PubMed Health⌕ Search

Biomedical subjects

M P Martin

Publications and source records attributed to M P Martin.

At least 19 recordsLinked to original sources
PubMed2006

The impact of variation at the KIR gene cluster on human disease.

Leukocyte behavior is controlled by a balance of inhibitory and stimulatory signals generated on ligand binding to a complex set of receptors located on the cell surface. The killer cell immunoglobulin-like receptor (KIR) genes encode one such, family of receptors expressed by natural killer (NK) cells, key components of the innate immune system that participate in early responses against infected or transformed cells through production of cytokines and direct cytotoxicity. KIRs are also expressed on a subset of T cells, where they contribute to the intensity of acquired immune responses. Recognition of self HLA class I ligands by inhibitory KIR allows NK cells to identify normal cells, preventing an NK cell-mediated response against healthy autologous cells. Activation of NK cells through stimulatory receptors is directed toward cells with altered expression of class I, a situation characteristic of some virally infected cells and tumor cells. The "missing self" model for NK cell activation was proposed to explain killing of cells that express little or no class I, while cells expressing normal levels of class I are spared. Studies performed over the last several years have revealed extensive diversity at the KIR gene locus, which stems from both its polygenic (variable numbers of genes depending on KIR haplotype) and multiallelic polymorphism. Given the role of KIR in both arms of the immune response, their specificity for HLA class I allotypes, and their extensive genomic diversity, it is reasonable to imagine that KIR gene variation affects resistance and susceptibility to the pathogenesis of numerous diseases. Consequently, the evolution of KIR locus diversity within and across populations may be a function of disease morbidity and mortality. Here we review a growing body of evidence purporting the influence of KIR polymorphism in human disease.

Autoimmune Diseases↗
PubMed2006

HLA class I diversity among rural rainforest inhabitants in Cameroon: identification of A*2612-B*4407 haplotype.

The population distribution of alleles of the classical HLA class I loci in Cameroon has not been well studied but is of particular interest given the AIDS and malarial epidemics afflicting this population. We investigated the genetic diversity of HLA-A, HLA-B and HLA-C alleles in remote populations of Cameroon. Subjects from seven small, isolated, indigenous populations (N = 274) in the rainforest of southern Cameroon were typed for HLA-A, HLA-B and HLA-C alleles using a polymerase chain reaction/sequence-specific oligonucleotide probe assay and sequence analysis. Multiple alleles of the HLA-A (N = 28), HLA-B (N = 41) and HLA-C (N = 21) loci were identified, of which A*2301[allele frequency (AF) = 12.8%], B*5802 (AF = 10.9%) and Cw*0401 (AF = 16.6%) were the most frequent individual alleles and A*02 (AF = 19.0%), B*58 (AF = 15.9%) and Cw*07 (AF = 22.4%) the most common serologically defined groups of alleles. Twenty-six (28.9%) alleles with a frequency of less than 1% (AF < 1%), 39 (43%) with a frequency of 2.0-15.0% (AF = 2.0-15.0%), three globally uncommon alleles [A*2612 (AF = 2.0%), B*4016 (AF = 0.7%) and B*4407 (AF = 1.4%)], and the A*2612-Cw*0701/06/18-B*4407 haplotype (haplotype frequency = 1.3%) were also identified. Heterozygosity values of 0.89, 0.92 and 0.89 were determined for HLA-A, HLA-B and HLA-C, respectively. The extensive allelic and haplotypic diversity observed in this population may have resulted from varied natural selective pressures on the population, as well as intermingling of peoples from multiple origins. Thus, from an anthropologic perspective, these data highlight the challenges in T-cell-based vaccine development, the identification of allogeneic transplant donors and the understanding of infectious disease patterns in different populations.

Cameroon↗
PubMed2006

Predation as a cause of neurologic signs and acute mortality in a pheasant flock.

