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Biomedical subjects

G M Shaw

Publications and source records attributed to G M Shaw.

At least 181 records · Page 10Linked to original sources
PubMed1990

Type-specific antigens for serological discrimination of HTLV-I and HTLV-II infection.

55 HTLV-I (human T-cell lymphotropic virus) and 45 HTLV-II carriers, confirmed by HTLV-type specific polymerase chain reaction (PCR), were distinguished by western blot assays with recombinant HTLV I or II envelope glycoproteins. Recombinant protein (RP) B1 contains aminoacids 166-201 from HTLV-I exterior glycoprotein gp46 and was reactive with HTLV-I samples only. RP-IIB, which contains aminoacids 96-235 from HTLV-II exterior glycoprotein gp52, was reactive with all HTLV-II samples. 39 patients (86.6%) had high reactivity by densitometry. Of 55 HTLV-I samples, 35 (65.5%) had antibody reactivity to RP-IIB, but only 1 (1.8%) had high reactivity by densitometry. RP B1 and IIB western blot assays may replace the PCR test in diagnosis of HTLV infection.

Blotting, Western↗
PubMed1990

Determination of a unique and immunodominant epitope of human T cell lymphotropic virus type I.

The identification and isolation of unique and immunogenic recombinant epitopes for human T cell lymphotrophic virus (HTLV) type I might allow the development of an antibody-based assay to differentiate between HTLV-I and HTLV-II infections. To test the feasibility of this approach, an HTLV-I envelope epitope was isolated by immunoscreening of a lambda gt11 recombinant HTLV-I DNA library with a human monoclonal antibody to HTLV-I. This recombinant epitope. MTA-4, when tested with sera from HTLV-I- or HTLV-II-infected individuals, was reactive with all HTLV-I and nonreactive with all HTLV-II antisera. These results indicate that MTA-4 is a unique and immunodominant epitope on HTLV-I and confirm the usefulness of human-derived monoclonal antibodies in an experimental approach to dissect the human humoral response to a viral pathogen.

Antibodies, Monoclonal↗
PubMed1990

An assessment of error in parental occupation from the birth certificate.

This study used data obtained through interview with the mother to determine whether parental occupations from the California birth certificate were representative of maternal occupations during the first trimester of pregnancy or paternal occupations 3 months before conception. For 71% of mothers and 80% of fathers, the occupation on the birth certificate was the same as the occupation elicited from the interview. The sensitivity of the birth certificate for determining whether a mother or father was employed or employed in a particular standard occupational category ranged from 50 to 100%. The bias to the odds ratio associated with a sensitivity of 75% and a specificity of 80% is presented. The results suggest that the use of birth certificate information on parental occupation to screen for associations with congenital malformations will miss all but very strong associations.

Adult↗
PubMed1990

Maternal water consumption during pregnancy and congenital cardiac anomalies.

This case-control study, conducted in a California county that had a local incident of water contamination in 1981, investigated the relation between a mother's reported consumption of tap water during pregnancy and congenital cardiac anomalies in their offspring born during 1981-1983. Data were obtained from telephone interviews with 145 mothers of children born with a severe cardiac anomaly and 176 mothers of children born without such an anomaly. A positive association between a mother's consumption of home tap water during the first trimester of pregnancy and cardiac anomalies in her infant was unrelated to the incident of water contamination, the mother's race, or her educational level. A negative relation was found between a mother's use of bottled water and cardiac anomalies among the infants. These findings corresponded primarily to births in 1981. These data could not fully distinguish between a potential causal agent in the water and differential reporting of exposure by study subjects.

California↗
PubMed1990

Molecular characterization of an attenuated human immunodeficiency virus type 2 isolate.

Naturally occurring strains of human immunodeficiency virus (HIV) can vary considerably in their in vitro biological properties, and such differences may also be reflected in their in vivo pathogenesis. In an attempt to define genetic determinants of viral pathogenicity, we have molecularly cloned, sequenced, and characterized an attenuated isolate of HIV type 2 (HIV-2/ST) that differs from prototype HIV-2 strains in its inability to fuse with and kill susceptible CD4-bearing target cells. A proviral clone, termed JSP4-27, was identified to be transfection competent and to fully exhibit the noncytopathic and nonfusogenic properties of its parental isolate. Nucleotide sequence analysis of this clone revealed a genomic organization very similar to that of cytopathic HIV-2 strains and an overall nucleotide sequence homology of 88 to 90%. Amino acid sequence comparison confirmed the integrity of all major viral gene products in JSP4-27 but identified two amino acid sequence substitutions in its envelope fusion region. To investigate whether these mutations were responsible for the nonfusogenic phenotype of JSP4-27, we amplified, cloned, and sequenced the envelope fusion regions of four additional HIV-2/ST strains, two of which represented in vitro-generated, fusogenic and cytopathic variants of HIV-2/ST. The analysis showed that all HIV-2/ST strains examined, including the fusogenic variants, contained the same amino acid sequence changes. On the basis of these findings, we conclude that the attenuated phenotype of JSP4-27, and that of its parental virus, is not due to a direct alteration of the envelope fusion domain. Our results also show, for the first time, that individual replication-competent proviral clones can be representative of attenuated strains of HIV.

