Identification of human CD4 residues affecting class II MHC versus HIV-1 gp120 binding

Clayton, Linda K.; Sieh, Monica; Pious, Donald; Reinherz, Ellis L.

doi:10.1038/339548a0

Cited by 221 publications

(146 citation statements)

References 37 publications

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“…5). The results of the two experiments apparently confirmed the general correlation between gp120 binding and affinity to class II MHC observed with mutant CD4 molecules (6,7).…”

Section: Developing An Assay System For Evaluating the Coreceptor Funsupporting

confidence: 72%

“…Several reports have claimed that the loss of gp120 binding ability of the human CD4 molecule is unavoidably accompanied by the loss of its affinity to class II MHC molecules, which is essential for its coreceptor function (6,7). Nevertheless, these studies employed adhesion assays that did not involve specific recognition of MHC molecules by T cell receptor (TCR).…”

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confidence: 99%

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Coreceptor Function of Mutant Human CD4 Molecules without Affinity to gp120 of Human Immunodeficiency Virus

Tachibana¹,

Siddiqi²,

Ikegami³

et al. 2000

Journal of Biological Chemistry

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Despite extensive mutational studies on the human CD4 molecule and its affinity to human immunodeficiency virus (HIV) envelope glycoprotein gp120, coreceptor functions of such mutant molecules have only been examined by indirect measurement of their affinity to class II major histocompatibility complex (MHC) molecules. In this report, coreceptor functions of mutant human CD4 molecules, which have no or reduced affinity to an HIV envelope protein, gp120, were assessed in a murine T cell receptor/class II MHC recognition system. The substitution of human C؆ ␤ strand with the murine homologous segment resulted in the loss of the coreceptor function as well as in the complete loss of gp120 binding capacity, corroborating the consensus that Phe-43 in C؆ ␤ strand plays crucial roles in both situations. However, simultaneous replacement of the C-C؆ loop along with the C؆ ␤ strand by homologous murine segments rescued the coreceptor function, whereas gp120 binding capacity remained negative. Further analysis indicated that insertion of lysine between Gly-41 and Ser-42 can partially compensate for the coreceptor function lost by the Phe-43 3 Val mutation. Although the coreceptor function of these mutant CD4 molecules in a human T cell recognition system is yet to be determined, these observations necessitate a re-evaluation of the role played by Phe-43 in coreceptor function. Examination of the sensitivities of the mutant CD4 molecules expressed on HeLa cells to infection by a T cell-tropic HIV-1 strain indicated that only those mutants that had completely lost gp120 binding capacity were resistant to the infection. All mutants having whole C؆ substitution, irrespective of additional substitutions or their coreceptor functions, were resistant to the infection.The most serious consequence of the human immunodeficiency virus type 1 (HIV-1) 1 infection is the acquired immunodeficiency syndrome characterized by severe deficiency of CD4 ϩ T cell functions. Such deficiency of CD4 ϩ T cells stems from the affinity of an HIV envelope protein, gp120, to the human CD4 molecule (1). Several etiological mechanisms causing the functional deficiency of CD4 ϩ T cells are involved; 1) targeted infection of CD4 ϩ cells initiated by the binding of the virus to CD4, 2) cell fusion induced by binding of HIV viruses resulting in apoptosis of CD4 ϩ T cells, and 3) inhibition of the specific recognition of antigenic peptide/class II major histocompatibility complexes (MHCs) by soluble gp120. Extensive mutational analyses on the human CD4 molecule have identified a CЈ-CЉ ridge of the D1 domain as the gp120 binding area (2-4). The murine CD4 molecule has no affinity to gp120, although it shares 55% sequence homology of the extracellular portion with its human counterpart. Segmental as well as single amino acid substitutions of the human CD4 molecule with murine sequences confirmed the crucial role played by an aromatic ring of Phe-43 in gp120 binding (5).Several reports have claimed that the loss of gp120 binding ability of the human CD4 molecul...

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“…5). The results of the two experiments apparently confirmed the general correlation between gp120 binding and affinity to class II MHC observed with mutant CD4 molecules (6,7).…”

Section: Developing An Assay System For Evaluating the Coreceptor Funsupporting

confidence: 72%

mentioning

confidence: 99%

Coreceptor Function of Mutant Human CD4 Molecules without Affinity to gp120 of Human Immunodeficiency Virus

Tachibana¹,

Siddiqi²,

Ikegami³

et al. 2000

Journal of Biological Chemistry

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“…Mutations in the CDR1-and CDR2-like regions as well as outside the predicted CDR loops affected binding (16). However, the strongest effects were observed for mutations in the CC' and C"D corners of domain 1 and along the A strand of domain 2 of the four Ig-like domains in CD4 .…”

Section: Discussionmentioning

confidence: 85%

“…A mutational analysis of amino acids in CD4 important for MHC class II binding has also been reported (16,39) . Mutations in the CDR1-and CDR2-like regions as well as outside the predicted CDR loops affected binding (16).…”

Section: Discussionmentioning

confidence: 99%

“…Con A-activated y/S T cells that are CD4 -8-can be induced to express the CD8 homodimer on a subset of cells . Thus, CD8 is differentially expressed during development, cell activation, and in lymphocyte subsets.Direct binding of CD8 to HLA class I and CD4 to HLA class II was shown using cell-cell adhesion assays in which CD8 or CD4 were expressed at high levels on the surface ofchinese hamster ovary (CHO) cells for CD8 (14) or monkey CV1 or COS 1 cells for CD4 (15,16) . Purified class I and CD8 molecules expressed in lipid-sealed spherical nylon vesicles also showed specific binding (17).…”

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confidence: 99%

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Mutations in CD8 that affect interactions with HLA class I and monoclonal anti-CD8 antibodies.

