I. Introduction to Viruses and HIV
II. Why Gene Therapy Might be a Reasonable Tool for Attacking HIV
III. The Grand Challenge: Engineering Immunity
Part I: Introduction to Viruses and HIV
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In this set of lectures, I describe the threat facing the world from the human immunodeficiency virus (HIV) and a bold proposal on how we might meet the challenge of eliminating this disease by engineering the immune system.
In part 1, I provide a broad introduction to viruses, describing their basic properties and my own history of studying the replication of RNA viruses which led to the discovery of reverse transcriptase. I also illustrate the distinguishing features of equilibrium viruses (e.g. the common cold) that have adapted to co-exist with their host and non-equilibrium viruses (e.g. HIV) that have recently jumped from another species, are not adapted to the new host, and which can lead to disastrous outcomes (e.g. loss of immune function with potential lethality in the case of HIV).
In part 2, I describe the growing health problem that is facing the world with the spread of HIV and the limitations of current drug therapies and vaccine strategies. We need new ideas for tackling this problem. Here and in the next segment, I describe bold strategies of using gene therapy to conquer HIV, The approach that I describe in this segment involves gene therapy to produce short hairpin RNAs (siRNA) that target the destruction of a critical co-receptor of HIV, which the viruses that needs to infect cells. I discuss initial proof-of-principle experiments that suggest this approach might be feasible and the next steps needed to develop this idea into a real therapy.
In this last segment, I describe another gene therapy strategy for HIV in which we propose to develop antibody-like proteins that can be expressed by a patient's B cells and will target the HIV virus for destruction. To achieve this objective, hematopoietic (blood) stem cells must to be targeted with the gene, which will ultimately develop into B cells that express the therapeutic molecule. The ultimate goal is to produce a life-long supply of anti-HIV neutralizing antibodies. In this lecture, I describe the molecular methods underlying this strategy and a development path from proof-of-principle studies in mouse to safe trials in humans. This project receives funding from the Bill and Melinda Gates Foundation.
After serving as President of the California Institute of Technology for nine years, in 2006 David Baltimore was appointed President Emeritus and the Robert Andrews Millikan Professor of Biology. Born in New York City, he received his B.A. in Chemistry from Swarthmore College in 1960 and a Ph.D. in 1964 from Rockefeller University, where he returned to serve as President from 1990-91 and faculty member until 1994.
For almost 30 years, Baltimore was a faculty member at Massachusetts Institute of Technology. While his early work was on poliovirus, in 1970 he identified the enzyme reverse transcriptase in tumor virus particles, thus providing strong evidence for a process of RNA to DNA conversion, the existence of which had been hypothesized some years earlier. Baltimore and Howard Temin (with Renato Dulbecco, for related research) shared the 1975 Nobel Prize in Physiology or Medicine for their discovery, which provided the key to understanding the life-cycle of HIV. In the following years, he has contributed widely to the understanding of cancer, AIDS and the molecular basis of the immune response. His present research focuses on control of inflammatory and immune responses as well as on the use of gene therapy methods to treat HIV and cancer in a program called "Engineering Immunity".
Baltimore played an important role in creating a consensus on national science policy regarding recombinant DNA research. He served as founding director of the Whitehead Institute for Biomedical Research at MIT from 1982 until 1990. He co-chaired the 1986 National Academy of Sciences committee on a National Strategy for AIDS and was appointed in 1996 to head the National Institutes of Health AIDS Vaccine Research Committee.
In addition to receiving the Nobel Prize, Baltimore's numerous honors include the 1999 National Medal of Science, election to the National Academy of Sciences in 1974, the Royal Society of London, and the French Academy of Sciences. For 2007/8, he is President of the AAAS. He has published more than 600 peer-reviewed articles.
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Qin XF, An DS, Chen IS, Baltimore D. Inhibiting HIV-1 infection in human T cells by lentiviral-mediated delivery of small interfering RNA against CCR5. Proc Natl Acad Sci U S A. 2003 100:183-8.