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PubMed2005

Type 1 diabetes and the OAS gene cluster: association with splicing polymorphism or haplotype?

BACKGROUND: The 2',5'-oligoadenylate synthetase genes (OAS1, OAS2, and OAS3) map to human chromosome 12q24 and encode a family of enzymes pivotal to innate antiviral defence. Recently, the minor allele of an OAS1 single nucleotide polymorphism (SNP) that alters splicing (rs10774671) was found to be associated with increased enzymatic activity and, in a case-sibling control study, with type 1 diabetes (T1D). METHODS: We have confirmed this T1D association in 784 nuclear families (two parents and at least one affected offspring) by the transmission disequilibrium test (TDT; G:A = 386:329, p = 0.033). However, because of linkage disequilibrium within OAS1 and with the other two OAS genes, functional attribution of the association to this SNP cannot be assumed. To help answer this question, we also genotyped two non-synonymous SNPs in OAS1 exons 3 and 7. RESULTS: All three SNPs showed significant transmission distortion. Three of the eight possible haplotypes accounted for 98.4% of parental chromosomes and two of them carried the non-predisposing A allele at rs10774671. Parents heterozygous for these two haplotypes showed significant transmission distortion (p = 0.009) despite being homozygous at rs10774671. CONCLUSIONS: We confirm the T1D association with rs10774671, but we conclude that it cannot be attributed (solely) to the splicing variant rs10774671. A serine/glycine substitution in OAS1 exon 3 is more likely a functional variant.

2',5'-Oligoadenylate Synthetase↗

PubMed1992

Genetic differences accounting for evolution and pathogenicity of simian immunodeficiency virus from a sooty mangabey monkey after cross-species transmission to a pig-tailed macaque.

We determined the nucleotide sequences of two related isolates of simian immunodeficiency virus from the sooty mangabey monkey (SIVsmm) that exhibit dramatic differences in virulence. These isolates are separated by one experimental cross-species transmission, from sooty mangabey to pig-tailed macaque. The parental virus (SIVsmm9), nonpathogenic in the original host (sooty mangabeys), causes a chronic AIDS-like disease in macaques. In contrast, the variant virus (SIVsmmPBj14) induces an acute lethal disease in various macaque species and is also pathogenic for sooty mangabeys. The combination of necessary and sufficient mutations that determined the acutely lethal phenotype on the SIVsmm9 genetic background is included within a maximal set of 57 point mutations, plus two insertions located in the long terminal repeat (22 bp spanning an NF-kappa B-like enhancer element) and in the surface envelope glycoprotein (5 amino acids). Comparisons of synonymous and nonsynonymous nucleotide substitutions in the genome of SIVsmm indicated that selective pressures, probably due to the host immune response, favored amino acid changes in the envelope. This immunoevolutionary mechanism could explain the increase in diversity and the apparition of new virulent phenotypes after cross-species transmission.

Animals↗

PubMed1997

Evolutionary dynamics of genetic variation in Epstein-Barr virus isolates of diverse geographical origins: evidence for immune pressure-independent genetic drift.

The question whether immune pressure exerted by cytotoxic T lymphocytes (CTLs) can influence the long-term evolution of genetically stable viruses such as Epstein-Barr virus (EBV) has generated considerable scientific interest, primarily due to its important implications for the overall biology of the virus. While arguing for a role of CTLs in the evolution of viruses, it is important to differentiate between genetic variation in virus and immune recognition of these variant virus by CTLs. To assess the role of genetic selection in the long-term evolution of EBV, we have analyzed a large panel of type 1 EBV isolates from African, Southeast Asian, Papua-New Guinean (PNG), and Australian Caucasian individuals. Seven different regions of the EBV genome, which include nine CTL epitopes restricted through a range of HLA class I alleles, were sequenced and compared. Although numerous nucleotide changes were identified within these isolates, comparison of synonymous and nonsynonymous substitutions in the CTL epitope indicated that the genetic variation was generated mostly independently of immune selection pressure. Surprisingly, an inverse correlation between genetic variation within certain CTL epitopes and the frequency distribution of HLA alleles that present the CTL epitopes was seen, suggesting that the evolutionary pressures on the CTL epitopes of the virus may be toward their conservation rather than their inactivation. Furthermore, molecular evolutionary genetic analysis of nucleotide sequences revealed that viral isolates from PNG are evolving as a lineage distinct from isolates from African, Southeast Asian, and Australian Caucasian individuals.

