Pediatrics

Research Overview

For the past nearly three decades, Dr. Srivastava's research has been focused on the following two parvoviruses, the non-pathogenic adeno-associated virus (AAV), and a common human pathogen, the parvovirus B19, and the development of recombinant parvovirus vectors for human gene therapy. His laboratory has made seminal contributions to the field of parvoviruses, which include: identification of cellular co-receptors for AAV as well as parvovirus B19; elucidation of various steps involved in parvovirus trafficking in the cell and nuclear transport; identification of cellular proteins involved in the regulation of AAV DNA replication and encapsidation; development of recombinant AAV and parvovirus B19 vectors; transgenic and knockout mouse models to study parvovirus-induced pathogenicity, and the use of parvovirus vectors for gene transfer and gene therapy. Parvovirus-based vectors have gained attention as a useful alternative for human gene therapy. The stable integration of the AAV genome, and the erythroid cell tropism of B19 have been exploited to construct the following two types of AAV-B19 hybrid vectors. Type I vectors allow stable integration of the viral DNA in infected cells but the viral gene expression occurs predominantly in the erythroid progenitor cells. Type II vectors allow efficient erythroid progenitor cell-specific gene delivery as well as expression of transduced genes. More recently, the next generation of recombinant AAV vectors has been developed that transduce cells and tissues more efficiently at lower vector doses. The current emphasis is on developing recombinant parvovirus vectors for gene therapy for genetic diseases such as B-thalassemia and sickle cell disease, and malignant disorders such as erythroleukemia, hepatoblastoma and hepatocellular carcinoma.

About

Dr. Srivastava is George H. Kitzman Professor of Genetics and Chief of Division of Cellular & Molecular Therapy in the Departments of Pediatrics, and Molecular Genetics & Microbiology, and Powell Gene Therapy Center. He also serves as Assistant Director of the University of Florida General Clinical Research Center. He received his Ph.D. degree from the Indian Institute of Science in Bangalore, India. After completing his postdoctoral training at the Memorial Sloan-Kettering Cancer Center in New York, he worked as a Research Associate at the University of Florida. For nearly two decades, he was on the faculty at Indiana University School of Medicine in Indianapolis, where he rose to the rank of Professor. He was recruited back to the University of Florida in 2004. He has mentored 5 Clinical Fellows and 31 Postdoctoral Fellows. Two students have graduated with MS degrees, and 5 students have received their PhD degrees from his laboratory. His research activities are currently supported by grants from the National Institutes of Health. He has also been awarded 3 US Patents on his research on human parvoviruses and their potential use as vectors in human gene therapy. He currently serves on two NIH Study Sections, and he is a member of the Medical Advisory Board of the Cancer Research Foundation and Prevention of America. He also serves on the Editorial Boards of Journal of Virology, Gene Therapy, Human Gene Therapy, Recent Patents on DNA and Gene Sequences, and Gene Therapy and Molecular Biology.

Key Publications

Dr. Srivastava has published 124 research articles, mostly on human parvoviruses, in peer-reviewed journals, reviews, and book chapters. Selected groundbreaking publications are listed below. Additional publications can be found in PubMed.

1. G.R. Jayandharan, L. Zhong, B. Li, B. Kachniarz, and A. Srivastava. Strategies for improving the transduction efficiency of single-stranded adeno-associated virus vectors in vitro and in vivo. Gene Therapy, in press, 2008.
2. L. Zhong, B. Li, C.S. Mah, L. Govindasamy, M. Agbandje-McKenna, M.A. Cooper, R.W. Herzog, I. Zolotukhin, K.H. Warrington, Jr., K.A. Weigel-Van Aken, J.A. Hobbs, S. Zolotukhin, N. Muzyczka, and A. Srivastava. Next generation of adeno-associated virus 2 vectors: Point mutations in tyrosines lead to high-efficiency transduction at reduced doses. Proceedings of the National Academy of Sciences, USA, 105: 7827-7832, 2008.
3. N. Maina, L. Zhong, X. Li, W. Zhao, Z. Han, D. Bischof, G. Aslanidi, S. Zolotukhin, K. Weigel-Van Aken, A.E. Rivers, W.B. Slayton, M.C. Yoder, and A. Srivastava. Optimization of recombinant adeno-associated virus serotype vectors for human B-globin gene transfer and transgene expression. Human Gene Therapy, 19: 365-375, 2008.
4. L. Zhong, X. Zhou, Y. Li, K. Qing, X. Xiao, R.J. Samulski, and A. Srivastava. Single-polarity recombinant adeno-associated virus 2 vector-mediated transgene expression in vitro and in vivo: Mechanism of transduction. Molecular Therapy, 16: 290-295, 2008.
5. K.A. Weigel-Kelley, M.C. Yoder and A. Srivastava. a5B1 integrin as a cellular co-receptor for human parvovirus B19: Requirement of B1 integrin activation for viral entry. Blood, 102: 3927-3933, 2003.
6. K.Y. Qing, C. Mah, J. Hansen, S.Z. Zhou, V.J. Dwarki and A. Srivastava. Human fibroblast growth factor receptor 1 is a co-receptor for infection by adeno-associated virus 2. Nature Medicine, 5: 71-77, 1999.