A flock of approximately 15,000 ring-necked pheasants (Phasianus colchicus) was evaluated for a sudden increase in mortality and acute neurological signs after having been previously diagnosed 3 wk earlier with a chronic respiratory disease of undetermined etiology. Approximately 25 live birds were displaying neurological signs including circling, ataxia, and obtunded behavior and 50 birds were dead. Three birds with neurological signs were submitted for evaluation. Extensive subcutaneous hemorrhage over the head and penetrating puncture wounds through the skull and into the brain were found. Trauma from a wild predatory mammal, most likely the long-tailed weasel (Mustela frenata) that had invaded the pheasant house and expressed surplus killing behavior was determined to be the cause of the acute neurological signs and mortality. The relationship of the chronic respiratory disease to the predation episode was not determined but it is possible that pheasants with severe respiratory disease may have had increased susceptibility to predation.

Animals↗
PubMed2005

Human leukocyte antigen class I and II haplotypes and risk of cervical cancer.

Human leukocyte antigen (HLA) variations may affect immune response to human papillomavirus infection and subsequent cervical neoplasia risk. We investigated the frequency and relationship between HLA-A-B and HLA-A-B-DR haplotypes among women with cervical cancer/high-grade lesions (n=365) and cytologically normal population controls (n=681) within three cervical neoplasia studies in the US and Costa Rica. Notable differences in haplotype frequencies were observed; the HLA-A*01-B*08 haplotype occurred in >5% of US Caucasians but in <1% of Costa Ricans. The most prevalent HLA-A*24-B*40-DR*04 haplotype in Costa Rica (5%) was found in <1% of US Caucasians. No HLA haplotype was significantly associated with cervical neoplasia, suggesting that individual allele associations reported to date (e.g. HLA-DR*13) are not likely explained by underlying haplotypes.

Costa Rica↗
PubMed2001

Effect of a single amino acid change in MHC class I molecules on the rate of progression to AIDS.

BACKGROUND: From studies of genetic polymorphisms and the rate of progression from human immunodeficiency virus type 1 (HIV-1) infection to the acquired immunodeficiency syndrome (AIDS), it appears that the strongest susceptibility is conferred by the major-histocompatibility-complex (MHC) class I type HLA-B*35,Cw*04 allele. However, cytotoxic T-lymphocyte responses have been observed against HIV-1 epitopes presented by HLA-B*3501, the most common HLA-B*35 subtype. We examined subtypes of HLA-B*35 in five cohorts and analyzed the relation of structural differences between HLA-B*35 subtypes to the risk of progression to AIDS. METHODS: Genotyping of HLA class I loci was performed for 850 patients who seroconverted and had known dates of HIV-1 infection. Survival analyses with respect to the rate of progression to AIDS were performed to identify the effects of closely related HLA-B*35 subtypes with different peptide-binding specificities. RESULTS: HLA-B*35 subtypes were divided into two groups according to peptide-binding specificity: the HLA-B*35-PY group, which consists primarily of HLA-B*3501 and binds epitopes with proline in position 2 and tyrosine in position 9; and the more broadly reactive HLA-B*35-Px group, which also binds epitopes with proline in position 2 but can bind several different amino acids (not including tyrosine) in position 9. The influence of HLA-B*35 in accelerating progression to AIDS was completely attributable to HLA-B*35-Px alleles, some of which differ from HLA-B*35-PY alleles by only one amino acid residue. CONCLUSIONS: This analysis shows that, in patients with HIV-1 infection, a single amino acid change in HLA molecules has a substantial effect on the rate of progression to AIDS. The different consequences of HLA-B*35-PY and HLA-B*35-Px in terms of disease progression highlight the importance of the epitope specificities of closely related class I molecules in the immune defense against HIV-1.

Acquired Immunodeficiency Syndrome↗
PubMed2001

A dendritic cell-specific intercellular adhesion molecule 3-grabbing nonintegrin (DC-SIGN)-related protein is highly expressed on human liver sinusoidal endothelial cells and promotes HIV-1 infection.

