty award, a large study will be performed to establish the prevalence of sexually transmitted diseases, including chlamydia, gonorrhea, and genital herpes in two different populations in the Dominican Republic. The principal goal of this project is to develop a sustainable clinical research infrastructure using an existing network of women's health clinics run by Profamilia, and an existing network of dermatology clinics run by another NGO health care provider, the Instituto Dermatologico. The latter provides comprehensive care including laboratory tests to patients with sexually transmitted diseases and infectious diseases with skin manifestations, and has an ongoing research training relationship with Columbia University Division of Infectious Diseases. The study team is initiating screening for, and treatment of, sexually transmitted diseases in all women seen in both clinic systems. It is hoped that the results of this study will enable the development of a national plan of screening and treatment.
Scott Hammer, MD
The Retrovirology Research Laboratory has been established to support HIV therapeutic and vaccine clinical trials with specialized virologic techniques that can be applied to clinical specimens to detect and quantify HIV expression in peripheral blood and tissue compartments, as well as to prepare specimens for HIV-specific immune assays. Dr Hammer's specific interests include HIV drug resistance and new assay development.
Frank Lowy, MD
Dr Lowy's research is focused on the pathogenesis and epidemiology of Staphylococcus aureus infections. Staphylococcus aureus remains a major cause of morbidity and mortality in both hospital- and community-acquired infections. The recent increase in antimicrobial resistance among strains of S. aureus has heightened concern about our limited understanding of the pathogenesis as well as the limited options available for the treatment of these life-threatening infections. Ongoing projects in Dr Lowy's laboratory include (1) identification and characterization of a staphylococcal protein that mediates binding to endothelial cells, (2) demographic and molecular epidemiologic investigation of staphylococcal colonization and disease in populations at high risk of S. aureus infection, (3) bacterial and cellular gene expression in murine models of infection, and (4) investigation of the biology of nasal colonization with S. aureus.
David Fidock, PhD
Dr. Fidock’s specialty Malaria drug resistance,
chemotherapy, pathogenesis, cell development. "A major focus of our group
is to elucidate the molecular basis of chloroquine resistance (CQR). By genetic
linkage and positional cloning, we earlier identified the pfcrt gene, located
within a chromosomal segment tightly linked to CQR, which encodes a novel
10-transmembrane transporter located on the intra-erythrocytic parasite’s
digestive vacuole. Using allelic exchange techniques, we recently proved that
mutations in this gene, identified in drug resistant parasites from around the
globe, are sufficient to confer CQR to CQ-sensitive parasites. Current work
focuses on understanding the contribution of the individual mutations to CQR,
determining their impact on parasite resistance to other antimalarials, and
investigating the biochemical basis of CQR. We are also developing animal models
to explore the role of pre-existing immunity on host clearance of drug-resistant
infections. In collaboration with Dr. Myles Akabas at AECOM, we are also
investigating the natural transport properties of pfcrt in heterologous cells.
Other studies focus on defining the role of PfATPase6, pfmdr1 and pfnhe in
contributing to parasite susceptibility to artemisinin, quinine and mefloquine.
We are also deeply involved in a major public/private
partnership, funded by the Medicines for Malaria Venture and the NIH, and
including GlaxoSmithKline and several academic partners, that aims to develop
new antimalarial drugs that target fatty acid biosynthesis in the malaria
parasite. Another aspect of our research is to investigate the
molecular basis of how parasitized erythrocytes bind to host endothelium,
enabling them to avoid splenic clearance. A variant antigen family, PfEMP1,
mediates this binding. We are investigating mechanisms of gene regulation that
contribute to this switching of gene expression between different members of
this family and exploring the genetic basis of endothelial receptor specificity.
The fourth area of research focuses on the
digestive vacuole, the site of CQ action. Specifically, we are examining which
ER or Golgi proteins are involved in protein trafficking to this compartment and
using transfection and bio-informatic approaches to define sequence motifs that
direct proteins to this site.
Dr. Fidock's Lab Page
Anne-Catrin Uhlemann, MD, PhD
Dr. Uhlemann’s laboratory investigates the evolution of bacterial pathogens such as Staphylococcus aureus and carbapenem-resistant Klebsiella pneumoniae.
S. aureus research: The past decade has witnessed a dramatic increase in Staphylococcus aureus infections acquired from the community. Yet there remains a limited understanding of how these strains spread and subsequently become established and persist within communities. Our research is focused on identifying molecular mechanisms that allow epidemic S. aureus strains such as USA300 to successfully disseminate. This project uses a combined approach of whole-genome comparative sequencing of longitudinally collected samples, genetic manipulation, and functional studies on bacterial adhesion and survival. These molecular studies are informed by ongoing epidemiological studies on S. aureus transmission in the local community. This work has identified a potentially newly emerging S. aureus strain, ST398, which was previously only associated with close contacts to animals. Ongoing studies are aimed at elucidating the molecular mechanisms of its cross-species transfer and current animal-independent spread.
