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Biomedical subjects

G M Shaw

Publications and source records attributed to G M Shaw.

At least 55 records · Page 3Linked to original sources
PubMed2000

Sensitivity of human immunodeficiency virus type 1 to the fusion inhibitor T-20 is modulated by coreceptor specificity defined by the V3 loop of gp120.

T-20 is a synthetic peptide that potently inhibits replication of human immunodeficiency virus type 1 by interfering with the transition of the transmembrane protein, gp41, to a fusion active state following interactions of the surface glycoprotein, gp120, with CD4 and coreceptor molecules displayed on the target cell surface. Although T-20 is postulated to interact with an N-terminal heptad repeat within gp41 in a trans-dominant manner, we show here that sensitivity to T-20 is strongly influenced by coreceptor specificity. When 14 T-20-naive primary isolates were analyzed for sensitivity to T-20, the mean 50% inhibitory concentration (IC(50)) for isolates that utilize CCR5 for entry (R5 viruses) was 0.8 log(10) higher than the mean IC(50) for CXCR4 (X4) isolates (P = 0. 0055). Using NL4.3-based envelope chimeras that contain combinations of envelope sequences derived from R5 and X4 viruses, we found that determinants of coreceptor specificity contained within the gp120 V3 loop modulate this sensitivity to T-20. The IC(50) for all chimeric envelope viruses containing R5 V3 sequences was 0.6 to 0.8 log(10) higher than that for viruses containing X4 V3 sequences. In addition, we confirmed that the N-terminal heptad repeat of gp41 determines the baseline sensitivity to T-20 and that the IC(50) for viruses containing GIV at amino acid residues 36 to 38 was 1.0 log(10) lower than the IC(50) for viruses containing a G-to-D substitution. The results of this study show that gp120-coreceptor interactions and the gp41 N-terminal heptad repeat independently contribute to sensitivity to T-20. These results have important implications for the therapeutic uses of T-20 as well as for unraveling the complex mechanisms of virus fusion and entry.

Anti-HIV Agents↗
PubMed2000

Biological parameters of HIV-1 infection in primary intestinal lymphocytes and macrophages.

Mucosal surfaces are the portal of entry for most HIV-1 infections and play an important role in disease pathogenesis. To characterize the biological parameters of HIV-1 infection in mucosal cells, we used purified lamina propria lymphocytes and macrophages from normal human small intestine to determine the distribution of the HIV-1 receptor and coreceptors on intestinal mononuclear cells and the permissiveness of these cells to HIV-1 infection. Lamina propria lymphocytes expressed CD4, CCR5, and CXCR4. In contrast, lamina propria macrophages expressed CD4 but not CCR5 or CXCR4. Intestinal lymphocytes supported replication by R5 and X4 isolates of HIV-1, but lamina propria macrophages were permissive to neither. RANTES, macrophage inflammatory protein-1alpha (MIP-1alpha), and MIP-1beta inhibited infection of intestinal lymphocytes by BaL, indicating that R5 infection of the intestinal lymphocytes was mediated by CCR5. Thus, resident lamina propria lymphocytes, not macrophages, are the target mononuclear cell for HIV-1 infection in the intestinal mucosa during early HIV-1 infection.

Animals↗
PubMed1999

Maternal corticosteroid use and risk of selected congenital anomalies.

Evidence for the teratogenicity of corticosteroids in humans is limited and has resulted in inconsistent recommendations regarding their use during early pregnancy. We examined the association between women's corticosteroid use during the periconceptional period (1 month before to 3 months after conception) and delivering infants with selected congenital anomalies. Data were derived from a population-based case-control study that included cases of orafacial clefts (n = 662), conotruncal heart defects (n = 207), neural tube defects (n = 265), and limb reduction defects (n = 165). Information on medication use was collected via maternal telephone interviews. Corticosteroid use was associated with an increased risk for isolated cleft lip with or without cleft palate (odds ratio 4.3, 95% confidence interval 1.1-17.2) and isolated cleft palate (odds ratio 5.3, 95% confidence interval 1.1-26.5). Increased risks were not observed for the other anomaly groups studied. These data in conjunction with other epidemiologic data suggest a possible causal association between cleft lip and palate and corticosteroid use.

Abnormalities, Drug-Induced↗
PubMed1999

Maternal supplemental and dietary zinc intake and the occurrence of neural tube defects in California.