The discovery of dendritic cell (DC)-specific intercellular adhesion molecule (ICAM)-3-grabbing nonintegrin (DC-SIGN) as a DC-specific ICAM-3 binding receptor that enhances HIV-1 infection of T cells in trans has indicated a potentially important role for adhesion molecules in AIDS pathogenesis. A related molecule called DC-SIGNR exhibits 77% amino acid sequence identity with DC-SIGN. The DC-SIGN and DC-SIGNR genes map within a 30-kb region on chromosome 19p13.2-3. Their strong homology and close physical location indicate a recent duplication of the original gene. Messenger RNA and protein expression patterns demonstrate that the DC-SIGN-related molecule is highly expressed on liver sinusoidal cells and in the lymph node but not on DCs, in contrast to DC-SIGN. Therefore, we suggest that a more appropriate name for the DC-SIGN-related molecule is L-SIGN, liver/lymph node-specific ICAM-3-grabbing nonintegrin. We show that in the liver, L-SIGN is expressed by sinusoidal endothelial cells. Functional studies indicate that L-SIGN behaves similarly to DC-SIGN in that it has a high affinity for ICAM-3, captures HIV-1 through gp120 binding, and enhances HIV-1 infection of T cells in trans. We propose that L-SIGN may play an important role in the interaction between liver sinusoidal endothelium and trafficking lymphocytes, as well as function in the pathogenesis of HIV-1.

Animals↗
PubMed2001

A novel upstream RNA polymerase III promoter element becomes essential when the chromatin structure of the yeast U6 RNA gene is altered.

The Saccharomyces cerevisiae U6 RNA gene, SNR6, possesses upstream sequences that allow productive binding in vitro of the RNA polymerase III (Pol III) transcription initiation factor IIIB (TFIIIB) in the absence of TFIIIC or other assembly factors. TFIIIC-independent transcription of SNR6 in vitro is highly sensitive to point mutations in a consensus TATA box at position -30. In contrast, the TATA box is dispensable for SNR6 transcription in vivo, apparently because TFIIIC bound to the intragenic A block and downstream B block can recruit TFIIIB via protein-protein interactions. A mutant allele of SNR6 with decreased spacing between the A and B blocks, snr6-Delta42, exhibits increased dependence on the upstream sequences in vivo. Unexpectedly, we find that in vivo expression of snr6-Delta42 is much more sensitive to mutations in a (dT-dA)(7) tract between the TATA box and transcription start site than to mutations in the TATA box itself. Inversion of single base pairs in the center of the dT-dA tract nearly abolishes transcription of snr6-Delta42, yet inversion of all 7 base pairs has little effect on expression, indicating that the dA-dT tract is relatively orientation independent. Although it is within the TFIIIB footprint, point mutations in the dT-dA tract do not inhibit TFIIIB binding or TFIIIC-independent transcription of SNR6 in vitro. In the absence of the chromatin architectural protein Nhp6, dT-dA tract mutations are lethal even when A-to-B block spacing is wild type. We conclude that the (dT-dA)(7) tract and Nhp6 cooperate to direct productive transcription complex assembly on SNR6 in vivo.

AT Rich Sequence↗
PubMed2000

Influence of CCR5 promoter haplotypes on AIDS progression in African-Americans.

OBJECTIVES: To test the hypothesis that the CCR5 promoter variants in HIV-1-infected African-Americans affect the rate of progression to AIDS and to determine the extent of linkage disequilibrium between the CCR5P1 allele and the CCR5 59029A variant (referred to here as CCR5-2459A), both of which have been shown independently to accelerate AIDS progression in Caucasians. DESIGN: We used survival analysis to assess the effects of CCR5 promoter variants in HIV-1 seroincident Caucasians and African-Americans. SUBJECTS AND METHODS: Genotypes were determined for 806 Caucasians and 1067 African-Americans, which included 700 seroconverters, enrolled in four HIV/AIDS natural history cohort studies. These genotypes were used to determine linkage and haplotypes for CCR2 and CCR5 alleles. Survival analysis was used to assess the effect of CCR2, CCR5, and CCR5 promoter haplotypes on progression to AIDS in seroincident African-Americans. RESULTS: A survey of Caucasians and African-Americans demonstrated complete linkage disequilibrium between CCR5P1 and CCR5-2459A sites. The composite CCR5P1 haplotype (including the CCR5-2459A allele) is shown to be associated with rapid progression to AIDS endpoints in both African-American and Caucasian cohorts, but the effect is recessive in Caucasians and dominant in African-Americans. This is probably due to the presence of modulating genes or as yet unidentified polymorphisms that may differ between racial groups.