Amino Acid Sequence↗

PubMed2003

Non-synonymous single nucleotide alterations in the microsomal epoxide hydrolase gene and their functional effects.

1. By sequencing genomic DNA from 72 established cell lines derived from Japanese individuals, we detected 25 single nucleotide alterations in the microsomal epoxide hydrolase (EPHX1) gene. Of them, five were exonic alterations resulting in amino acid alterations (77C>G, T26S; 128G>C, R43T; 337T>C, Y113H; 416A>G, H139R; 823A>G, T275A). The T26S, R43T, Y113H and H139R substitutions were found at relatively high frequencies and seemed to be polymorphic, and T26S and T275A were novel. 2. To examine the effects of these amino acid alterations on EPHX1 function, EPHX1 cDNA constructs of wild-type and five variants were transfected into COS-1 cells, and their hydrolytic activities for cis-stilbene oxide were determined in vitro. Although all of the transfectants expressed EPHX1 mRNA and protein at similar levels, the variant H139R protein was expressed at a significantly higher level (128% of the wild-type). K(m) values were not significantly different between the wild-type and variants. 3. Increase (140%) in the enzymatic activity (V(max)) of the variant H139R was accompanied by the increased EPHX1 protein level without any significant change in the intrinsic EPHX1 activity. On the other hand, the variant R43T showed increased values for V(max) and clearance (V(max)/K(m)) (around 130%) both on a microsomal protein basis and on a EPHX1 protein basis. 4. These results suggest that R43T as well as H139R increase epoxide hydrolase activity.

Amino Acid Substitution↗

PubMed2006

Evidence for association of DNA sequence variants in the phosphatidylinositol-4-phosphate 5-kinase IIalpha gene (PIP5K2A) with schizophrenia.

Linkage studies in schizophrenia have identified a candidate region on chromosome 10p14-11 as reported for several independent samples. We investigated association of DNA sequence variants in a plausible candidate gene located in this region, the gene for phosphatidylinositol-4-phosphate 5-kinase IIalpha (PIP5K2A), in a sample of 65 sib-pair families for which linkage had been reported. Evidence for association was obtained for 15 polymorphisms spanning 73.6 kb in the genomic region of the gene between intron 4 and the 3' untranslated region, a region with high degree of linkage disequilibrium. Single nucleotide polymorphism (SNP) rs10828317 located in exon 7 and causing a non-synonymous amino-acid exchange (asparagine/serine) produced a P-value of 0.001 (experiment-wide significance level 0.00275) for over-transmission of the major allele coding for serine, analysed by transmission disequilibrium test using FAMHAP. Association of this SNP with schizophrenia has been also described in a sample of 273 Dutch schizophrenic patients and 580 controls (P=0.0004). PIP5K2A is involved in the biosynthesis of phosphatidylinositol-4,5-bisphosphate (PI(4,5)P2), one of the key metabolic crossroads in phosphoinositide signalling. PI(4,5)P2 plays a role in membrane transduction of neurotransmitter signals as well as in intracellular signalling, pathways that may be impaired in schizophrenia.

Base Sequence↗

PubMed2025

SARS-CoV-2 genomic diversity and within-host evolution in individuals with persistent infection in the UK: an observational, longitudinal, population-based surveillance study.