The authors investigated the association between maternal preconceptional supplemental and dietary zinc intake and risk of neural tube defects (NTDs) in a population-based case-control study conducted between 1989 and 1991 in California. Cases were 430 NTD-affected fetuses/infants, and controls were 429 randomly selected non-malformed infants. Mothers reported their preconceptional use of vitamin, mineral, and food supplements, and completed a 98-item food frequency questionnaire. Increased total preconceptional zinc intake was associated with a reduced risk for NTDs (quintile 5 vs. quintile 1, odds ratio (OR) = 0.65, 95% confidence interval (CI) 0.43, 0.99). Phytate intake, a constituent of the diet known to impede zinc absorption, appeared to modify the zinc - NTD association. In addition, increased servings of animal products, the most bioavailable food source of zinc, was associated with a reduced risk for NTDs (quintile 5 vs. quintile 1, OR = 0.49, 95% CI 0.32, 0.76). Risk estimates for zinc intake were changed little after controlling for multiple sociodemographic factors and total folate intake, but were attenuated after controlling for nutrients highly correlated with dietary sources of zinc, such as protein. In sum, the analyses indicate that risk of NTDs in infants and fetuses decreased with increasing maternal preconceptional zinc intake. However, it remains unclear whether increased zinc intake, or another nutrient or combination of nutrients highly correlated with zinc intake in the diet, is causally associated with reduced NTD risk.

Body Mass Index↗
PubMed1999

Constant mean viral copy number per infected cell in tissues regardless of high, low, or undetectable plasma HIV RNA.

Quantitative analysis of the relationship between virus expression and disease outcome has been critical for understanding HIV-1 pathogenesis. Yet the amount of viral RNA contained within an HIV-expressing cell and the relationship between the number of virus-producing cells and plasma virus load has not been established or reflected in models of viral dynamics. We report here a novel strategy for the coordinated analysis of virus expression in lymph node specimens. The results obtained for patients with a broad range of plasma viral loads before and after antiretroviral therapy reveal a constant mean viral (v)RNA copy number (3.6 log10 copies) per infected cell, regardless of plasma virus load or treatment status. In addition, there was a significant but nonlinear direct correlation between the frequency of vRNA+ lymph node cells and plasma vRNA. As predicted from this relationship, residual cells expressing this same mean copy number are detectable (frequency <2/10(6) cells) in tissues of treated patients who have plasma vRNA levels below the current detectable threshold (<50 copies/ml). These data suggest that fully replication-active cells are responsible for sustaining viremia after initiation of potent antiretroviral therapy and that plasma virus titers correlate, albeit in a nonlinear fashion, with the number of virus-expressing cells in lymphoid tissue.

Antiviral Agents↗
PubMed1999

Origin of HIV-1 in the chimpanzee Pan troglodytes troglodytes.

The human AIDS viruses human immunodeficiency virus type 1 (HIV-1) and type 2 (HIV-2) represent cross-species (zoonotic) infections. Although the primate reservoir of HIV-2 has been clearly identified as the sooty mangabey (Cercocebus atys), the origin of HIV-1 remains uncertain. Viruses related to HIV-1 have been isolated from the common chimpanzee (Pan troglodytes), but only three such SIVcpz infections have been documented, one of which involved a virus so divergent that it might represent a different primate lentiviral lineage. In a search for the HIV-1 reservoir, we have now sequenced the genome of a new SIVcpzstrain (SIVcpzUS) and have determined, by mitochondrial DNA analysis, the subspecies identity of all known SIVcpz-infected chimpanzees. We find that two chimpanzee subspecies in Africa, the central P. t. troglodytes and the eastern P. t. schweinfurthii, harbour SIVcpz and that their respective viruses form two highly divergent (but subspecies-specific) phylogenetic lineages. All HIV-1 strains known to infect man, including HIV-1 groups M, N and O, are closely related to just one of these SIVcpz lineages, that found in P. t. troglodytes. Moreover, we find that HIV-1 group N is a mosaic of SIVcpzUS- and HIV-1-related sequences, indicating an ancestral recombination event in a chimpanzee host. These results, together with the observation that the natural range of P. t. troglodytes coincides uniquely with areas of HIV-1 group M, N and O endemicity, indicate that P. t. troglodytes is the primary reservoir for HIV-1 and has been the source of at least three independent introductions of SIVcpz into the human population.

Acquired Immunodeficiency Syndrome↗
PubMed1999

Analysis of select folate pathway genes, PAX3, and human T in a Midwestern neural tube defect population.