Acquired Immunodeficiency Syndrome↗
PubMed2000

Formation of circular amplifications in Saccharomyces cerevisiae by a breakage-fusion-bridge mechanism.

Primary gene amplification, the mutation from one gene copy per genome to two or more copies per genome, is a major mechanism of oncogene overexpression in human cancers. Analysis of the structures of amplifications can provide important evidence about the mechanism of amplification formation. We report here the analysis of the structures of four independent spontaneous circular amplifications of ADH4:CUP1 in the yeast Saccharomyces cerevisiae. The structures of all four amplifications are consistent with their formation by a breakage-fusion-bridge (BFB) mechanism. All four of these amplifications include a centromere as predicted by the BFB model. All four of the amplifications have a novel joint located between the amplified DNA and the telomere, which results in a dicentric chromosome, and is adjacent to all the copies of the amplified DNA as predicted by the BFB model. In addition we demonstrated that two of the amplifications contain most of chromosome VII in an unrearranged form in a 1:1 ratio with the normal copy of chromosome VII, again consistent with the predictions of the BFB model. Finally, all four amplifications are circular, one stable endpoint for molecules after breakage- fusion-bridge.

Carrier Proteins↗
PubMed2000

Telomere sequences at the novel joints of four independent amplifications in Saccharomyces cerevisiae.

Primary gene amplification, the mutation from one copy of a gene per genome to two or more genes per genome is a major mechanism of oncogene overexpression. We previously developed a system in the yeast Saccharomyces cerevisiae to phenotypically detect primary amplifications of a reporter cassette, ADH4:CUP1. We present here the sequence analysis of novel joints from four independent, spontaneous circular amplifications identified by the ADH4:CUP1 system. All four novel joints consist of C(1-3) A telomeric repeats joined to short (14- to 16-bp) CA-rich tracts between ADH4 and the telomere of chromosome VII. In three of the four amplifications, the telomeric sequence and the CA-rich tract that are joined in the amplification are normally located in inverted orientation to each other on chromosome VII. In the fourth amplification, the CA-rich tract on chromosome VII is joined to telomere sequences from another chromosome. We suggest that formation of these amplifications was initiated by recombination between these CA-rich tracts and a telomere. The resulting dicentric chromosome could start a breakage-fusion-bridge cycle that could be resolved by the formation of a circular amplification structure.

Base Sequence↗
PubMed1999

HLA and HIV-1: heterozygote advantage and B*35-Cw*04 disadvantage.

A selective advantage against infectious disease associated with increased heterozygosity at the human major histocompatibility complex [human leukocyte antigen (HLA) class I and class II] is believed to play a major role in maintaining the extraordinary allelic diversity of these genes. Maximum HLA heterozygosity of class I loci (A, B, and C) delayed acquired immunodeficiency syndrome (AIDS) onset among patients infected with human immunodeficiency virus-type 1 (HIV-1), whereas individuals who were homozygous for one or more loci progressed rapidly to AIDS and death. The HLA class I alleles B*35 and Cw*04 were consistently associated with rapid development of AIDS-defining conditions in Caucasians. The extended survival of 28 to 40 percent of HIV-1-infected Caucasian patients who avoided AIDS for ten or more years can be attributed to their being fully heterozygous at HLA class I loci, to their lacking the AIDS-associated alleles B*35 and Cw*04, or to both.

Acquired Immunodeficiency Syndrome↗
PubMed1999

Effect of chemokine receptor mutations on heterosexual human immunodeficiency virus transmission.