Amino Acid Sequence↗
PubMed1988

Extensive variation of human immunodeficiency virus type-1 in vivo.

Genotypic variation among independent isolates of human immunodeficiency virus type-1 (HIV-1) is well known, but its molecular basis and biological consequences are poorly understood. We examined the genesis of molecular variation in HIV-1 by sequential virus isolations from two chronically infected individuals and analysis of recombinant HIV-1 genomic clones. In three different virus isolates full-length HIV-1 clones were identified and found to consist, respectively, of 17, 9 and 13 distinguishable, but highly-related, viral genotypes. Thirty-five viral clones derived from two HIV-1 isolates obtained from the same individual but 16 months apart showed progressive change, yet were clearly related. Similar changes in the HIV-1 genome did not occur in vitro during virus isolation and amplification. The results indicate that HIV-1 variation in vivo is rapid, that a remarkably large number of related but distinguishable genotypic variants evolve in parallel and coexist during chronic infection, and that 'isolates' of HIV-1, unless molecularly or biologically cloned, generally consist of complex mixtures of genotypically distinguishable viruses.

Base Sequence↗
PubMed1988

Biologically diverse molecular variants within a single HIV-1 isolate.

AIDS is a disorder characterized by a slow progressive impairment of immune function and by infection of human immunodeficiency viruses (HIV-1, HIV-2). Our knowledge of how these viruses cause disease in man, or how the related lentiviruses (visna and equine infectious anaemia virus) cause disease in animals, is still fragmentary. In particular, the significance of genetic variation in HIV-1, occurring within populations, within individuals and over periods of time, and the mechanisms of viral persistence remain unclear. To address these issues we prepared a series of proviral clones of HIV-1 originating from a single patient and compared their biological properties. Here we show that hybrid genomes (in which the envelope region of six viral clones were separately substituted into a prototype HIV-1 genome) generated viruses with widely differing capacity to grow in human T cells, cell lines and monocytoid cultures. These data suggest that extensive biological variation exists in vivo within an infected individual and is in part determined at the level of the viral envelope.

Acquired Immunodeficiency Syndrome↗
PubMed1988

West African HIV-2-related human retrovirus with attenuated cytopathicity.

Clinical and seroepidemiological studies in West Africa indicate that human immunodeficiency virus type 2 (HIV-2) is widespread and associated with immunodeficiency states of variable degree. In this study, an isolate of HIV-2 from a patient in Senegal was molecularly cloned and characterized. This isolate (HIV-2ST) was shown by hybridization and restriction enzyme analysis to be more related to the prototype HIV-2ROD than to other human or primate retroviruses. Cultures of HIV-2ST showed genotypic polymorphism, and clones of the virus had transmembrane envelope glycoproteins of 30 and 42 kilodaltons. Unlike other immunodeficiency viruses, HIV-2ST did not cause cell death or induce cell fusion in peripheral blood lymphocytes or in any of four CD4+ cell lines tested. Although HIV-2ST entered cells by a CD4-dependent mechanism and replicated actively, cell-free transmission of the virus was retarded at the level of cell entry. These findings suggest that immunodeficiency viruses prevalent in West African populations are members of the HIV-2 virus group and that certain strains of this virus have attenuated virulence.

Cell Line↗
PubMed1988

Location and chemical synthesis of a binding site for HIV-1 on the CD4 protein.

The human immunodeficiency virus type 1 (HIV-1) uses the CD4 protein as a receptor for infection of susceptible cells. A candidate structure for the HIV-1 binding site on the CD4 protein was identified by epitope mapping with a family of eight functionally distinct CD4-specific monoclonal antibodies in conjunction with a panel of large CD4-derived synthetic peptides. All of the seven epitopes that were located reside within two immunoglobulin-like disulfide loops situated between residues 1 and 168 of the CD4 protein. The CD4-specific monoclonal antibody OKT4A, a potent inhibitor of HIV-1 binding, recognized a site between residues 32 and 47 on the CD4 protein. By analogy to other members of the immunoglobulin superfamily of proteins, this particular region has been predicted to exist as a protruding loop. A synthetic analog of this loop (residues 25 to 58) showed a concentration-dependent inhibition of HIV-1-induced cell fusion. It is proposed that a loop extending from residues 37 to 53 of the CD4 protein is a binding site for the AIDS virus.

Antibodies, Monoclonal↗
PubMed1988

An examination of three spatial disease clustering methodologies.