BACKGROUND: Persistent SARS-CoV-2 infections in hospitalised immunocompromised individuals are known to facilitate accelerated within-host viral evolution, potentially contributing to the emergence of highly divergent variants. However, little is known about the evolutionary dynamics and transmission risks of persistent infections in the general population. We aimed to characterise the within-host evolution of SARS-CoV-2 during persistent infections identified through a large community surveillance study. METHODS: We used data from the Office for National Statistics COVID-19 Infection Survey (ONS-CIS), a large-scale, longitudinal, population-based surveillance study conducted in the UK from April, 2020, to March, 2023. For this analysis, we focused on infections with high viral load (cycle threshold ≤30) and available genome sequences, from seven major SARS-CoV-2 lineages (alpha, delta, BA.1, BA.2, BA.4, BA.5, and XBB). ONS-CIS participants were randomly selected from the general population and tested regularly by RT-PCR, regardless of symptoms. We defined persistent infections as those with sustained or rebounding high viral RNA titres for 26 days or longer. We examined associated host characteristics and used raw sequence data to identify de novo mutations and estimate within-host synonymous and non-synonymous evolutionary rates across the SARS-CoV-2 genome. FINDINGS: Between Nov 2, 2020, and March 21, 2023, we identified 576 persistent infections with at least two sequences, including 11 alpha, 106 delta, 102 BA.1, 204 BA.2, 16 BA.4, 133 BA.5, and 4 XBB. Persistent infections were more common in males than females (p<0·0001) and individuals older than 60 years (p=0·0027). The median within-host genome-wide evolutionary rate was 7·9 × 10-4 substitutions per site per year (IQR 7·0-9·0 × 10-4), with high inter-individual variability driven largely by non-synonymous mutations, particularly in the N-terminal and receptor-binding domains of the spike protein. Longer infection duration was associated with higher evolutionary rates, while no associations were found with age, sex, vaccination status, previous infection, or virus lineage. We found no clear evidence of transmission beyond the first month of infection in any of the 84 persistent infections lasting 56 days or longer. In total, we identified 379 recurrent mutations, including many with known or predicted negative fitness effects and low prevalence at the population level, as well as de novo reversions to the Wuhan-Hu-1 reference sequence, which were likely under positive selection within those individuals. INTERPRETATION: This study highlights the heterogeneous nature of within-host SARS-CoV-2 evolution in individuals with persistent infection in the community. Notably, a small subset of persistent infections with high viral loads underwent accelerated viral evolution or recurrently acquired hallmark mutations found in novel variants. In addition, onward transmission from a persistent infection during the later stages of infection is likely to be rare. These insights have important implications for prioritising genomic surveillance and managing patients with persistent infections. FUNDING: Department of Health and Social Care.

Humans↗

PubMed1996

The evolutionary rate of nonpathogenic simian immunodeficiency virus (SIVagm) is in agreement with a rapid and continuous replication in vivo.

African green monkeys (AGMs) are divided into four species (Cercopithecus aethiops, C. pygerythrus, C. sabaeus, C. tantalus), each harboring a species-specific simian immunodeficiency virus (SIVagm). Little is known about the host and/or viral factors that are responsible for the apathogenicity of SIVagm infections in their natural hosts. In order to analyze the specific selective pressures exerted by the host on the virus in vivo, we compared the genetic evolution of SIVagm.tan in its natural host (C. tantalus) and in a foreign host species (Erythrocebus patas), in which we could obtain a reproducible and persistent infection by SIVagm.tan. As in AGMs, patas monkeys do not develop any disease following SIVagm infection. Our longitudinal study in env (V3-C3-V4-C4-V5) of SIVagm.tan from three AGMs and three patas monkeys revealed a high ratio of synonymous to nonsynonymous mutation frequencies (1.5-6.2). These data indicate that the selective pressures for stability exerted by AGMs and patas monkeys on SIVagm override positive selection for change reported in pathogenic HIV-1 infections. The rapid accumulation of mutations observed in AGMs and patas monkeys (0.4-7.2 x 10(-2) nucleotide substitutions per site per year) suggests a continuous replication of SIVagm viruses in vivo. We thus propose that nonpathogenic SIVagm infections are the result of a long-term selection of SIVagm variants whose dissemination can be controlled in the host, rather than being explained by a low ability of the virus to replicate in vivo.