To assess the effect of mutations at the CCR-2 and CCR-5 loci on heterosexual human immunodeficiency virus (HIV) transmission, 144 persons heterosexually exposed to HIV (infected and uninfected [EU]) and 57 HIV-positive index partners were genotyped. A significantly higher frequency of 64I heterozygotes at CCR-2 was observed in HIV-positive than in EU women (P=.02, relative risk=1.6). The allele frequency of 64I in women was 8% in HIV-positive contacts and 1% in EUs (P<.02). At CCR-5, no difference in the frequency of Delta32 was seen between groups, and the CCR-5 genotypes did not differ in accumulated "at-risk" exposure in EUs. Combining the analysis of the Delta32 and 64I mutations in index partners suggested an additive effect on transmission (P=.10). Thus heterozygosity for 64I at CCR-2 acts as a risk factor for HIV infection of women after heterosexual contact but heterozygosity for Delta32 at CCR-5 has no detectable effect.

Cohort Studies↗
PubMed1999

Genetics of HIV-1 infection: chemokine receptor CCR5 polymorphism and its consequences.

The chemokine receptor gene, CCR5, has become a central theme in studies of host genetic effects on HIV-1 pathogenesis ever since the discovery that the CCR5 molecule serves as a major cell surface co-receptor for the virus. A growing number of genetic variants within the coding and 5' regulatory region of CCR5 have been identified, several of which have functional consequences for HIV-1 pathogenesis. Here we review the CCR5 literature describing CCR5 polymorphism and the functional ramifications that several of these variants have on HIV-1 infection and progression to AIDS. The multiplicity of CCR5 genetic effects on HIV-1 disease underscores the critical importance of this gene in controlling AIDS pathogenesis and provides the logic for develop-ment of therapeutic strategies that target the interaction of HIV-1 envelope and CCR5 in HIV-1 associated disease.

Genetic Variation↗
PubMed1998

Genetic acceleration of AIDS progression by a promoter variant of CCR5.

The CCR5 gene encodes a cell surface chemokine receptor molecule that serves as the principal coreceptor, with CD4, for macrophage-tropic (R5) strains of human immunodeficiency virus-type 1 (HIV-1). Genetic association analysis of five cohorts of people with acquired immunodeficiency syndrome (AIDS) revealed that infected individuals homozygous for a multisite haplotype of the CCR5 regulatory region containing the promoter allele, CCR5P1, progress to AIDS more rapidly than those with other CCR5 promoter genotypes, particularly in the early years after infection. Composite genetic epidemiologic analyses of genotypes bearing CCR5P1, CCR5-Delta32, CCR2-64I, and SDF1-3'A affirmed distinct regulatory influences for each gene on AIDS progression. An estimated 10 to 17 percent of patients who develop AIDS within 3.5 years of HIV-1 infection do so because they are homozygous for CCR5P1/P1, and 7 to 13 percent of all people carry this susceptible genotype. The cumulative and interactive influence of these AIDS restriction genes illustrates the multigenic nature of host factors limiting AIDS disease progression.

Acquired Immunodeficiency Syndrome↗
PubMed1998

Characterization of 12 microsatellite loci of the human MHC in a panel of reference cell lines.

The human genome contains a large number of interspersed microsatellite repeats which exhibit a high degree of polymorphism and are inherited in a Mendelian fashion, making them extremely useful genetic markers. Several microsatellites have been described in the HLA region, but allele nomenclature, a set of broadly distributed controls, and typing methods have not been standardized, which has resulted in discrepant microsatellite data between laboratories. In this report we present a detailed protocol for genotyping microsatellites using a semi-automated fluorescence-based method. Twelve microsatellites within or near the major histocompatibility complex (MHC) were typed in the 10th International Histocompatibility Workshop homozygous typing cell lines (HTCs) and alleles were designated based on size. All loci were sequenced in two HTCs providing some information on the level of complexity of the repeat sequence. A comparison of allele size obtained by genotyping versus that obtained by direct sequencing showed minor discrepancies in some cases, but these were not unexpected given the technical differences in the methodologies. Fluorescence-based typing of microsatellites in the MHC described herein is highly efficient, accurate, and reproducible, and will allow comparison of results between laboratories.

Alleles↗