K. pneumoniae infections in transplant recipients: Infections with carbapenem-resistant Enterobacteriaceae (CRE) have emerged as an urgent threat to healthcare, the “category of highest concern” in the 2013 CDC antimicrobial threat report. These multi-drug resistant infections are associated with high mortality. Recipients of solid organ transplantation, in particular liver transplant recipients are at increased risk for CRE infections. While intestinal colonization with CREs has been proposed as a potential risk factor for infections during CRE outbreaks, its actual contribution to infection remains incompletely understood. Moreover, there is a fundamental gap in knowledge on how these antibiotic resistant organisms transition from colonization to infection within affected hosts. We have established a cohort study of patients undergoing liver transplantation in which we aim to investigate the contribution of colonization to subsequent CRE infection. The long-term goal of this project is to elucidate at the bacterial genome level how CRE infections emerge and spread. Understanding these processes is critical to developing intervention and real-time clinical monitoring approaches to limit the impact of CRE infections at an individual and population level.
Jonathan Dworkin, PhD
Dr. Dworkin’s lab is interested in how dormant cells of various bacteria (B. subtilis, M. tuberculosis, and M. luteus) re-initiate growth and we have identified a well-conserved, eukaryotic-like Ser/Thr kinase that is essential for these bacteria to exit dormancy in response to muropeptides generated by growing bacteria. A target of this kinase is Elongation Factor G (EF-G), the essential GTPase regulating translation, and we are examining how this phosphorylation changes the activity of this protein. In addition, Dr. Dworkin is examining the role of this kinase in antibiotic resistance and survival during stationary phase in B. subtilis, M. luteus and S. aureus.
Stephen Goff, PhD Dr Stephen Goff is the Higgins Professor of Biochemistry and Molecular Biophysics and a professor of microbiology. The central focus of his laboratory for several years has been a detailed genetic analysis of the replication cycle of the Moloney murine leukemia virus (M-MuLV). The major approach has been to create mutations in a cloned DNA copy of the viral genome by site-directed mutagenesis and to determine the effect of the mutations on the viral life cycle after transfer of the altered DNAs into mouse cells in culture. These genetic analyses have defined the functional domains of various viral proteins and the sites of their action on viral nucleic acids. Dr Goff's group has also expressed reverse transcriptase and integrase in bacteria and studied these enzymes biochemically. Recently, they have applied the yeast two-hybrid system to monitor protein-protein interactions between viral proteins, and to identify new host proteins that interact with the gag, pol and env gene products. Other members of the group are interested in the functions of several viral oncogenes, especially the tyrosine kinases v-abl and v-src, and related signal transduction molecules, including the axl/ark receptor kinase; mpl, the thrombopoietin receptor; pdeg, the retinal cGMP phosphodiesterase; and various cytokine receptors. Finally, embryonic stem cell technologies are being used to generate knock out mice deficient in these transduction molecules. For more information, please visit the Goff lab home page.
Vincent Racaniello, PhD Dr Vincent Racaniello is the Higgins Professor of Microbiology. Research in this laboratory is aimed at understanding the replication and pathogenesis of picornaviruses. These RNA-containing viruses cause a variety of human diseases including paralysis, myocarditis, conjunctivitis, and the common cold. Dr Racaniello's studies focus on the interaction of viruses with cell receptors, translation of the viral genome, and the molecular basis of viral pathogenesis. Dr Racaniello's group has developed a mouse model that is being used to address questions on the pathogenesis of poliomyelitis, such as how poliovirus infection is restricted to specific cell types such as neurons, how the virus spreads in the infected animal, and the basis for the attenuation phenotype of the live poliovirus vaccines. A similar approach has been utilized to establish mouse models for diseases caused by other picornaviruses, including echoviruses, rhinoviruses, and enteroviruses. For more information, please visit the Racaniello lab home page.
Howard Shuman, PhD Dr Shuman is a professor of microbiology. His group has been studying the interaction between an intracellular pathogen, Legionella pneumophila and human macrophages. His approach has been based on using bacterial genetics to understand complex systems at the molecular level. Dr Shuman's group has identified and characterized a group of Legionella genes called icm genes which are important in formation of the specialized phagosomes which L. pneumophila inhabit. The Icm gene products are absolutely required for intracellular multiplication in eukaryotic hosts but are dispensable for growth on bacteriologic media. In the wild, Legionella and related species probably grow as parasites or endosymbionts in protozoa. Some of the Icm proteins are related to known conjugal and secretion systems in other organisms. Dr Shuman's group is testing the hypothesis that a subset of the icm products are transferred to host cells and directly prevent phagosome–lysosome fusion. In collaboration with the Columbia Genome Center, they have recently begun a complete analysis of the Legionella genome in order to elucidate the genetic basis for intracellular pathogenesis and symbiosis.
The Division of Infectious Diseases has affiliations throughout Columbia University Medical Center. Additional basic-science research opportunities for fellows are available with other faculty in the Department of Microbiology, the Pediatric Infectious Diseases Division, and other divisions and departments within CUMC.