Amino Acid Sequence↗

PubMed2005

[Malignant fibrous histiocytoma: pleomorphic sarcoma NOS or pleomorphic fibrosarcoma].

The entity and nosology of pleomorphic malignant fibrous histiocytoma (MFH) is still ambiguous. The actual WHO-Classification uses pleomorphic malignant fibrous histiocytoma (MFH) and pleomorphic sarcoma NOS (not otherwise specified) synonymously. On the other hand text and illustrations convey the impression, that these tumors also could be pleomorphic lipo-, leio- or rhabdomyosarcomas etc. It would have been more informative to emphasize, that with the above mentioned specific sarcoma types MFH-like appearance may occur. Furthermore it would have been more up to date to consider pleomorphic sarcomas NOS as pleomorphic fibrosarcomas and include them in the chapter of fibroblastic and myofibroblastic tumors. This concept already has been carried out for the former myxoid variant of MFH, nowadays preferentially called myxofibrosarcoma. There is controversial discussion about the clinical significance of exact typing of pleomorphic sarcomas. Problems may also occur due to the lack of standards, which degree of desmin expression signifies leiomyosarcoma or just indicates myofibroblasts in MFH. The requirement of exclusion of other tumor-types before diagnosing pleomorphic fibrosarcoma still remains obligatory. After verification of the diagnosis pleomorphic sarcoma NOS or pleomorphic fibrosarcoma, grading e.g. according to criteria of the FFCCS can be carried out. Most cases of pleomorphic fibrosarcoma will qualify as high grade malignant.

Diagnosis, Differential↗

PubMed2000

Neutral evolution of the sex-determining gene transformer in Drosophila.

The amino acid sequence of the transformer (tra) gene exhibits an extremely rapid rate of evolution among Drosophila species, although the gene performs a critical step in sex determination. These changes in amino acid sequence are the result of either natural selection or neutral evolution. To differentiate between selective and neutral causes of this evolutionary change, analyses of both intraspecific and interspecific patterns of molecular evolution of tra gene sequences are presented. Sequences of 31 tra alleles were obtained from Drosophila americana. Many replacement and silent nucleotide variants are present among the alleles; however, the distribution of this sequence variation is consistent with neutral evolution. Sequence evolution was also examined among six species representative of the genus Drosophila. For most lineages and most regions of the gene, both silent and replacement substitutions have accumulated in a constant, clock-like manner. In exon 3 of D. virilis and D. americana we find evidence for an elevated rate of nonsynonymous substitution, but no statistical support for a greater rate of nonsynonymous relative to synonymous substitutions. Both levels of analysis of the tra sequence suggest that, although the gene is evolving at a rapid pace, these changes are neutral in function.

Animals↗

PubMed2001

Evolutionarily conserved RNA secondary structures in coding and non-coding sequences at the 3' end of the hepatitis G virus/GB-virus C genome.

Hepatitis G virus (HGV)/GB virus C (GBV-C) causes persistent, non-pathogenic infection in a large proportion of the human population. Epidemiological and genetic evidence indicates a long-term association between HGV/GBV-C and related viruses and a range of primate species, and the co-speciation of these viruses with their hosts during primate evolution. Using a combination of covariance scanning and analysis of variability at synonymous sites, we previously demonstrated that the coding regions of HGV/GBV-C may contain extensive secondary structure of undefined function (Simmonds & Smith, Journal of Virology 73, 5787-5794, 1999 ). In this study we have carried out a detailed comparison of the structure of the 3'untranslated region (3'UTR) of HGV/GBV-C with that of the upstream NS5B coding sequence. By investigation of free energies on folding, secondary structure predictive algorithms and analysis of covariance between HGV/GBV-C genotypes 1-4 and the more distantly related HGV/GBV-C chimpanzee variant, we obtained evidence for extensive RNA secondary structure formation in both regions. In particular, the NS5B region contained long stem-loop structures of up to 38 internally paired nucleotides which were evolutionarily conserved between human and chimpanzee HGV/GBV-C variants. The prediction of similar structures in the same region of hepatitis C virus may allow the functions of these structures to be determined with a more tractable experimental model.

