Abstract
BackgroundHIV-1 infection of target cells is mediated via the binding of the viral envelope protein, gp120, to the cell surface receptor CD4. This interaction leads to conformational rearrangements in gp120 forming or revealing CD4 induced (CD4i) epitopes which are critical for the subsequent recognition of the co-receptor required for viral entry. The CD4-bound state of gp120 has been considered a potential immunogen for HIV-1 vaccine development. Here we report on an alternative means to induce gp120 into the CD4i conformation.ResultsCombinatorial phage display peptide libraries were screened against HIV-1 gp120 and short (14aa) peptides were selected that bind the viral envelope and allosterically induce the CD4i conformation. The lead peptide was subsequently systematically optimized for higher affinity as well as more efficient inductive activity. The peptide:gp120 complex was scrutinized with a panel of neutralizing anti-gp120 monoclonal antibodies and CD4 itself, illustrating that peptide binding does not interfere with or obscure the CD4 binding site.ConclusionsTwo surfaces of gp120 are considered targets for the development of cross neutralizing antibodies against HIV-1; the CD4 binding site and CD4i epitopes. By implementing novel peptides that allosterically induce the CD4i epitopes we have generated a viral envelope that presents both of these surfaces simultaneously.
Highlights
HIV-1 infection of target cells is mediated via the binding of the viral envelope protein, gp120, to the cell surface receptor CD4
Isolation of a novel gp120-binding peptide The HIV envelope undergoes conformational rearrangements upon association with CD4. These conformational changes can be monitored by the acquisition of binding of CD4 induced (CD4i) monoclonal antibodies (mAbs) that are specific for the CD4-complexed gp120
CD4i mAbs can be divided into two categories; relaxed mAbs that bind gp120 albeit with a preference for the gp120:CD4 complex, as is the case for mAb 17b [9,11]; and stringent CD4i mAbs (e.g., CG10, 19e and N12-i15 [14,15,16,17,25,38,39,40]) that have an absolute strict requirement for bound CD4 before gp120 can be recognized
Summary
HIV-1 infection of target cells is mediated via the binding of the viral envelope protein, gp120, to the cell surface receptor CD4 This interaction leads to conformational rearrangements in gp120 forming or revealing CD4 induced (CD4i) epitopes which are critical for the subsequent recognition of the co-receptor required for viral entry. The binding of HIV-1 gp120 to cellular CD4 is the first of these critical steps [1,2], triggering conformational rearrangements in both proteins, forming and revealing CD4 induced (CD4i) epitopes [3,4,5,6,7]. MAbs that target the CD4 binding site (CD4bs) and CD4i epitopes are generated and not surprisingly, constitute hallmark components of broadly cross neutralizing (BCN) serum of those HIV-1 infected individuals that are able to keep the virus in check (e.g. natural viral suppressors) [25,26,27,28,29,30,31]
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