Recent data suggests that HIV-1 evades humoral responses by erecting a """"""""glycan shield"""""""" that blocks access to key antigenic epitopes on gp120. However, it is also likely that the glycans attached to HIV-1 associated glycoproteins could act as functional groups to enable the virus to interfere with normal immune recognition and adhesion events. It is very possible that HIV-1 glycoproteins on different viral subtypes could potentially present the diversity of glycan sequences essential for many crucial immune cell interactions by employing the mutational and infective capabilities of the virus. Moreover, this acquisition would require selection of appropriate viral subtypes that could overcome the human immune response, resulting in an extremely protracted period of infection prior to death. There is now good evidence that the initial induction of tolerance to the fetus requires glycoconjugates bearing unusual carbohydrate sequences that mediate specific immunomodulatory effects in the pregnant uterus. It is very likely that HIV-1 glycoproteins could acquire the same carbohydrate sequences, thereby enabling this virus to couple its survival to the reproductive imperative. There are also specific linkages to tumorigenesis. For example, the N-glycans linked to gp120 isolated from chronically infected human H9 T lymphoblastoid cells have recently been shown to be identical to those attached to the tumor mucin CA125. Preliminary data indicates that both CA125 and model glycoconjugates bearing CA125 associated glycans elicit specific immunomodulatory effects in vitro. Since CA125 is also produced in the endometrium during pregnancy, it is very possible that the specific effects on the immune response observed during the development of AIDS, pregnancy and human tumors may be linked via shared carbohydrate functional groups. The primary goal of the current study is to investigate the potential role of glycosylation in the modulation of immune responses elicited by HIV-1 glycoproteins.
The first aim of this study is to completely characterize all glycans linked to gp120 derived from H9 lymphoblastoid cells and CHO cells. The other aim is to analyze the effects of gp120 on different immune cell subsets to determine if they mirror the response mediated by CA125. Nonglycosylated HIV-1 glycoproteins will be employed as controls for these studies. These preliminary studies will be crucial for determining if HIV-1 is employing its carbohydrate sequences as functional groups to mediate immune suppression. ? ?
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