Viewing AIDS from a glycobiological perspective: potential linkages to the human fetoembryonic defence system hypothesis.

Gary F.Clark 2 Anne Dell 1 Howard R.Morris 1 Manish Patankar 2 Sergio Oehninger 0 Markku Sepp ala 3 0 Department of Obstetrics and Gynecology, Eastern Virginia Medical School , Norfolk, VA 23501 , USA 1 Department of Biochemistry, Imperial College , London, SW7 2AZ , UK 2 Department of Biochemistry, Eastern Virginia Medical School , 700 Olney Road, Norfolk, VA 23501-1980 3 Department of Obstetrics and Gynaecology, University Central Hospital , Helsinki, FIN-00290 , Finland 5To whom correspondence should be addressed The primary molecular changes that lead to development of acquired immunodeficiency syndrome (AIDS) are very poorly understood, as are the mechanisms underlying the protection of the developing human from the maternal immune response. Recent data suggests that the human immunodeficiency virus (HIV) may be using the glycosylation system of the T lymphocytes to acquire glycans for its glycoproteins that enable it to disrupt carbohydrate dependent immune cell interactions or induce aberrant immune reactions. Consistent with this hypothesis, gp120 from HIV infected human H9 lymphoblastoid cells expresses biantennary N-linked glycans with a bisecting GlcNAc sequence on 11% of their total oligosaccharides. This specific carbohydrate sequence has recently been shown to protect K562 erythroleukemic cells from natural killer (NK) cell responses when presented on the cell surface. We have recently demonstrated that bisecting biantennary type N-linked glycans are also expressed on the human zona pellucida (ZP); previous lectin binding studies indicate that it is also expressed on human spermatozoa. Thus both the human gametes and HIV produced by H9 cells carry this same protective carbohydrate epitope on their outer surfaces. Human afetoprotein expressed in the developing human also carries the bisecting GlcNAc sequence, indicating that it may be suppressing the emerging fetal immune response by using its carbohydrate sequence as a functional group. We have suggested that the developing human and the gametes are also protected by soluble immunosuppressive glycoproteins found in the amniotic fluid and seminal plasma known as glycodelin-A (GdA) and glycodelin-S (GdS) respectively. Structural analysis of their N-linked oligosaccharides combined with other functional studies suggest that GdA and GdS employ their very unusual carbohydrate sequences as functional groups that enable them to manifest their immunosuppressive activities. GdA and GdS are significant components of our recently proposed model for the protection of the developing human and gametes designated the human fetoembryonic defence system hypothesis. A striking relationship now emerging is that the same unusual carbohydrate sequences associated with these immunosuppressive glycodelins are also specifically expressed on intravascular helminthic parasites, Helicobacter pylori, human tumour cells, and HIV infected T lymphocytes. The information presented in this review suggests that two new corollaries should be added to our recently proposed defence system hypothesis: (i) mimicry or acquisition of glycans that are used in this protective system by pathogens or tumour cells may enable them to either subvert or misdirect the human immune response, thereby greatly increasing their pathogenicity; and (ii) expression of glycoconjugates used in this system by normal cells and tissues outside the reproductive system may protect them from immune responses, especially in those cases where major histocompatibility recognition is either absent or minimal. A better understanding of this hypothesis and its corollaries may enable us to address the molecular mechanisms underlying not only AIDS but also a host of other very serious pathological conditions in the human. - The protection of the developing human from the maternal immune response is a vital function in reproduction (Hegde, 1991). Similarly, defending human spermatozoa and eggs from potential immune responses would also be beneficial for the propagation of the species. We have recently proposed that the developing human and the gametes are protected by a system of soluble and cell surface associated glycoconjugates that are localized to the male and female reproductive systems (Clark et al., 1996). We have referred to this model as the human fetoembryonic defence system hypothesis. Thus both the human reproductive system and human immunodeficiency virus (HIV) induce immunosuppression in the human, the first in a spatially and temporally regulated manner, the other in a disseminated fashion that induces a systemic loss of immune response. It has previously been suggested that HIV could disrupt the carbohydrate dependent adhesion/signalling system required by the immune system to manifest its biological activities (Adachi et al., 1988; Kashiwagi et al., 1994; Velupillai and Harn, 1994). However, to our knowledge, a coherent paradigm detailing how acquired immunodeficiency syndrome (AIDS) could be caused by aberrant glycosylation processes induced by HIV infection has not yet been presented. Also, there has been no suggestion that HIV is using the same system that protects the developing human and the gametes from the immune response to manifest its pathological activities. We will outline some new lines of evidence relating to the immunosuppressive glycodelins (Dell et al., 1995; Koistinen et al., 1996; Morris et al., 1996) that complement relevant older data supporting the concept that AIDS is the result of carbohydrate dependent pathological effects evoked by HIV infection. Moreover, it is now apparent that not only HIV but many other pathogens may integrate themselves into this system to protect themselves and promote their infectivity and pathological effects. Glycosylation of HIV glycoproteins: the development of diversity Complex N-linked glycans are assembled in a multienzyme process involving the action of specific glycosidases and glycosyltransferases in both the endoplasmic recticulum and Golgi apparatus (Kornfeld and Kornfeld, 1985; Dennis, 1991). The potential types of glycan sequences that can be synthesized by any specific cell type will be determined in part genetically by the cell specific expression of these enzymes. However, the type of glycan that will be attached to any particular protein will be dependent upon the interaction of these glycosidases and glycosyltransferases with their protein substrates (Helenius, 1994). Therefore the three-dimensional structure of a protein and the location of its specific glycosylation sites will also be crucial factors for determining the structure of the glycans attached to a glycoprotein. Logically, the specificity of this combination could provide a mechanism for cell specific functionality in certain cases. An understanding of these factors is essential for comprehending how aberrant glycosylation processes could play a key role in the development of AIDS. HIV is unique because of its ability to pr (...truncated)