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Journal of Virology, April 2005, p. 4927-4935, Vol. 79, No. 8
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.8.4927-4935.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Induction of Humoral Immune Responses following Vaccination with Envelope-Containing, Formaldehyde-Treated, Thermally Inactivated Human Immunodeficiency Virus Type 1

Departments of Medicine,¹ Microbiology, Immunology and Molecular Genetics,² Pediatrics, David Geffen School of Medicine at University of California, Los Angeles,⁴ UCLA AIDS Institute,³ Elizabeth Glaser Pediatric AIDS Foundation,⁵ Department of Biostatistics, UCLA Center for the Health Sciences,⁸ Department of Medicine, VA Greater Los Angeles Healthcare System, Los Angeles,¹⁰ ViroLogic Inc., South San Francisco, California,⁹ Yerkes National Primate Research Center,⁶ School of Medicine, Emory University, Atlanta, Georgia⁷

Received 22 July 2004/ Accepted 3 December 2004

The lack of success of subunit human immunodeficiency virus type 1 (HIV-1) vaccines to date suggests that multiple components or a complex virion structure may be required. We previously demonstrated retention of the major conformational epitopes of HIV-1 envelope following thermal treatment of virions. Moreover, antibody binding to some of these epitopes was significantly enhanced following thermal treatment. These included the neutralizing epitopes identified by monoclonal antibodies 1b12, 2G12, and 17b, some of which have been postulated to be partially occluded or cryptic in native virions. Based upon this finding, we hypothesized that a killed HIV vaccine could be derived to elicit protective humoral immune responses. Shedding of HIV-1 envelope has been described for some strains of HIV-1 and has been cited as one of the major impediments to developing an inactivated HIV-1 vaccine. In the present study, we demonstrate that treatment of virions with low-dose formaldehyde prior to thermal inactivation retains the association of viral envelope with virions. Moreover, mice and nonhuman primates vaccinated with formaldehyde-treated, thermally inactivated virions produce antibodies capable of neutralizing heterologous strains of HIV in peripheral blood mononuclear cell-, MAGI cell-, and U87-based infectivity assays. These data indicate that it is possible to create an immunogen by using formaldehyde-treated, thermally inactivated HIV-1 virions to induce neutralizing antibodies. These findings have broad implications for vaccine development.

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