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HUMAN HIV VACCINE TRIALS: DOES ANTIBODY-DEPENDENT ENHANCEMENT POSE A GENUINE RISK? DONALD S. BURKE* Introduction Under well-defined laboratory conditions, HIV-specific human antibodies can enhance HIV growth in certain types of cultured human cells; several independent research teams using different methodologies have reported reproducible increases of HIV growth in cell cultures in vitro, brought about by antibodies in sera from HIV-infected persons [1—5]. These experiments raise concerns that if HIV antibodies can increase virus growth in vitro, then the same mechanisms might be operative in vivo in humans. It is conceivable that vaccine-induced HIV antibodies might be harmful by predisposing to, rather than protecting from, infection and disease. Hundreds of healthy, non-HIV-infected volunteers in the United States and elsewhere have been inoculated with investigational HIV vaccines, and many have developed HIV antibodies. If volunteer sera, like patient sera, is demonstrated to enhance HIV The opinions or assertions contained herein are the private views of the author and are not to be construed as reflecting the views of the U.S. Department of the Army or the Department of Defense. Abbreviations Used: Immune Molecules: C3 The third component of complement CD4 Cluster of differentiation 4, the cell surface marker of the T lymphocyte helperinducer subset Fc The constant region of immunoglobulin Viruses: HIV Human Immunodeficiency Virus SIV Simian Immunodeficiency Virus *Address: Division of Retrovirology, Walter Reed Army Institute of Research, 13 Taft Court, Suite 201, Rockville, Maryland 20850. Reprint requests: Department of Academic Affairs, Walter Reed Institute of Research, Walter Reed Army Medical Center, Washington , DC 20307-5100.© 1992 by The University of Chicago. All rights reserved. 0031-5982/92/3504-0790$01.00 Perspectives in Biology and Medicine, 35, 4 ¦ Summer 1992 511 growth in vitro, is this sufficient reason to halt volunteer trials? By virtue of life-style, many of the volunteers in ongoing vaccine trials may be at significant risk of infection. If (inevitably, when) a vaccinated volunteer does become infected, will this be sufficient reason to terminate human HIV vaccine trials? Clearly the phenomenon of HIV antibody dependent enhancement exists in vitro, but is it important, or even extant, in vivo [6, 7]? What studies must be done to determine whether antibodydependent enhancement should be a rate-limiting step on HIV vaccine development? Antibody Dependent Enhancement: The Dengue Hemorrhagic Fever Example The concept that partial or incomplete immunity might exaggerate rather than ameliorate disease emerged in Bangkok, Thailand, in the early 1960s, when Halstead and colleagues noted that severe manifestations of dengue virus infections were almost invariably associated with an anamnestic or secondary antibody response to the infecting virus. They postulated that sequential infections, first by one serotype, and then by another heterologous serotype, after an interval of months to years, resulted in severe disease [8]. Independently and coincidentally, in Australia in 1964, Hawkes observed that the apparent infectivity of Murray Valley encephalitis virus, when assayed on chick embryo fibroblasts, was increased by the addition of specific antisera prepared in domestic fowls [9]. He coined the term enhancement for this in vitro phenomenon and speculated about the mechanism. in the presence of a given cell population only a proportion of the virus population is capable of infecting the cells. When the virus particles are coated with antibody they are altered in such a way (for example, in surface charge) that the proportion of infectious particles in the population is increased. The link between serum antibody-dependent enhancement activity and more severe disease in humans (dengue hemorrhagic fever) was established during the 1980s, again in Bangkok. Burke, Kliks, and colleagues demonstrated in a prospective study of thousands of school children that serum-enhancing activity was a powerful predictor of severe disease [10]. Antibody-dependent enhancement is now widely accepted as a significant factor in the pathogenesis of dengue infection. Indeed, for several years now the Dengue Vaccine Advisory Committee of the World Health Organization has wrestled with strategies to eliminate or circumvent antibody-dependent enhancement as a potential adverse consequence of dengue vaccination [H]. 512 Donald S. Burke ¦ HIV Vaccine Triah Antibody-Dependent Enhancement as a General Property of Enveloped Viruses Antibody-dependent enhancement of virus growth can be found virtually...


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