Paul Spearman, M.D.

Department of Pediatrics, Division of Infectious Diseases, Epidemiology, and Imunology

• Ph.D., University of Texas Southwestern Medical School, 1986
• B.A., Austin College, 1982

Research Interests: We seek to understand the assembly process of human immunodeficiency virus (HIV) and to develop a vaccine that can effectively neutralize HIV. HIV assembly is a process directed by the viral Gag polyprotein. Gag is a myristoylated precursor protein that is translated in the cytoplasm and then traffics to the plasma membrane or to endosomal vesicles for assembly. We have recently described an interaction between Gag and the delta subunit of the AP-3 adaptor protein complex (1). The mechanism and structural basis for this interaction is now under intense study. Our hypothesis is that the AP-3 interation is responsible for the trafficking of Gag to the multivesicular body (MVB) and that this event is part of a normal productive paritcle assembly pathway. The Vpu protein of HIV assists the virus assembly process through a poorly-defined mechanism. We have presented evidence that Vpu overcomes a host cell restriction to assembly (2). Vpu appears to act through interactions with the recycling pathways in the cell, rather than directly interacting with Gag (3). The nature of the host restriction to assembly that Vpu overcomes is a focus of our ongoing work.

HIV vaccines that have been tested in human clinical trials have generally failed to elicit broadly neutralizing antibodies against circulating, primary isolate strains. We have been developing enhanced HIV-1 pseudovirion vaccines based upoon a simple Gag and Env (envelope glycoprotein) platform that is capable of presenting native, trimeric envelope complexes to the immune system (4). The use of primary isolate-derived, pseudovirion immunogens may allow broad neutralizing antibodies to be generated (5). This platform will be enhanced by the use of alterations in Env structure and through the addition of molecules that trigger specific Toll-like receeptors or enhance T-cell help. Current efforts in this project include development of this platform as a viable translational vaccine candidate and the use of pseudovirions to dissect basic aspects of B cell responses in HIV-infected individuals.