Neural tube defects (NTDs) are a common birth defect, seen in approximately 1/1,000 births in the United States. NTDs are considered a complex trait where several genes, interacting with environmental factors, create the phenotype. Using a Midwestern NTD population consisting of probands, parents, and siblings from Iowa, Minnesota, and Nebraska, we analyzed a range of candidate genes, including 5,10-methylenetetrahydrofolate reductase (MTHFR), folate receptors-alpha (FOLR1; hereafter abbreviated "FR-alpha") and -beta (FOLR2; hereafter, "FR-beta"), methionine synthase (hereinafter, "MS"), T, the human homolog of the murine Brachyury gene, and the paired-box homeotic gene 3 (PAX3), for association with NTDs. We were unable to demonstrate an association using a previously described Ala-->Val mutation in MTHFR and the majority of our NTD populations. However, we discovered a silent polymorphism in exon 6 of MTHFR which conserved a serine residue and which showed significant association with NTDs in our Iowa population. Analysis of exon 7 of MTHFR then demonstrated an Ala-->Glu mutation which was significantly associated with our Iowa NTD population; however, we could not replicate this result either in a combined Minnesota/ Nebraska or in a California NTD population. Using polymorphic markers for MS, FR-beta, T, and PAX3, we were unable to demonstrate linkage disequilibrium with our NTD populations. A mutation search of FR-alpha revealed one proband with a de novo silent mutation of the stop codon. This work provides a new panel of genetic variants for studies of folate metabolism and supports, in some NTD populations, an association between MTHFR and NTDs.

5,10-Methylenetetrahydrofolate Reductase (FADH2)↗
PubMed1999

Maternal periconceptional use of electric bed-heating devices and risk for neural tube defects and orofacial clefts.

Electric and magnetic fields are of concern as risk factors for adverse reproductive outcomes, including congenital anomalies. Among residential exposures to electric and magnetic fields, electric bed-heating devices such as electric blankets may be a substantial source of such exposures, and their use is fairly common. Two population-based case-control studies were analyzed to investigate whether the periconceptional use of electric blankets, bed warmers, or electrically heated waterbeds increased the risk of women to deliver infants or fetuses with neural tube defects (NTDs) or orofacial clefts. We obtained information on bed-heating devices from 538 NTD cases and their 539 controls in one study, and 265 NTD cases and 481 controls and 652 orofacial cleft cases and their 734 controls from another study. Our results revealed a few modestly elevated risks of certain anomaly phenotypes with maternal use of certain bed-heating devices, but risks tended to be imprecise. In general, women who reported more frequent use of a bed-heating device, or longer duration of use, did not appear to have a higher risk for delivering offspring with anomalies than were women who reported less frequent or shorter-duration use.

Electromagnetic Fields↗
PubMed1999

The role of folate transport and metabolism in neural tube defect risk.

Neural tube defects (NTDs) are common congenital malformations in humans. While etiologically heterogeneous, for the most part they are multifactorial in their pathogenesis, having both genetic and environmental factors contributing to their development. In recent years, there has been a great deal of epidemiologic evidence demonstrating that women who received multivitamins containing folic acid periconceptionally had significantly reduced occurrence and recurrence risks for producing infants with such malformations. Unfortunately, the mechanism(s) underlying the beneficial effects of folic acid is not well understood. In this article, we review the fundamental embryological processes involved in closing the neural tube, the relevant epidemiologic data on folic acid supplementation and relative NTD risk, as well as several recent studies of candidate genes for NTD sensitivity that are involved in folate transport and metabolism.

Biological Transport↗
PubMed1999

Intestinal macrophages display reduced permissiveness to human immunodeficiency virus 1 and decreased surface CCR5.

BACKGROUND & AIMS: Because the role of intestinal mononuclear cells in the pathogenesis of human immunodeficiency virus 1 (HIV-1) disease has not been elucidated, we determined the biological properties of HIV-1 infection in primary intestinal macrophages. METHODS: Mucosal macrophages purified from normal human jejunum were infected with well-characterized macrophage-tropic isolates of HIV-1 (ADA, DJV, and Ba-L). RESULTS: Productive HIV-1 infection of intestinal macrophages was demonstrated by the release of p24 antigen, the presence of proviral DNA, and zidovudine inhibition of infection. Surprisingly, the titer of virus needed to establish infection of intestinal macrophages was 100-1000-fold higher than that required to infect peripheral blood derived macrophages. This marked reduction in the permissiveness of intestinal macrophages to HIV-1 was not caused by the isolation procedure or differences in CD4 expression. Instead, intestinal macrophages expressed almost no CCR5, the principal coreceptor for macrophage-tropic HIV-1, compared with blood-derived macrophages, although both cell types contained comparable levels of CCR5 messenger RNA. Exposure of blood-derived but not intestinal macrophages to HIV-1 or gp120 led to increased surface expression of CCR5. CONCLUSIONS: Intestinal macrophages express reduced levels of HIV-1, probably because of impaired permissiveness to HIV-1 entry associated with the near absence of cell surface CCR5.

