Research Projects
Human Immune Responses in Emerging Viral Diseases
Our group is defining human T lymphocyte responses to viral infection and their role in protective immunity and disease pathogenesis. Our research focus is on a variety of emerging and re-emerging viral pathogens, including flaviviruses (dengue, West Nile, yellow fever, and Japanese encephalitis viruses), poxviruses (vaccinia virus), hantaviruses, influenza virus, hepatitis C virus, and human immunodeficiency virus (HIV).
Our research is largely clinically based because these diseases do not have good animal models. We employ a variety of cell culture and molecular biology approaches, such as isolation and characterization of human CD4+ and CD8+ T cell clones, expression of viral genes in recombinant viruses, sequence analysis of T cell receptor genes, and quantitative analysis of viral RNA and cytokine mRNAs using PCR. The long-term goals of our research are:
- to define new approaches to treatment of viral disease based on the molecular mechanisms of disease pathogenesis, and
- to define optimal approaches for development of effective vaccines to prevent infection.
Our current research projects include:
Dengue- Our studies focus on defining the immunological responses that are responsible for the increased frequency of severe dengue disease during secondary dengue virus infections. We are participating in several international collaborative clinical studies to define the risk factors for and pathophysiology of severe dengue disease in humans. Clinical studies being conducted in Thailand include a detailed analysis of dengue viral replication and immune responses in children with acute dengue virus infections, and a prospective study of dengue virus transmission and disease in primary schoolchildren.
West Nile virus- Our studies aim to elucidate the role of T lymphocyte responses in the pathogenesis of disease in naturally-infected humans. In addition, we are studying cell mediated immune responses to candidate West Nile virus vaccines.
Influenza- Our studies focus on defining the molecular targets for cytotoxic T lymphocytes that are cross-reactive against a wide array of influenza viral strains. In collaboration with investigators at other institutions, we are studying new approaches to induce broader protective immune responses than standard inactivated influenza vaccines based on these findings.
Vaccinia virus- We are studying the protective immunity induced by the standard smallpox vaccine and novel vaccine candidates. We also study T lymphocyte responses to vaccination as a model for understanding the induction and persistence of immunological memory.
Hantavirus- We are studying the immunopathological basis of hantavirus pulmonary syndrome and hemorrhagic fever with renal syndrome. We are collaborating with clinicians in the Americas, Europe, and Asia to define T lymphocyte responses associated with more advanced disease.
Hepatitis C- We are studying cytotoxic T lymphocyte responses in patients with chronic HCV infections and their association with hepatic inflammation and viral persistence, in collaboration with investigators in the Department of Medicine, Division of Digestive Diseases and Nutrition.
Human Immunodeficiency Virus (HIV-1)- Our studies focus on improving methods for detection and quantitation of human memory HIV-specific cytotoxic T lymphocyte responses to HIV and experimental HIV vaccines in phase I clinical trials.
Clinical Vaccine Research
Our research emphasis has been to develop validated assays of virus-specific T cell immunity for application to vaccine trials, and to identify immunological markers of vaccine-derived protective (or pathological) immunity in humans. These studies are conducted in conjunction with phase I/II clinical trials conducted at UMMS and other sites. Current studies include analysis of human T cell responses to seasonal and pandemic influenza virus vaccines, a DNA-protein prime-boost HIV vaccine, standard and newly developed smallpox vaccines, and novel vaccines against flaviviruses, including West Nile and dengue viruses.