As judged from the pattern of soluble cytokines in plasma and the effect of the plasma on monocyte activation by LPS, mild, localized infection can induce a systemic response that is predominantly anti-inflammatory.
As judged from the pattern of soluble cytokines in plasma and the effect of the plasma on monocyte activation by LPS, mild, localized infection can induce a systemic response that is predominantly anti-inflammatory.
Sera from human immunodeficiency viruspositive (HIV+; Walter Reed stage 6) individuals inhibit the interaction between recombinant human CD4 and recombinant gpl20 from HIV (rCD4 and rgpl2O, respectively), thereby interfering with the ability of soluble rCD4 to block infection with HIV or rCD4-toxin conjugates to kill HIV-infected cells.In this report we demonstrate that the inhibitory activity of such sera is caused primarily by anti-gpl20 antibodies that do not recognize the CD4 interaction site on gpl20. To circumvent the problem of inhibition, we have generated a construct containing a peptide of CD4 (residues 41-84) conjugated to ovalbumin (three to five peptides per molecule). This multivalent conjugate binds to rgpl20 and binding is not inhibited by antibodies in HIV+ sera.Sera from human immunodeficiency virus-positive (HIV+) individuals inhibit the binding of 1251I-labeled recombinant gpl20 from HIV (rgpl20) to CD4+ cells, whereas sera from HIV-individuals are only marginally inhibitory (1)(2)(3)(4)20). In one study, those sera that inhibited binding had high titers of anti-gp160/gpl20 antibodies, suggesting the involvement of these antibodies in blocking (2). In contrast, other reports suggest that there is no correlation between the ability of sera from HIV+ individuals to inhibit the binding of gp120 to CD4 and their titers of anti-gpl20 (3). This discrepancy could be explained by the observation that there are at least two types of anti-gp120 antibodies in the serum of patients with AIDS. One type is directed against the immunodominant epitope in the V3 domain of gpl20 (amino acids 308-332). Antibodies against this epitope may not always block the binding of gpl20 to CD4 (5-7). Another type is directed against the less immunogenic epitope on C3 (amino acids 397-439) that is involved in CD4 binding (4,8). The presence of antibody that can block the binding of CD4 to gp120 would seriously undermine CD4-based therapies for patients with AIDS (9, 10, 20). To circumvent this blocking by HIV+ sera, we have used smaller segments of the CD4 molecule. We describe CD4 peptides bound to ovalbumin (OVA) that bind to rgpl20 in the presence of antibodies presumably directed against sites on gp120 not involved in its interaction with CD4.
MATERIALS AND METHODSPreparation of Peptide-OVA Conjugates. CD4-derived peptides were synthesized on an Applied Biosystems model 430A solid-phase peptide synthesizer. These peptides contained (i) amino acid residues 40-57 (Gln-Gly-Ser-Phe-LeuThr-Lys-Gly-Pro-Ser-Lys-Leu-Asn-Asp-Arg-[3H]Ala-AspSer) to which alanine (penultimate) and cysteine (C-terminal) were added; (ii) amino acid residues 81-92 (Thr-Tyr-Ile-CysGlu-Val-Glu-Asp-Gln-Lys-Glu-Glu) with [3H]alanine at the N-terminal end; and (iii) amino acid residues 41-84 (Gly-SerPhe-Leu-Thr-Lys-Gly-Pro-Ser-Lys-Leu-Asn-Asp-Arg-AlaAsp-Ser-Arg-Arg-Ser-Leu-Trp-Asp-Gln-Gly-Asn-Phe-ProLeu-Ile-Ile-Lys-Asn-Leu-Lys-Ile-Glu-Asp-Ser-Asp-ThrTyr-Ile-Cys) with [3H]alanine in position 55. The peptides were purified by reverse-phase HPLC and ...
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