The major histocompatibility complex (MHC) loci are known to be highly polymorphic in humans, mice and certain other mammals, with heterozygosity as high as 80-90% (ref. 1). Four different hypotheses have been proposed to explain this high degree of polymorphism: (1) a high mutation rate, (2) gene conversion or interlocus genetic exchange, (3) over dominant selection and (4) frequency-dependent selection. In an attempt to establish which of these hypotheses is correct, we examined the pattern of nucleotide substitution between polymorphic alleles in the region of the antigen recognition site (ARS) and other regions of human and mouse class I MHC genes. The results indicate that in ARS the rate of nonsynonymous (amino acid altering) substitution is significantly higher than that of synonymous substitution in both humans and mice, whereas in other regions the reverse is true. This observation, together with a theoretical study and other considerations, supports the hypothesis of overdominant selection (heterozygote advantage).

Human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) infections are characterized by early peaks of viraemia that decline as strong cellular immune responses develop. Although it has been shown that virus-specific CD8-positive cytotoxic T lymphocytes (CTLs) exert selective pressure during HIV and SIV infection, the data have been controversial. Here we show that Tat-specific CD8-positive T-lymphocyte responses select for new viral escape variants during the acute phase of infection. We sequenced the entire virus immediately after the acute phase, and found that amino-acid replacements accumulated primarily in Tat CTL epitopes. This implies that Tat-specific CTLs may be significantly involved in controlling wild-type virus replication, and suggests that responses against viral proteins that are expressed early during the viral life cycle might be attractive targets for HIV vaccine development.

The loci of the vertebrate major histocompatibility complex encode cell-surface glycoproteins that present peptides to T cells. Certain of these loci are highly polymorphic, and the mechanisms responsible for this polymorphism have been intensely debated. Four independent lines of evidence support the hypothesis that MHC polymorphisms are selectively maintained: (a) The distribution of allelic frequencies does not fit the neutral expectation. (b) The rate of nonsynonymous nucleotide substitution significantly exceeds the rate of synonymous substitution in the codons encoding the peptide-binding region of the molecule. (c) Polymorphisms have been maintained for long periods of time ("trans-species polymorphism"). (d) Introns have been homogenized relative to exons over evolutionary time, suggesting that balancing selection acts to maintain diversity in the latter, in contrast to the former.

To study the mechanism of maintenance of polymorphism at major histocompatibility complex (MHC) loci, synonymous and nonsynonymous (amino, acid-altering) nucleotide substitutions in the putative antigen-recognition site (included in the first domain of the MHC molecule) and other regions of human and mouse class II genes were examined. In the putative antigen-recognition site, the rate of nonsynonymous substitution was found to exceed that of synonymous substitution, whereas in the second domain the former was significantly lower than the latter. In light of a previous theoretical study and parallel findings in class I MHC loci, we conclude that the unusually high degree of polymorphism at class II MHC loci is caused mainly by overdominant selection (heterozygote advantage) operating in the antigen-recognition site.The major histocompatibility complex (MHC) includes several genetic loci that are highly polymorphic in humans, mice, and other vertebrates (1). Four hypotheses have been proposed to account for this polymorphism: (i) an unusually high mutation rate (2), (ii) gene conversion or interlocus genetic exchange (3, 4), (iii) overdominant selection (5, 6), and (iv) frequency-dependent selection (7,8). To decide which of these hypotheses is correct, we previously studied rates of synonymous and nonsynonymous nucleotide substitution between alleles from human and mouse class I MHC loci and found that the nonsynonymous rate is higher than the synonymous rate in the 57 codons encoding the antigenrecognition site but is lower than the latter in other regions of the gene (9). Since overdominant selection is known to increase the rate of codon substitution as well as the extent of polymorphism (10), we concluded that class I polymorphism is caused mainly by overdominant selection that operates in the antigen-recognition site. Here we extend our analysis to class II MHC genes.Both class I and class II genes encode glycoproteins that are expressed on cell surfaces and that function to provide a context for recognition of intracellularly processed foreign peptides (antigens) by specific immune-system cells (1). Class I antigens are expressed on all nucleated cells, whereas class II antigens are expressed on antigen-presenting cells of the immune system, which present foreign antigens to helper T cells (1, 11). In the case of class I molecules, the amino acid residues involved in binding the foreign peptide and in T-cell recognition have been identified (12), making it possible to study the pattern of nucleotide substitution in the DNA region encoding the antigen-recognition site (ARS). In the case of class II molecules, the ARS has yet to be identified, but antigen recognition by helper T cells is known to be localized in the first domains of both a and (3 chains of the molecule, as opposed to the second domains (13,14).Furthermore, by analogy with the class I molecule, a putative ARS in domain 1 has been reported (15). In this paper we compare the rates of synonymous and nonsynonymous nucleotide substit...