Patterns of disease in space are often analysed to determine whether a relationship exists between a disease outcome and environmental exposures. This report examines the performance of three cluster analytical methods when applied to a single data set. These methods, designed to assess the purely spatial variation of events, have been examined to assess their ability to detect clustering in an area where disease rates have previously been shown to be significantly elevated. The ability of these methods to detect spatial clustering was also examined using simulation techniques. All three methods were found to be poor at detecting spatially localized disease rates which were approximately three time the expected rate, as measured by the relative risk.

California↗
PubMed1988

Identification of a novel retroviral gene unique to human immunodeficiency virus type 2 and simian immunodeficiency virus SIVMAC.

Human and simian immunodeficiency-associated retroviruses are extraordinarily complex, containing at least five genes, tat, art, sor, R, and 3' orf, in addition to the structural genes gag, pol, and env. Recently, nucleotide sequence analysis of human immunodeficiency virus type 2 (HIV-2) and simian immunodeficiency virus SIVMAC revealed the existence of still another open reading frame, termed X, which is highly conserved between these two viruses but absent from HIV-1. In this report, we demonstrate for the first time that the X open reading frame represents a functional retroviral gene in both HIV-2 and SIVMAC and that it encodes a virion-associated protein of 14 and 12 kilodaltons, respectively. We also describe the production of recombinant TrpE/X fusion proteins in Escherichia coli and show that sera from some HIV-2-infected individuals specifically recognize these proteins.

Amino Acid Sequence↗
PubMed1988

Methodological considerations in the study of parental occupational exposures and congenital malformations in offspring.

The existence of hazardous substances in the workplace has raised concerns about the potential of these substances for adverse reproductive effects. Identification of associations between parental occupational exposures and congenital malformations in the offspring may provide the opportunity for preventing such exposures and thus reduce the risk of malformations. However, there are many methodological considerations inherent in studying the potential relation between parental occupational exposures and congenital malformations in the offspring. Considerations relating to outcome include methods and timing of ascertaining cases with malformations, diagnostic criteria, and problems in grouping malformations for purposes of analysis. With regard to measuring exposures, issues include methods for obtaining valid estimates of the nature, duration, timing of exposure, and exposure-response relationship. Other methodological issues discussed include selection of appropriate reference groups, sample size, and multiple hypothesis testing.

Congenital Abnormalities↗
PubMed1988

Individuals infected with HIV possess antibodies against IL-2.

Studies are presented here which demonstrate that antibodies reacting with human interleukin-2 (IL-2) are present in the sera of patients infected with the human immunodeficiency virus (HIV). It is likely that these antibodies are present due to a homology between the HIV envelope protein and IL-2. The homologues are six amino acids in length corresponding to the carboxy terminus of gp41, Leu-Glu-Arg-Ile-Leu-Leu (LERILL), and residues 14-19 of secreted IL-2, Leu-Glu-His-Leu-Leu-Leu (LEHLLL). Thus, we questioned whether antibodies made against this HIV envelope peptide would cross-react with IL-2. Not only do a high percentage of the HIV-infected individuals tested here have antibodies against LERILL, but these antibodies cross-react with the IL-2 sequence, LEHLLL. Additional antigenic processing of IL-2 is suggested by the finding that epitopes other than this sixmer are also recognized by antibodies in patients' sera. Thus, these studies suggest a mechanism by which infection with HIV can induce a potentially suppressive autoimmune response. Specifically, antibodies against an HIV envelope peptide cross-react with an epitope in IL-2.

Acquired Immunodeficiency Syndrome↗
PubMed1987

Computer-assisted analysis of envelope protein sequences of seven human immunodeficiency virus isolates: prediction of antigenic epitopes in conserved and variable regions.

Independent isolates of human immunodeficiency virus (HIV) exhibit a striking genomic diversity, most of which is located in the viral envelope gene. Since this property of the HIV group of viruses may play an important role in the pathobiology of the virus, we analyzed the predicted amino acid sequences of the envelope proteins of seven different HIV strains, three of which represent sequential isolates from a single patient. By using a computer program that predicts the secondary protein structure and superimposes values for hydrophilicity, surface probability, and flexibility, we identified several potential antigenic epitopes in the envelope proteins of the seven different viruses. Interestingly, the majority of the predicted epitopes in the exterior envelope protein (gp120) were found in regions of high sequence variability which are interspersed with highly conserved regions among the independent viral isolates. A comparison of the sequential viral isolates revealed that changes concerning the secondary structure of the protein occurred only in regions which were predicted to be antigenic, predominantly in highly variable regions. The membrane-associated protein gp41 contains no highly variable regions; about 80% of the amino acids were found to be conserved, and only one hydrophilic area was identified as likely to be accessible to antibody recognition. These findings give insight into the secondary and possible tertiary structure of variant HIV envelope proteins and should facilitate experimental approaches directed toward the identification and fine mapping of HIV envelope proteins.

Acquired Immunodeficiency Syndrome↗