A sequence of four amino acid residues amino-terminal to the only intramolecular disulphide bond of the human immunodeficiency virus type 1 (HIV-1) transmembrane protein gp41 is recognized by an anti-idiotypic antibody (9G5A) raised against another monoclonal antibody (M38), which recognizes the C5 region of gp120. 9G5A is an Ab2 beta antibody (internal image of the M38 epitope) in that it inhibits the interaction of M38 to its antigen. The binding of 9G5A to gp41 can be inhibited by M38 showing that the two antibodies interact via their paratopes. 9G5A neutralizes HIV-1 infection and syncytia formation. Ab3 antibodies induced in mice and rabbits immunized with 9G5A also can neutralize virus in both assays. These data show that the M38-defined epitope of the carboxy-terminal region of gp120 interacts with the 9G5A-defined epitope of gp41, and that this interaction can be reproduced by the idiotypic mimicry of the two antibodies. The results are consistent with a proposed molecular model of the two env regions which predicts the presence, within the C5 region of gp120, of a large intramolecular pocket that is contacted by the gp41 cysteine loop.
Several groups have reported that sulfated polysaccharides are potent and selective in vitro inhibitors of human immunodeficiency virus type 1 (HIV-1); however, their therapeutic application is limited by their anticoagulant activity. In view of possible improvements in therapeutic potential, a number of heparin derivatives with reduced anticoagulant activity were studied for their inhibitory activity of an HIV-dependent syncytium formation assay, in comparison with standard anionic polysaccharides, such as sodium heparin, dextran sulfate, and heparin sulfate. The chemical modifications introduced in the heparin molecule included succinylation of desulfated N groups (Suc-H), exhaustive periodate oxidation and reduction (RO-H), and controlled nitrous acid degradation (LMW-H). The most pronounced anti-HIV activity was observed with RO-H, Suc30-H (standard heparin, 30% succinylated), and Suc100-LMW-H (low molecular weight heparin, 100% succinylated); the latter retained only 5% of the anticoagulant activity of standard heparin, whereas RO-H and Suc30-H retained approximately 35% of the anticoagulant activity of standard heparin. A safety ratio (arbitrary units of anti-HIV activity per anticoagulant international unit) was calculated: by this parameter, RO-H, Suc30-H, and Suc100-LMW-H were, respectively, 48-, 3.6-, and 1644-fold more safe than standard heparin.
Human lymphocyte CD4 becomes undetectable in the presence of exogenous gangliosides (CD4 masking), as originally described by Offner et al. (J. Immunol. 1987. 139: 3295). CD4 masking is apparently due to in situ rearrangement of the glycoprotein; since no direct binding of ganglioside to CD4 could be demonstrated, it was suggested that the effect could be mediated by interactions with other, as yet unidentified, surface structures. To gain insight into the structural requirements of the interaction(s) that leads to CD4 masking, we assayed the effects of a battery of gangliosides and of ganglioside derivatives on (a) CD4 masking; (b) cholera toxin binding (as a well known ganglioside-protein interaction) and (c) inhibition of lymphocyte mitogenic proliferation (as a second ganglioside interaction with a lymphocyte surface target). Our results indicate that the three interactions are distinctly different, since ganglioside chemical groups which are essential for one of the interactions are irrelevant for the others, and lead to the conclusion that gangliosides can interact with lymphocyte surface targets in a number of ways, causing a number of independent biological effects.
Using the HPLC procedure reported in the previous communications (1,2), we carried out the determination of purine nucleotides in normal PBL, in PBL from seropositive and AIDS patients, and in all the other previously described cells, both normal and infected with HIV-1 virus (3). Typical chromatograms are shown in Figures 1 and 2; the legends indicate the cells from which the nucleotides were extracted.In most cell lines, the purine nucleotide levels were of the same order of magnitude as in PBL.However, considerable differences in the levels of the different nucleotides could be observed between healthy PBL and the other normal cell lines, as well as between the different cell lines.From the figures, it is also evident that the nucleotide pattern in the various cell lines was different before and after infection with HIV-1 virus.The principal observations are: in the 8B51 cells the monophosphates clearly increased, while ATP and GTP decreased, compared to A3.01.In asymptomatic patients diphosphates are significantly decreased. In ARC a return to the basal values of PBL was evident whereas in the last stage of the disease, the levels of di-and triphosphates were A 301 GMP A I P I' 0 4 5 9 0 8 E51 0 45 90 Fig.1: The Hrm: W profile of A3.01 and 8B51 perchloric extract. The cells were cultured in RRlI 1640 medium containing 10% fetal calf serum and underwent a specific treatment for the mycoplasma removal (MU from FILM Laboratories). A NAD ADP 4TP arc II, minutes Fig.2 The HPLC W profile of lymphocytic extracts from HIV-1 seropositive patients at different stages of the disease: A -Asymptomatic, B -ARC and C -AIDS. (For healthy subject, see Fig. lA of the precedent communication).even higher. While we consider that our results are only preliminary, and that it is necessary to extend them to a larger population. we underline that infection with HIV-1 virus seems to involve several interations in purine nucleotide metabolismwhich may even differ in the various cells. These alterationa require further investigation.
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