3' Untranslated Regions↗

PubMed2000

Influence of age and HLA type on interferon-gamma (IFN-gamma) responses to a naturally occurring polymorphic epitope of Plasmodium falciparum liver stage antigen-1 (LSA-1).

Antigenic polymorphism and HLA restriction may limit the immunogenicity of a subunit vaccine against liver-stage Plasmodium falciparum. We examined 59 clinical isolates and five laboratory clones of P. falciparum for polymorphism in the N- and C-terminal regions of LSA-1, evaluated binding of the corresponding peptides to selected HLA class I alleles, and measured IFN-gamma responses in residents of a malaria-endemic area of Papua New Guinea where HLA-A*1101, -24, -B13, and -B40 are the most common class I alleles. LSA-1 polymorphism was limited to a single non-synonymous mutation encoding serine (S), proline (P), or threonine (T) at amino acid 85. Nine-mer 84-92 peptides with S, T, or P at the primary anchor position bound differentially to HLA-A11, -A2, and -B7. IFN-gamma ELISPOT responses increased with age in malaria-exposed subjects: 14-16% and 30-36% of 2-5- and 6-54-year-olds, respectively, had > or =10 IFN-gamma-secreting cells/106 peripheral blood mononuclear cells when stimulated with at least one peptide variant (P<0.05). IFN-gamma responses to all three peptides were also greater for older than younger individuals. No children < 3 years old had lymphocytes that responded to all three 84-92 peptides, whereas 45% of adults (mean age 48 years) had aggregated IFN-gamma responses. These data support the notion that age-related cumulative exposure to P. falciparum increases the frequency of IFN-gamma responses to polymorphic epitopes of liver-stage antigens such as LSA-1.

Adolescent↗

PubMed1978

The proportion of all point mutations which are unacceptable: an estimate based on hemoglobin amino acid and nucleotide sequences.

Statistical analysis of the distribution of 156 kinds of human hemoglobin beta (Hbbeta) chain variants suggests that mutations are essentially random in their location. Thus differential fitness, not differential mutability, is the principal source of nonrandom distribution of interspecies differences in Hbbeta amino acid sequence. Similar analyses of both the location and the kind of interspecies differences detected among primates support this viewpoint and lead us to estimate that at least 95% of all amino acid subsitutions,i.e., nonsynonymous mutations, in Hbbeta are functionally unacceptable in homozygous state. Through the combined use of this estimate and the number of nonsynonymous and synonymous substitutions per nucleotide site inferred from comparisons of entire human and rabbit HbbetamRNA nucleotide sequences, we calculate (a) approximately 70% of synonymous Hbbeta mutations are adaptively undersirable and (b) the mutation rate underlying all changes is lesser than or equal to 10(-8) nucleotide substitutions per nucleotide site per year. Apart from such calculations, analyses of nucleotide patterns in HbbetamRNA as well as in rat preproinsulin mRNA reinforce the notion that a large portion of synonymous mutations are functionally unacceptable and rendered so by selective constraint, at a pretranslational level, of the abundance of particular nucleotide doublets such as CpG.

Amino Acid Sequence↗

PubMed2006

SSADH variation in primates: intra- and interspecific data on a gene with a potential role in human cognitive functions.

In the present study we focus on the nucleotide and the inferred amino acid variation occurring in humans and other primate species for mitochondrial NAD(+)-dependent succinic semialdehyde dehydrogenase, a gene recently supposed to contribute to cognitive performance in humans. We determined 2527 bp of coding, intronic, and flanking sequences from chimpanzee, bonobo, gorilla, orangutan, gibbon, and macaque. We also resequenced the entire coding sequence on 39 independent chromosomes from Italian families. Four variable coding sites were genotyped in additional populations from Europe, Africa, and Asia. A test for constancy of the nonsynonymous vs. synonymous rates of nucleotide changes revealed that primates are characterized by largely variable d(N)/d(S) ratios. On a background of strong conservation, probably controlled by selective constraints, the lineage leading to humans showed a ratio increased to 0.42. Human polymorphic levels fall in the range reported for other genes, with a pattern of frequency and haplotype structure strongly suggestive of nonneutrality. The comparison with the primate sequences allowed inferring the ancestral state at all variable positions, suggesting that the c.538(C) allele and the associated functional variant is indeed a derived state that is proceeding to fixation. The unexpected pattern of human polymorphism compared to interspecific findings outlines the possibility of a recent positive selection on some variants relevant to new cognitive capabilities unique to humans.

