Biomedical subjects

T Charbonneau

Publications and source records attributed to T Charbonneau.

5 recordsLinked to original sources

PubMed2001

Occurrence of HIV-1 reverse transcriptase gene mutation at codon 215 in HIV-infected infants.

BACKGROUND: The nucleoside reverse transcriptase inhibitor Zidovudine (ZDV) decreases mother to child transmission of HIV infection. Nevertheless, significant proportions of mothers who are treated during pregnancy with ZDV still transmit the virus. Along with other factors, failure of ZDV prophylaxis may be due to maternal infection with ZDV-resistant strains and their consequent vertical transmission. OBJECTIVES: The purpose of the study was to investigate the occurrence of mutations at codon 215 in HIV-1 infected infants and its association with clinical status and virological parameters. STUDY DESIGN: The cohort consisted of 49 HIV-1 infected infants. Mononuclear cell DNA was isolated from whole blood and served as the input DNA for both a qualitative DNA PCR and the codon 215 assay (nested PCR). HIV-1 viral load (RNA PCR) was measured in plasma by the Roche Amplicor Monitor assay. RESULTS: Twelve of the 49 (24.5%) demonstrated viral strains with mutation at codon 215. A significant difference was found in infants born between 1992 and 1994 (6.3%) compared to those born in 1998-1999 (33.3%). Furthermore, in those infants born in 1998-1999, there was a trend toward an increase in the frequency of zidovudine resistant mutations at codon 215 corresponding to an increase in maternal zidovudine treatment. The mixture of wild and mutant HIV-1 strains was detected in two of 14 infants (14.3%) with a low viral load (<750000 c/ml) compared to nine of 19 (47.4%) infants with extremely high levels of HIV-1 RNA concentration (>750000 c/ml). Only two of 33 tested infants were HIV symptomatic and in both, a mixture of wild and mutant HIV-1 strains was detected. In both infants, the viral load was >750000 c/ml. CONCLUSIONS: This study showed that the overall frequency of ZDV resistant strains in infants born in 1998-1999 was significantly higher than that found in infant samples from 1992 to 1994. By 1998, the standard of care for mothers known to be infected with HIV was treatment with either monotherapy using ZDV or combined therapy using a variety of antiretroviral agents including ZDV. Although the exact role of ZDV resistance in limiting the effectiveness of therapies aimed at blocking vertical transmission of HIV remains to be defined, it is clear that drug resistant strains of HIV are occurring more frequently in all types of HIV infection, including infants.

Anti-HIV Agents↗

PubMed1999

CCR5 genotype and resistance to vertical transmission of HIV-1.

A human gene has been identified that affects susceptibility to HIV-1 infection. The gene codes for CCR5, the coreceptor for macrophage-tropic strains of HIV-1. Individuals who are homozygous for a deleted, mutant form of the gene, delta32, display a high degree of natural resistance to sexual and parenteral transmission of HIV-1. To investigate whether delta32 plays a role in vertical transmission, we determined the CCR5 genotype of 552 children born to infected mothers in the United States and correlated the genotypes with HIV-1 infection status. Of these children, 13% were white, 30% Latino, and 56% African American, reflecting the ethnic makeup of infected women in the United States. The delta32 gene frequency varied among these groups, ranging from 0.08 in whites to 0.02 in both Latinos and African Americans. Approximately 27% of the children in each ethnic group were infected. Four children were identified as delta32 homozygotes, two uninfected whites (3.77%) and two uninfected Latinos (1.68%). None of the infected children displayed the delta32 homozygous genotype. Among Latinos and whites, the number of uninfected children who carried the homozygous delta32 mutation was significantly greater than that predicted by the Hardy-Weinberg equilibrium (p < .001 for Latinos, p = .044 for whites). This association was noted in Latino and white children whose mothers were either treated or untreated with zidovudine. These data document the occurrence of the homozygous delta32 genotype among children of HIV-1-infected mothers and suggest that this mutant genotype may confer protection from mother-to-child transmission of HIV-1. They also suggest that sexual, parenteral, and vertical transmission all involve processes that use CCR5 as a coreceptor for primary HIV-1 infection. Therefore, blocking the CCR5 receptor may provide an additional strategy to prevent HIV-1 vertical transmission.

