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Initial events of human immunodeficiency virus infection: Rôle of carbohydrate and possibilities for intervention

Understanding the attachment and penetration of HIV into human cells is of paramount importance for a rational approach to medical intervention and prophylaxis against infection. As the surface glycoproteins of any enveloped virus are natural targets for a humoral immune response, efforts to create a vaccine against HIV infection focus on the heavily glycosylated major envelope glycoprotein, gp120. The studies in this thesis have examined the carbohydrate part of gp120, based on the hypothesis that the carbohydrate part could be a target for interference with attachment or entry, a possibility which has not previously been investigated. Initially lectins were used to characterize the main types of oligosaccharides on gp120, and it was found that all three main types of N-linked oligosaccharides (high mannose, hybrid and complex) were present (1). Lectins, which bound to gpl20, also blocked HIV infection and syncytium formation by binding to virus and infected cells (1, 2). While gp 120-binding lectins would probably not be of much use for therapy, these results showed that the oligosaccharides themselves could present targets for interference with infection. A large panel of monoclonal antibodies (MAbs) against defined carbohydrate epitopes (3) was therefore screened. Not only was it possible to further extend the characterization of those Nlinked oligosaccharides, which had up till now remained obscure, but a hitherto unknown class of 0-linked oligosaccharides was discovered on gp 120 and its precursor gp160 (3, 4). The structures revealed by these carbohydrate specific MAbs are cancer-related neoantigens not normally expressed in healthy tissues. Most importantly, these MAbs bound to gp120 and blocked HIV infection (4). For one of the carbohydrate neutralization epitopes, it was found that its expression was restricted by the genetically regulated glycosylation apparatus of the infected cell (5 ) . However, antibodies against the simple 0-linked carbohydrate neoantigen Tn neutralized a broad range of HIV-1 and HIV-2 strains propagated in different cells when tested in infectivity assays using both lymphocytic and monocytic cells as target cells for HIV infection (4). The way the carbohydrate specific MAbs interfered with HIV infection was by blocking some initial event in infection (3). The CD4 molecule was found to be essential for infection but also the CD18 antigen of target cells was involved (7). While the exact mechanism by which the carbohydrate specific MAbs interfere with HIV infection has not been determined, anti-Tn MAbs bound to gp120 and blocked HIV attachment to the target cell (4). For some of the other MAbs it was found that while they blocked infection of lymphocytic cells they could also enhance infection of monocytic cells, probably through binding to Fc-receptors of these cells (6). This work has focused on some relatively uncharted aspects of HIV infection which, especially concerning the regulation of glycosylation and acquisition of carbohydrate determinants on viral glycoproteins, may have implications for viral infections in general and could provide an interesting link to the glycosylation changes seen in cancer. The most significant part of this work is the discovery that special carbohydrate structures exist on