Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019693 (HIV)
 170,526 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The HIV-1 envelope glycoprotein gp120 displays inefficient intracellular transport, which is caused by its retention in the endoplasmic reticulum. Coexpression in insect cells (Sf9) of HIV-1 gp120 with calnexin has shown that their interaction was modulated by the signal sequence of HIV-1 gp120. gp120, with its natural signal sequence, showed a prolonged association with calnexin with a t1/2 of greater than 20 min. Replacement of the natural signal sequence with the signal sequence from mellitin led to a decreased time of association of gp120 with calnexin (t1/2 < 10 min). These different times of calnexin association coincided both with the folding of gp120 as measured by the ability of bind CD4 and with endoplasmic reticulum to Golgi transport as analyzed by the acquisition of partial endoglycosidase H resistance. Using a monospecific antibody to the HIV-1 gp120 natural signal peptide, we showed that calnexin associated with N-glycosylated but uncleaved gp120. Only after dissociation from calnexin was gp120 cleaved, but very inefficiently. Only the small proportion of signal-cleaved gp120 molecules acquired transport competence and were secreted. This is the first report demonstrating the effect of the signal sequence on calnexin association.
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PMID:Effects of inefficient cleavage of the signal sequence of HIV-1 gp 120 on its association with calnexin, folding, and intracellular transport. 879 Mar 77

Mannose-binding lectin (MBL) is a C-type lectin of the innate immune system that binds to carbohydrates on the surface of certain microorganisms. Previous studies showed that MBL binds to gp120, the envelope glycoprotein of HIV-1. gp120 is extensively glycosylated, with N-linked complex and high mannose carbohydrates accounting for about half of the molecular weight. The objectives of this study were to determine the types of glycans on gp120 important for MBL binding and to determine if alteration of complex glycans with neuraminidase (NA) could enhance the interaction of MBL with virus. Lectin blot analyses revealed that MBL interacted with recombinant gp120 (rgp120) from both T cell-tropic and M-tropic virus strains. Treatment of rgp120 with endoglycosidase H (eH) or endoglycosidase F1 (eF1) abrogated binding of MBL, but did not decrease binding of wheat germ agglutinin indicating that high mannose and/or hybrid N-linked glycans were required for MBL binding. Removal of sialic acids from rgp120 with NA enhanced MBL binding. Treatment of intact virus from T cell lines or primary isolates with eF1 also significantly decreased HIV binding to MBL, while treatment with NA substantially increased binding. Treatment of virus with both eF1 and NA did not decrease binding compared to NA alone suggesting that NA treatment exposed binding sites on gp120 that are not high mannose glycans. These studies provide evidence that MBL binds to HIV via high mannose carbohydrates on gp120 and shows that the interaction of MBL with virus is regulated by sialylation.
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PMID:High mannose glycans and sialic acid on gp120 regulate binding of mannose-binding lectin (MBL) to HIV type 1. 1248 19

The chemo-enzymatic synthesis of a glycopeptide, which involves the chemical synthesis of N-acetylglucosaminyl peptide and the enzymatic transfer of oligosaccharide, is described. The first step of the chemo-enzymatic method is the chemical synthesis of N-acetylglucosaminyl peptide with an N-acetylglucosamine moiety bound to the asparaginyl residue of the peptide by a solid-phase method. The second step is transglycosylation of a complex-type oligosaccharide derived from a glycopeptide to an N-acetylglucosaminyl peptide by endo-beta-N-acetylglucosaminidase of Mucor hiemalis (Endo-M). Peptide T can block HIV infection of human T cells. We added the sialo-complex-type oligosaccharide to chemically synthesized N-acetylglucosaminyl Peptide T using the transglycosylation activity of Endo-M. The glycosylated Peptide T thus produced showed a higher degree of resistance to protease digestion than Peptide T. We also prepared calcitonin glycopeptide. Calcitonin is a calcium-regulating hormone that is widely used in therapy for hypercalcemia, and is glycosylated by the chemo-enzymatic method described above. This glycopeptide demonstrated sufficient physiological activity. Comparison of NMR data between native calcitonin and calcitonin glycopetide revealed that the glycosylation does not affect the binding topology of the peptide. N-Acetylglucosaminyl glutamine was also a good glycoside acceptor of Endo-M. We were able to add the sialo-complex-type oligosaccharide to the glutamine residue of the Substance P neuropeptide using the transglycosylation activity of Endo-M. The glycosylated Substance P was biologically active, although its activity was rather low, and stable against peptidase digestion. The oligosaccharide moiety attached to the l-glutamine residue of the peptide was not liberated by PNGase that liberated asparagine-linked oligosaccharide from glycopeptides.
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PMID:Chemo-enzymatic synthesis of bioactive glycopeptide using microbial endoglycosidase. 1623 37