Adaptation, Biological↗

PubMed2005

Restriction enzyme analysis of RT-PCR amplicons as a rapid method for detection of genetic diversity among bovine respiratory syncytial virus isolates.

Our current knowledge of antigenic variability of the bovine respiratory syncytial virus (BRSV) is quite limited and is mainly dependent on the use of monoclonal antibodies (mAb). In this study, we present not only analysis of the antigenic, but also of the genetic variability of BRSV. Using a panel of BRSV-specific mAb we distinguished five main reactivity patterns, three of which corresponded to the previously established subgroups A, B and AB. A single viral strain yielded the fourth pattern, while four viral strains did not react with any of the used mAbs forming the fifth pattern. To investigate the genetic basis for the antigenic heterogeneity of the BRS virus G protein, DNA of 11 BRSV isolates was directly sequenced. The comparison of the obtained nucleotide or amino acid sequences to those BRSV strains present in the GenBank revealed 88.1-99.4% and 77.7-98.4% similarity, respectively. These results supported the previously stated suggestion to type BRSV isolates according to their genetic relationship. In order to introduce a rapid and simple method to study the genetic variability of BRSV, we utilized the restriction enzyme analysis of RT-PCR products derived from mRNAs corresponding to the most variable region of the BRSV glycoprotein G ectodomain. Using this restriction enzyme analysis we were able to identify genetic variability among BRSV isolates. The detected non-synonymous mutations led frequently to a change in digestion pattern and were predominantly located in two mucin-like regions of the G protein gene. A correlation has been found between grouping of isolates in the phylogenetic tree and their restriction patterns clustering together isolates with the same restriction profiles. However, viruses placed distant in the tree sharing the same restriction patterns were detected supposing that phylogenetic analysis should be necessary for BRSV typing. Thus, we propose to use DNA restriction polymorphism for a rapid detection of genetic variants among BRSV isolates circulating in cattle population and as a preliminary tool for their typing.

Amino Acid Sequence↗

PubMed2003

Human catecholamine sulfotransferase (SULT1A3) pharmacogenetics: functional genetic polymorphism.

Sulfotransferase (SULT) 1A3 catalyzes the sulfate conjugation of catecholamines and structurally related drugs. As a step toward studies of the possible contribution of inherited variation in SULT1A3 to the pathophysiology of human disease and/or variation in response to drugs related to catecholamines, we have resequenced all seven coding exons, three upstream non-coding exons, exon-intron splice junctions and the 5'-flanking region of SULT1A3 using DNA samples from 60 African-American (AA) and 60 Caucasian-American (CA) subjects. Eight single nucleotide polymorphisms (SNPs) were observed in AA and five in CA subjects, including one non-synonymous cSNP (Lys234Asn) that was observed only in AA subjects with an allele frequency of 4.2%. This change in amino acid sequence resulted in only 28 +/- 4.5% (mean +/- SEM) of the enzyme activity of the wild-type (WT) sequence after transient expression in COS-1 cells, with a parallel decrease (54 +/- 2.2% of WT) in level of SULT1A3 immunoreactive protein. Substrate kinetic studies failed to show significant differences in apparent Km values of the two allozymes for either dopamine (10.5 versus 10.2 micro m for WT and variant, respectively) or the cosubstrate 3'-phosphoadenosine 5'-phosphosulfate (0.114 versus 0.122 micro m, respectively). The decrease in level of immunoreactive protein in response to this single change in amino acid sequence was due, at least in part, to accelerated SULT1A3 degradation through a proteasome-mediated process. These observations raise the possibility of ethnic-specific inherited alterations in catecholamine sulfation in humans.

