Designing New Therapies for HIV and Cancer
David Markovitz heads a multidisciplinary research team that includes five other faculty members, Ph.D. postdoctoral fellows, Ph.D. students, M.D./Ph.D. students, medical students, physicians, physicians-in-training, students from the School of Public Health, and undergraduates from the University of Michigan. The members of the research group come from multiple different scientific and medical disciplines and collaborate with a number of groups at the University of Michigan, as well as with laboratories at other institutions in the United States and in other countries. The Markovitz group studies the interactions of retroviruses, such as HIV, with human cellular factors. The goal of this work is to design and implement new therapies both for HIV infection and cancers that are related to retroviral infection.
In the course of studying human cellular factors that impact on retroviral infection, the Markovitz Laboratory became interested in the DEK protein. They have demonstrated that DEK is an important oncoprotein involved in the pathogenesis of melanoma and have revealed that DEK, a single non-histone protein with no known enzymatic activity, is vital to heterochromatin integrity. In addition to its intranuclear life, DEK also can be secreted or released from dying cells under certain conditions and can act as a pro-inflammatory factor. This is of quite some interest, as DEK has been identified as one of the few known autoantigens in juvenile idiopathic arthritis (JIA). Thus, the laboratory is also studying the mechanisms by which DEK might participate in autoimmunity, and also looking at DEK as both a therapeutic target and biomarker for the management of JIA, which is a common and poorly understood disease.
Another aspect of cell biology under investigation by the Markovitz group is the role of the vimentin intermediate filament protein in immunity. This highly abundant protein has been enigmatic, and although it has been studied intensively by multiple laboratories its fundamental function(s) has remained elusive. The Markovitz Laboratory has shown, surprisingly, that vimentin can be secreted, and in both its extracellular and intracellular roles it can modulate inflammation.
Recently, in a quest to develop a vaginal microbicide to prevent the transmission of HIV, the Markovitz Laboratory has shown that a banana lectin, termed BanLec, can markedly inhibit the entry of HIV into cells and thus block replication. Remarkably, the laboratory has discovered that by mutating a single amino acid BanLec loses its mitogenicity while retaining its antiviral activity. Therefore, the laboratory group is studying whether this mutant version of BanLec can be used in a vaginal microbicide and in the treatment of HIV and other viral infections. In addition, the group is investigating the molecular basis of lectin-mediated mitogencity. These findings provide an opportunity to understand how to molecularly engineer lectins for the benefit of therapy and other uses.
HIV belongs to the family of retroviruses, and a remarkable 8% of the normal human genome is made up of old retroviruses that over millions of years have inserted themselves into our genetic inheritance. These viruses have long been considered dormant passengers in the human body, but the Markovitz laboratory has now discovered that some of them may come alive and be important in the causation of several very wide-spread and deadly malignancies, such as lymphoma, breast cancer, and melanoma. The group is therefore vigorously investigating whether these ancient retroviruses can be targeted in the therapy of cancer. Thus, by closely studying the interaction between human cells and retroviruses, the Markovitz research group, consisting of both clinicians and basic scientists, aims to help in combating AIDS, cancer, and juvenile arthritis.