Immunoglobulin and T-cell receptor (TCR) molecules are central to the adaptive immune system. Sequence conservation, similarities in domain structure, and usage of similar recombination signal sequences and recombination machinery indicate that there was probably a time during evolution when an ancestral receptor diverged to the modern-day immunoglobulin and TCR. Other molecules that undergo rearrangement have not been described in vertebrates, nor have intermediates been identified that have features of both these gene families. We report here the isolation of a new member of the immunoglobulin superfamily from the nurse shark, Ginglymostoma cirratum, which contains one variable and five constant domains and is found as a dimer in serum.

Engendering cytotoxic T-lymphocyte (CTL) responses is likely to be an important goal of HIV vaccines. However, CTLs select for viral variants that escape immune detection. Maintenance of such escape variants in human populations could pose an obstacle to HIV vaccine development. We first observed that escape mutations in a heterogeneous simian immunodeficiency virus (SIV) isolate were lost upon passage to new animals. We therefore infected macaques with a cloned SIV bearing escape mutations in three immunodominant CTL epitopes, and followed viral evolution after infection. Here we show that each mutant epitope sequence continued to evolve in vivo, often re-establishing the original, CTL-susceptible sequence. We conclude that escape from CTL responses may exact a cost to viral fitness. In the absence of selective pressure upon transmission to new hosts, these original escape mutations can be lost. This suggests that some HIV CTL epitopes will be maintained in human populations.

CD8(+) cytotoxic T lymphocytes (CTL) are thought to control hepatitis C virus (HCV) replication and so we investigated why this response fails in persistently infected individuals. The HCV quasispecies in three persistently infected chimpanzees acquired mutations in multiple epitopes that impaired class I MHC binding and/or CTL recognition. Most escape mutations appeared during acute infection and remained fixed in the quasispecies for years without further diversification. A statistically significant increase in the amino acid replacement rate was observed in epitopes versus adjacent regions of HCV proteins. In contrast, most epitopes were intact when hepatitis C resolved spontaneously. We conclude that CTL exert positive selection pressure against the HCV quasispecies and the outcome of infection is predicted by mutations in class I MHC restricted epitopes.

Cytotoxic T-lymphocyte (CTL) responses peak coincident with the decline in acute HIV viremia. Despite two reports of CTL-resistant HIV variants emerging during acute infection, the contribution of acute CTL escape to HIV pathogenesis remains unclear. Difficulties inherent in studying acute HIV infection can be overcome by modeling virus-host interactions in SIV-infected rhesus macaques. We sequenced 21 complete simian immunodeficiency virus (SIV)mac239 genomes at four weeks post-infection to determine the extent of acute CTL escape. Here we show that viruses from 19 of 21 macaques escaped from CTLs during acute infection and that these escape-selecting CTLs were responsive to lower concentrations of peptide than other SIV-specific CTLs. Interestingly, CTLs that require low peptide concentrations for stimulation (high 'functional avidity') are particularly effective at controlling other viral infections. Our results suggest that acute viral escape from CTLs is a hallmark of SIV infection and that CTLs with high functional avidity can rapidly select for escape variants.