Black or African American↗

PubMed1985

A comparative study of albumin variants found in Brazil.

10 rare albumin variants found in Brazil have been compared with 6 others, discovered elsewhere, through horizontal starch gel electrophoresis in four buffer systems. Belém V can be clearly distinguished from Naskapi but shows the same mobility as Máku (= Belém III) in two different pHs. Coari II, Manaus I and Porto Alegre II can be separated from all others in three buffer systems. Belém II (= Mexico) and Belém I also show unique patterns, but Coari I, Porto Alegre I and Belém IV could not be distinguished from Santa Ana. The possibly synonymous Belém III-Belém V-Máku should have originated from an Amerindian gene pool, but Coari I-Porto Alegre I-Belém IV-Santa Ana may have a Caucasoid origin.

Adult↗

PubMed1999

Language-independent automatic acquisition of morphological knowledge from synonym pairs.

Medical words exhibit a rich and productive morphology. Beyond simple inflection, derivation and composition are a common way to form new words. Morphological knowledge is therefore very important for any medical language processing application. Whereas rich morphological resources are available for the English medical language with the UMLS Specialist Lexicon, no such resources are publicly available for French or most other languages. We propose a simple and powerful method to help acquire automatically such knowledge. This method takes advantage of the synonym terms present in medical terminologies. In a bootstrapping step, it detects morphologically related words from which it learns "derivation rules". In an expansion step, it then applies these rules to the whole vocabulary available. Our goal is to acquire data for French and other languages for which they are not available. However, to evaluate the efficiency of the method, we tested it on English in a setting which is close to that prevailing for French, and we confronted its results to those obtained with the Specialist lexical variant generation tool.

Electronic Data Processing↗

PubMed1992

Cytotoxic T lymphocytes do not appear to select for mutations in an immunodominant epitope of simian immunodeficiency virus gag.

Studies to date assessing HIV escape from CTL in vivo have yielded conflicting results. Previous studies have demonstrated that simian immunodeficiency virus of macaques (SIVmac)-infected rhesus monkeys expressing the MHC class I allele Mamu-A*01 reproducibly develop a gag-specific CTL response limited to a 9-amino acid epitope of the SIVmac gag protein (residues 182-190 within peptide 11C). To determine whether CTL have a role in selecting for AIDS virus mutants, we examined mutations in SIVmac proviral DNA encoding this gag CTL epitope in PBL of infected rhesus monkeys. Three Mamu-A*01+ rhesus monkeys were infected with SIVmac and assessed for gag- and peptide 11C-specific CTL responses. This specific CTL response was maintained in two monkeys, but lost in the third animal 2 yr after infection. The generation of proviral gag mutations was then determined by sequencing 500-bp proviral fragments amplified from fresh PBL obtained from the monkeys more than 2.5 yr after infection. Although numerous point mutations were characterized in 131 polymerase chain reaction-generated clones of SIVmac gag, only four mutations within the gag CTL epitope-coding region of the genome were identified. Comparison of synonymous and nonsynonymous nucleotide substitutions in the regions encoding peptide 11C (p11C) and the flanking gag protein indicated a lack of selective pressure for viral mutations in the CTL epitope coding region. Interestingly, a predominant gag mutant encoding a single amino acid change in p11C was found in a monkey which lost its CTL activity. However, even in this setting there was no evidence for selection of mutations in the CTL epitope coding region when compared with the flanking region. Furthermore, synthetic peptides corresponding to all naturally occurring variants in the gag epitope-coding region were recognized by cloned and bulk cultured effector cells of the infected monkeys with persistent CTL. These results indicate that SIVmac gag- and p11C-specific CTL do not select for mutations in the immunodominant epitope-coding region and that the naturally occurring mutants do not appear to escape CTL recognition.

Amino Acid Sequence↗