Role of Cellular Sialidase in Pathogenesis of HIV-1

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DESCRIPTION (provided by applicant): Immediate and long-term career goals: (i) To conduct clinically-relevant research at a major medical center, (ii) To care for patients on an Infectious Diseases/Medicine ward and (iii) To train graduate students and medical fellows and residents. Research career development plan: I am now at a point in my career where my clinical skills are solid and need the training to develop a solid research program. A major objective during this training period is to acquire the scientific and organizational expertise needed to conduct competitive and innovative biomedical research independently. I will achieve this goal by increasing my knowledge of glycobiology, virus-cell interactions and new techniques of molecular and cellular biology and by developing an appreciation of statistical analyses with which to evaluate my data. The research, academic and clinical environments of the Institute of Human Virology and the Medical Center of the University of Maryland will provide the perfect opportunities to meet these goals. Research - Background and Aims: The biological activity of glycoproteins distributed throughout nature is influenced by modulation of their sialic acid content. Neuraminidase (referred to as sialidase in mammalian cells) removes terminal sialyl residues from glycoconjugates, and thus influences protein and cell function. We have demonstrated that desialylation of glycoconjugates on the surface of PBMCs enhances infectivity of HIV-1. The aims of this proposal are (I) to clarify the relationship between desialylation of cellular glycoproteins and infection of PBMCs by HIV-l by determining whether (1) desialylation of purified lymphocytes and monocytes promotes infection and (2) there is a direct correlation between the amount and type of glycosidic linkage of sialic acid removed from the cell surface and the degree of enhancement in infectivity and (II) to elucidate the mechanism(s) for the enhanced growth of HIV -1 in desialylated PBMCs by determining whether (1) desialylation of cellular surface glycoconjugates influences early events in the virus-cell interaction, (2) CD4 and the co-receptors for HIV-1 are relatively hyposialylated in activated PBMCs and (3) desialylation of cellular surface glycoconjugates activates PBMCs, induces production of cytokines or upregulates the surface expression of CD4 and co-receptors for HIV-1.