Viral Peptides、病毒肽

Definition

Several viralpeptides are cytotoxic T lymphocytes (CTL) epitopes or H-2Db-restricted epitope, help in T cell receptor recognition process and there by clearance of virus-infected cells.

Discovery

Tsomides TJ et al., in 1994 have established an assay system based on several newly developed cell lines that stably and uniformly express HIV-1 and CTL obtained from HIV-seropositive individuals. They identified HIV peptides presented endogenously by MHC-I molecules 1. Such peptides can be extracted from virus-infected cells by acid elution. Both the naturally processed H–2-Db-restricted and H–2-Kd-restricted peptides from influenza nucleoprotein are smaller than the corresponding synthetic peptides, which have first been used to determine the respective CTL epitopes. As with minor histocompatibility antigens, occurrence of viral peptides seems to be heavily dependent on MHC class I molecules, because infected H–2d cells do not contain the H–2-Db-restricted peptide, and infected H–2b cells do not contain the H–2-Kd-restricted peptide. Data provide direct experimental proof for the above notion on MHC-associated viral peptides on virus-infected cells 2.

Structural Characteristics

The x-ray structures of a murine MHC class I molecule (H-2Kb) were determined in complex with two different viral peptides, derived from the vesicular stomatitis virus nucleoprotein, VSV-8, and the Sendai virus nucleoprotein, SEV-9. The H-2Kb complexes were refined at 2.3 ? for VSV-8 and 2.5 ? for SEV-9. The structure of H-2Kb exhibits a high degree of similarity with human HLA class I, although the individual domains can have slightly altered dispositions. Both peptides bind in extended conformations with most of their surfaces buried in the H-2Kb binding groove. The nanomer peptide maintains the same amino- and carboxyl-terminal interactions as the octamer primarily by the insertion of a bulge in the center of an otherwise beta conformation. Most of the specific interactions are between side-chain atoms of H-2Kb and main-chain atoms of peptide. This binding scheme accounts in large part for the enormous diversity of peptide sequences that bind with high affinity to class I molecules. Small but significant conformational changes in H-2Kb are associated with peptide binding, and these synergistic movements may be an integral part of the T cell receptor recognition process 3.

Mode of Action

MHC-restricted CTL play a central role in immune responses against many viruses by destroying virus infected cells. Unlike antibodies, CD8+ CTL recognize conserved sequences from intracellular viral proteins in addition to sequences from virus-encoded cell surface glycoproteins. Several viruses express genes that down-regulate expression of class I MHC proteins, thus providing them with a means of escape from cytotoxic T lymphocytes but rendering them susceptible to lysis by NK cells. The almost ubiquitous expression of class I MHC molecules provides one means by which NK cells discriminate among modified target cells that may have lost or down-regulated surface class I MHC molecule. The absence or dysregulation of class I MHC proteins may partially explain how NK cells survey tissue for the normal expression of class I MHC, the missing self hypothesis. Tumor cells down-regulate expression of class I MHC proteins, and those that express class I proteins are more resistant to killing by NK cells than derivatives that specifically lack class I MHC expression. Class I negative mutant cell lines sensitive to NK lysis can be rescued by transfection of appropriate class I MHC molecules 4,5.

Functions

Elimination of virus infected cell, virus-infected cells can be eliminated by CTL, which recognize virus-derived peptides bound to MHC class I molecules on the cell surface 2.

Natural killer (NK) cells are inhibited by specific allotypes of class I major histocompatibility complex ligands recognized by polymorphic inhibitory receptors (e.g., NKIR1 and NKIR2). NK1- and NK2-specific clones recognize two groups of HLA-C allotypes that are distinguished by a dimorphism at residue 80 in the α1 helix (αLys-80 and αAsn-80, respectively). Peptides derived from glutamic acid decarboxylase or coxsackie virus (each of which has been associated with autoimmune diabetes mellitus) abrogated this inhibitory recognition 6.

CD8 + CTL specific for diverse HIV products (e.g., gag, pol, nef, env) appear within 1-2 wk of infection, and the importance of these CTL is suggested by their unusually high frequencies: they can often be detected in freshly isolated PBMC without the in vitro antigenic stimulation usually required to demonstrate CTL activity in other viral infections  1.

References

Tsomides TJ, Aldovini A, Johnson RP, Walker BD, Young RA, Eisen HN (1994). Naturally processed viral peptides recognized by cytotoxic T lymphocytes on cells chronically infected by human immunodeficiency virus type 1. J Exp Med., 180(4):1283-1293.

Rötzschke O, Falk K, Deres K, Schild H, Norda M, Metzger J, Jung G, Rammensee HG (1990). Isolation and analysis of naturally processed viral peptides as recognized by cytotoxic T cells. Nature, 348(6298):252-254.

Fremont DH, Matsumura M, Stura EA, Peterson PA, Wilson IA (1992). Crystal structures of two viral peptides in complex with murine MHC class I H-2Kb. Science, 257(5072):919-927.

Ljunggren H-G, Karre K (1990). In search of the 'missing self': MHC molecules and NK cell recognition. Immunol Today., 11(7):237-244.

Kärre K, Ljunggren HG, Piontek G, Kiessling R. (1986). Selective rejection of H-2-deficient lymphoma variants suggests alternative immune defence strategy. Nature, 319:675–678.

Mandelboim O, Wilson SB, Valés-Gómez M, Reyburn HT, Strominger JL (1997). Self and viral peptides can initiate lysis by autologous natural killer cells. PNAS., 94(9):4604-4609.