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116 In Vivo Alteration of the Highly Conserved 370 Residue of Human Immunodeficiency Virus Type 1 gp120 Determines Neutralization Sensitivity against CD4-Bnding Site and gp41-Directed Agents
T. Beaumont*1, A. van Nuenen1, S. Broersen1, D. Schols2, and H. Schuitemaker1
1CLB Sanquin and Univ. of Amsterdam, The Netherlands and 2Rega Inst. for Med. Res., Leuven, Belgium
We previously reported the reversion of the T-cell line-adapted human immunodeficiency virus type-1 (HIV-1) IIIB virus toward a neutralization-resistant phenotype in an accidentally infected laboratory worker. This increased resistance coincided with 38 amino acid substitutions in the gp120/gp41 envelope glycoprotein, among which was a change of the highly conserved glutamate to an alanine at amino acid position 370 (HXB2d sequence numbering). This residue is prominently situated in the core of gp120 within the CD4-binding site (bs) and is considered to make direct side-chain contact with CD4. Here we show, upon prolonged culturing of this Ala-370 HIV-IIIB variant, the outgrowth of a virus variant containing a glutamate at position 370. Glu-370 amino acid substitutions in vitro have indeed been described to result in a less viable virus, although the Ala-370 and Glu-370 variants here showed identical short term replication kinetics in PBMC. In contrast to the Ala-370 variant, the Glu-370 variant was highly sensitive to neutralization by soluble CD4 and the IgG1b12 MAb. Neutralization with agents directed against other viral epitopes was not influenced by the different 370 residues. Our data thus suggest that the in vivo selected mutations that confer neutralization resistance to agents other than CD4, compensate for the 370 Glu to Ala substitution, resulting in a similarly fit virus. In addition, in this background a Glu to Ala substitution at position 370 was sufficient to induce resistance to reagents directed against the CD4 binding site but interestingly increased the sensitivity to neutralization by anti-gp41-directed MAbs, suggesting an influence of this residue on the gp120-gp41 interaction.
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