CD4 Antigens↗
PubMed1999

Maternal periconceptional alcohol consumption and risk for orofacial clefts.

OBJECTIVE: To investigate whether periconceptional maternal alcohol consumption increased the risk of delivering infants with orofacial cleft phenotypes. DESIGN: Data were derived from a large population-based case control study of fetuses and infants among a cohort of California births from 1987 to 1989 (n = 548,844). Information concerning alcohol consumption was obtained by telephone interviews with mothers of 731 infants (84.7% of eligible) with orofacial clefts and of 734 (78.2%) infants in a nonmalformed control group. RESULTS: Thirty-nine percent of mothers in the case group and 42% of mothers in the control group reported that they consumed alcohol during the period 1 month before through 3 months after conception. Relative to nonconsumers, women who reported alcohol consumption ( /=5 drinks per drinking occasion compared with those who did not, we observed increased risks for isolated (no other major congenital anomaly) cleft lip with or without cleft palate, odds ratio = 3.4 (95% confidence interval, 1.1 to 9.7); multiple cleft lip with or without cleft palate, odds ratio = 4.6 (1. 2 to 18.8); and "known syndrome" clefts, odds ratio = 6.9 (1.9 to 28. 6). Adjustment for maternal cigarette smoking, race, education, or vitamin use did not substantially change observed risks. CONCLUSION: We observed a lack of increased risks of clefts for relatively low quantities of maternal alcohol consumption and increased risks of clefts for higher quantities of maternal alcohol consumption.

Adult↗
PubMed1999

Human papillomavirus DNA replication compartments in a transient DNA replication system.

Many DNA viruses replicate their genomes at nuclear foci in infected cells. Using indirect immunofluorescence in combination with fluorescence in situ hybridization, we colocalized the human papillomavirus (HPV) replicating proteins E1 and E2 and the replicating origin-containing plasmid to nuclear foci in transiently transfected cells. The host replication protein A (RP-A) was also colocalized to these foci. These nuclear structures were identified as active sites of viral DNA synthesis by bromodeoxyuridine (BrdU) pulse-labeling. Unexpectedly, the great majority of RP-A and BrdU incorporation was found in these HPV replication domains. Furthermore, E1, E2, and RP-A were also colocalized to nuclear foci in the absence of an origin-containing plasmid. These observations suggest a spatial reorganization of the host DNA replication machinery upon HPV DNA replication or E1 and E2 expression. Alternatively, viral DNA replication might be targeted to host nuclear domains that are active during the late S phase, when such domains are limited in number. In a fraction of cells expressing E1 and E2, the promyelocytic leukemia protein, a component of nuclear domain 10 (ND10), was either partially or completely colocalized with E1 and E2. Since ND10 structures were recently hypothesized to be sites of bovine papillomavirus virion assembly, our observation suggests that HPV DNA amplification might be partially coupled to virion assembly.

Cell Nucleus↗
PubMed1999

The effect of congenital anomalies on mortality risk in white and black infants.

OBJECTIVES: This population-based study examined the effect of all major congenital anomalies on the mortality of White and Black infants by infant sex, birthweight, gestational age, and lethality of the anomaly. The study also determined the total contribution of anomalies to infant mortality. METHODS: California Birth Defects Monitoring Program data were merged with linked birth-death files for 278,646 singleton non-Hispanic White and Black infants born in 1983 through 1986. Malformed infants were compared with nonmalformed infants to determine the effect of anomalies on mortality. RESULTS: The presence of any congenital anomaly increased mortality 9.0-fold (95% CI = 7.3, 11.1) for Black infants and 17.8-fold (95% CI = 16.2, 19.6) for White infants. Even "non-lethal" anomalies increased mortality up to 8.9-fold. Overall, anomalies contributed to 33% of White infant deaths, to 19% of Black infant deaths, and to over 60% of deaths among Black and White neonates weighing over 1499 g. CONCLUSIONS: The contribution of congenital anomalies to mortality of both low- (< 2500 g) and normal-birth-weight infants is substantially higher than previously estimated, representing a large public health problem for both Black and White infants.

Age Distribution↗