Sanders

Fox

Kavathas

1991

The Journal of Experimental Medicine

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SummaryThe T cell co-receptor, CD8, binds to the 0 domain of HLA class I (Salter, R .D., R .J. Benjamin, P.K . Wesley, S .E. Buxton, T.P.J . Garrett, C. Clayberger, A.M . Krensky, A .M . Norman, D.R. Littman, and P Parham . 1990. Nature (Lond]. 345 :41; Connolly, J.M ., TA. Potter, E.M. Wormstall, and TH . Hansen. 1988 . J. ExpL Med. 168 :325 ; and Potter, TA., TV. Rajan, R.F. Dick II, and J .A . Bluestone . 1989 . Natur e (Lond.j. 337 :73). To identify regions of CD8 that are important for binding to HLA class I, we performed a mutational analysis of the CD8 molecule in the immunoglobulin (1g)-like variable domain. Our mutational analysis was based on our finding that using a cell-cell adhesion assay murine CD8 (Lyt-2) did not bind to human class I . Since the interaction of human CD8 with HLA class I is species specific, we substituted nonconservative amino acids from mouse CD8 and analyzed the ability of the mutated CD8 molecules expressed in COS 7 cells to bind HLA class I-bearing B lymphoblastoid cells, UC. Mutants with the greatest effect on binding were located in a portion of the molecule homologous to the first and second hypervariable regions of an antibody combining site. In addition, a panel of 12 anti-CD8 monoclonal antibodies were used to stain the 10 CD8 mutants, and amino acids that affected antibody binding were localized on the crystal structure of the BenceJones homodimer, REI . Support for an Ig-like structure of CD8 can be found in the pattern of substitutions affecting antibody binding. This work supports the similar tertiary structure of the CD8 a-terminal domain and an Ig variable domain.T he TCR-CD3 complex associates with CD8 or CD4 to form a multimeric complex interacting with peptide and HLA class I or HLA class II, respectively, during T cell activation . In addition to their function as adhesion molecules, CD8 and CD4 also serve as signalling molecules. The cytoplasmic domains of CD4 and CDSa bind to the NH2-terminal domain of the intracellular tyrosine protein kinase p56kk (1-3) . Antibody crosslinking of CD8 and CD4 to the TCR-CD3 complex leads to enhanced calcium flux and phosphorylation of a set of proteins, which includes the r chain of the TCR complex (4-6) . The ability of CD8 to induce these changes is dependent on its ability to associate with p56kk . CD8 and CD4 are also important for positive and negative selection in the thymus (7, 8). TCR specificity in T cell repertoire selection is determined by both the TCRa/(3 heterodimer and CD4 or CD8 accessory molecules (9, 10) .The human CD8 molecule is expressed either as an al a homodimer or as an a/(3 heterodimer. The homodimer is expressed exclusively on subsets of TCR-y/S cells and NK cells, and is co-expressed with CD80 on peripheral T cells and thymocytes . Individual human peripheral T cells can express varying amounts of CD8 a/a and alai complexes, and these appear to be differentially regulated upon T cell activation (11). CD8 expression can be induced on human CD4 cells upon activation with mitogens (12) and on murin...

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Immunoglobulin superfamily proteins: Structure, mechanisms, and drug discovery

Huang¹,

Li²,

Korngold³

1997

Biopolymers

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We review the recent progress made in our laboratories in structure‐based drug design targeting proteins of the immunoglobulin superfamily (IgSF). We will focus on the CD4 protein, which is involved in T cell function, as a specific example of how the general concept and methodologies can be applied. Recent studies of CD4 structure and function have revealed new insight into possible mechanisms for CD4 self‐association and its role in binding to major histocompatibility complex (MHC) class II molecules and initiation of T cell activation. This has led to the formulation of a hypothetical model of co‐oligomerization of CD4, MHC class II, and T cell receptor (TCR). Such a basic understanding of CD4 structure and mechanisms has aided the development of a new generation of potential immunotherapeutics targeting specific CD4 surface functional sites. The design and discovery of small molecular inhibitors of CD4 and other IgSF proteins, in peptide, peptidomimetic, and nonpeptidic organic forms have opened new avenues for chemical research in which peptide, organic, and more recently combinatorial chemistry techniques can be used to further develop these promising lead analogs into a new generation of effective pharmaceuticals. © 1998 John Wiley & Sons, Inc. Biopoly 43: 367–382, 1997

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Identification of human CD4 residues affecting class II MHC versus HIV-1 gp120 binding

Cited by 221 publications

References 37 publications

Coreceptor Function of Mutant Human CD4 Molecules without Affinity to gp120 of Human Immunodeficiency Virus

Coreceptor Function of Mutant Human CD4 Molecules without Affinity to gp120 of Human Immunodeficiency Virus

Mutations in CD8 that affect interactions with HLA class I and monoclonal anti-CD8 antibodies.

Immunoglobulin superfamily proteins: Structure, mechanisms, and drug discovery

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