Human immunodeficiency virus type 1 (HIV-1) envelope (gp120) binding to DC-SIGN, a C-type lectin that can facilitate HIV infection in cis and in trans, is largely dependent on high-mannose-content moieties. Here, we delineate the N-linked glycosylation (N-glycan) sites in gp120 that contribute to optimal DC-SIGN binding. Soluble DC-SIGN was able to block 2G12 binding to gp120, but not vice versa, suggesting that DC-SIGN binds to a more flexible combination of N-glycans than 2G12. Consistent with this observation, HIV strain JRCSF gp120 prebound to 2G12 was 10-fold more sensitive to mannan competition than gp120 that was not prebound in a DC-SIGN cell surface binding assay. The analysis of multiple mutant forms of the 2G12 epitope revealed one triple glycosylation mutant form, termed 134mut (carrying N293Q, N382Q, and N388Q mutations), that exhibited a significant increase in sensitivity to both mannan competition and endoglycosidase H digestion compared to that of the 124mut form (carrying N293Q, N328Q, and N388Q mutations) and wild-type gp120 in a DC-SIGN binding assay. Importantly, no such differences were observed when binding to Galanthus nivalis was assessed. The 134mut form of gp120 also exhibited decreased binding to DC-SIGN in the context of native envelope spikes on a virion, and virus bearing 134mut exhibited less efficient DC-SIGN-mediated infection in trans. Significantly, 124mut and 134mut differed by only one glycosylation site mutation in each construct, and both 124mut and 134mut viruses exhibited wild-type levels of infectivity when used in a direct infection assay. In summary, while DC-SIGN can bind to a flexible combination of N-glycans on gp120, its optimal binding site overlaps with specific N-glycans within the 2G12 epitope. Conformationally intact envelopes that are DC-SIGN binding deficient can be used to probe the in vivo biological functions of DC-SIGN.
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PMID:Identification of the optimal DC-SIGN binding site on human immunodeficiency virus type 1 gp120. 1752 23

The identification of surfactant protein A (SP-A) as an important innate immune factor of the lungs, amniotic fluid, and the vaginal tract suggests that it could play an important role during various stages of HIV disease progression and transmission. Therefore, we examined whether SP-A could bind to HIV and also had any effect on viral infectivity. Our data demonstrate that SP-A binds to HIV in a calcium-dependent manner that is inhibitable by mannose and EDTA. Affinity capture of the HIV viral lysate reveals that SP-A targets the envelope glycoprotein of HIV (gp120), which was confirmed by ELISA using recombinant gp120. Digestion of gp120 with endoglycosidase H abrogates the binding of SP-A, indicating that the high mannose structures on gp120 are the target of the collectin. Infectivity studies reveal that SP-A inhibits the infection of CD4+ T cells by two strains of HIV (BaL, IIIB) by >80%. Competition assays with CD4 and mAbs F105 and b12 suggest that SP-A inhibits infectivity by occlusion of the CD4-binding site. Studies with dendritic cells (DCs) demonstrate that SP-A enhances the binding of gp120 to DCs, the uptake of viral particles, and the transfer of virus from DCs to CD4+ T cells by >5-fold at a pH representative of the vaginal tract. Collectively, these results suggest that SP-A acts as a dual modulator of HIV infection by protecting CD4+ T cells from direct infection but enhancing the transfer of infection to CD4+ T cells mediated by DCs.
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PMID:Surfactant protein A binds to HIV and inhibits direct infection of CD4+ cells, but enhances dendritic cell-mediated viral transfer. 1856 27

Long-lasting sweet proteins: The chemoenzymatic synthesis of a triazole (T)-linked glycosylated C34 fragment from HIV-1 gp41 is described. The glycopeptide shows high solubility, excellent fusion inhibition, and as shown in the graph, promising protease resistance. Endoglycosidase-catalyzed transglycosylation of triazole-linked glucose (Glc) and N-acetylglucosamine (GlcNAc)-containing dipeptides and polypeptides was achieved by using synthetic sugar oxazoline as the donor substrate. It was found that both N- and C-linked Glc/GlcNAc-containing triazole derivatives were effective substrates for endo-beta-N-acetylglucosaminidase from Arthrobacter (Endo-A) for transglycosylation; this demonstrates a broad acceptor substrate specificity for Endo-A. This chemoenzymatic method was successfully used for the synthesis of a novel triazole-linked C34 glycopeptide derived from the HIV-1 envelope glycoprotein, gp41. We found that the synthetic C34 glycopeptide possesses potent anti-HIV activity with an IC(50) of 21 nM. The triazole-linked C34 glycopeptide demonstrated a much enhanced stability against protease- and glycoamidase-catalyzed digestion; this shows the protective effects of glycosylation and the stability of the triazole linkage. These favorable properties suggest that the triazole-linked C34 glycopeptide might be valuable for further development as an anti-HIV drug candidate.
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PMID:Enzymatic glycosylation of triazole-linked GlcNAc/Glc-peptides: synthesis, stability and anti-HIV activity of triazole-linked HIV-1 gp41 glycopeptide C34 analogues. 1935 9


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