Ashok Aiyar, Ph. D

Dr. Aiyar's laboratory uses genetic, cellular, and molecular approaches to study the etiology and therapeutic approaches to human infectious disease.

There are five major research interests in Dr. Aiyar's laboratory, three of which are focused on Epstein-Barr virus (EBV). EBV was the first oncogenic human virus identified. EBV causes Burkitt's lymphoma, AIDS-related lymphomas, nasopharyngeal carcinoma, and gastric carcinoma. EBV is latent in these proliferating tumor cells, meaning that a small number of viral genes are expressed, and infectious virus is rarely, if ever, released.

Research Project 1: EBV genome replication and partitioning in malignantly transformed cells. EBV replicates as an extra-chromosomal nuclear episome in malignantly transformed cells. This episome replicates in synchrony with cellular chromosomes, and like chromosomes is partitioned equally during cell division. Both replication and partitioning require a single viral protein called EBNA1 that binds human chromosomes (Figure 1) and also binds EBV genomes. Therefore EBNA1 acts as a molecular tether between chromosomes and EBV genomes, to piggy-back genomes on chromosomes (Figure 2). Our research has defined the mechanism by which this piggy-backing occurs. If piggy-backing is disrupted, EBV-transfomed cells undergo apoptosis very rapidly, and therefore this aspect of EBV replication within transformed cells is an attractive target against such malignancies.





Research Project 2: Regulation of EBV transcription in malignant cells.In addition to functioning as a piggy-back tether, EBNA1 is a also a transactivator that is necessary for transcription of other EBV genes in several malignancies. Our research has focused on identifying the mechanism by which EBNA1 transactivates. We have shown recently that EBNA1 requires zinc for transactivation, and that EBNA1's ability to transactivate is regulated by the cellular microenvironment, particularly oxygen tension, and oxidative stress (Figure 3). These findings are of significance because malignancies caused by EBV have dramatically different properties in body compartments that differ in oxygen tension. Our studies are likely to yield new approaches that modulate intracellular oxidative stress as a therapeutic target against malignancies caused by EBV.


Research Project 3: Role of EBV in the pathogenesis of multiple sclerosis. This is a new project in our laboratory, conducted in collaboration with Dr. Bridget Bagert, Dept. of Neurosurgery, LSUHSC. Proliferating EBV infected cells are found in ectopic B-cell follicles in the neural meninges of patients who have succumbed to multiple sclerosis (MS). Numerous older studies have also implicated EBV in the pathogenesis of MS. Together with Dr. Bagert we are attempting to recover EBV-infected cells from the cerebrospinal fluid of MS patients to determine various virological parameters, such as EBV gene expression, associated with these cells. The ultimate goal of our collaboration is to identify therapeutic targets against MS.

Research Project 4: The function of an AT-hook protein in the parasite Leishmania. Leishmania is a protozoan parasite responsible for the disease leishmaniasis that aries from disfiguring skin lesions to fatal visceral infections. This project is conducted in collaboration with Dr. Ben Kelly, also of the MIP department at LSUHSC. We have identified a novel chromosome binding protein in Leishmania that contains the same chromosome-binding domain as the EBNA1 protein of EBV. In these studies, we have demonstrated that this Leishmania protein functions like EBNA1 when expressed in mammalian cells. We have developed novel pharmaceuticals that disrupt EBNA1's functions, and these drugs also severely impact Leishmania biology and replication (Figure 4). Our goal is to develop new therapies against leishmaniasis.


Research Project 5: Retroviral/Lentiviral vector technology. This project is conducted in collaboration with Professor William Miller of the Department of Biochemical Engineering at Northwestern University (Evanston, IL). Together, we have developed methods that increase the efficiency and stability of retroviral and lentiviral vectors by modulating the expression levels of the envelope glycoprotein used in these vectors. We have also altered cellular lipid profiles to dramatically increase infection of primary human cells by such vectors. The vectors, and vector technologies developed by us are used as tools in our EBV research. Other groups at LSUHSC and at Northwestern University also use them as research tools.