Alleles↗

PubMed1992

Coxsackievirus B4 infection alters thymic, splenic, and peripheral lymphocyte repertoire preceding onset of hyperglycemia in mice.

Diabetogenic Coxsackievirus B4 infection may trigger autoimmune islet loss in diabetes-susceptible mice, resulting in hyperglycemia in nearly 90% of the animals at 6-8 weeks postinfection (p.i.). To ascertain whether changes in lymphocyte repertoire following infection could predispose these animals to diabetes, alterations in their thymic, splenic, and peripheral lymphocytes were analyzed. Additionally, lymphocyte changes were correlated with the virus load in these tissues and with lymphocyte migration to the inflammatory pancreas. Splenic B lymphocytes more than doubled at 72 hr p.i. and then continuously decreased by 16% of the noninfected controls at 8 weeks p.i. T lymphocytes (CD4+ + CD8+) decreased by about 50% at 72 hr and then increased to the control level by 8 weeks p.i.; CD8+ subset continuously decreased by 40% of the control at 8 weeks, resulting in a 67% increase in CD4+/CD8+ ratio. Macrophages and CD5+ B subset increased at 72 hr and then dipped by 93% and 84%, respectively, at 8 weeks. In contrast, peripheral B lymphocytes increased by 74% and T lymphocytes decreased by 11% at 8 weeks p.i. Macrophages increased by twofold at 72 hr and then dipped slightly (6%) at 8 weeks, whereas CD5+ B subset increased by 245%. Most prominent thymic T lymphocyte alteration was reflected by about 150% increase in CD4- CD8- cells at 8 weeks p.i. The peak viremia occurred at 72 hr p.i., with highest and lowest virus in the spleen and thymus, respectively. The thymus cleared virus by 3 days, the other tissues by 7 days. Insulitis and acinar necrosis followed infection; infiltrating lymphocytes were mostly CD4+. Virus-induced abnormal lymphocyte maturation may contribute to the development of insulitis and hyperglycemia.

Animals↗

PubMed1981

Environmental chemical-induced macrophage dysfunction.

Immunomodulation by environmental chemical contaminants and the role immune parameters play in toxicity and risk assessment studies is of increasing concern. Although considerable evidence has indicated that various xenobiotics may be immunosuppressive, little attention has been directed toward ascertaining a specific cellular locus which could be responsible for the impaired immune responsiveness. Since previous studies had suggested a macrophage defect in xenobiotic-induced immunosuppression and since macrophages are integral components of an immune response, an in-depth evaluation of macrophage function was conducted in xenobiotic-exposed mice. Macrophages isolated from mice receiving PCB, HCB, and dieldrin had no alteration in their in vitro O2 consumption while at rest or during phagocytosis. In addition, no alteration in in vitro phagocytic activity, phagocytic capacity or microbicidal activity was demonstrated. However, a significant impairment in the in vivo phagocytic clearance of a labelled antigen and an altered tissue distribution of the antigen was observed and was, perhaps, related, in part, to a significant decrease in serum fibronectin, an opsonic alpha 2 surface-binding glycoprotein. Furthermore, animals exposed to HCB and dieldrin, but not to PCB, had a profound decrease in their resistance to a challenge tumor cell implant which was related to a select alteration in tumor cell killing. The adherent spleen cells from HCB-treated mice had a profound suppression in their tumoricidal activity which was in contrast to dieldrin-treated mice, where the target cell type appeared to be the nonadherent cells. However, although dieldrin-exposed adherent cells (macrophages ?) did nt appear to have an altered tumoricidal capacity, all four macrophage types isolated from dieldrin-treated mice had a significantly impaired ability to process a cellular antigen. Splenic and alveolar macrophages appeared to be the most sensitive cell types to dieldrin. The present studies suggest that macrophage dysfunction may be an integral part of xenobiotic-induced immunosuppression and that the effector but not affector component of macrophage function may be the site of alteration.

Animals↗

PubMedDate not supplied

Changes in neutrophil aggregation and chemotaxis response during 18-hour cold storage.

Providing neutrophil transfusions to septic neonatal patients with depleted neutrophil reserves can be troublesome and require unscheduled blood donations. Buffy coats from stored whole blood are a potential source of neutrophils provided they remain viable during the interval between the whole blood collection and the buffy coat production. This study determined neutrophil function during storage of whole blood at 4 degrees C for 18 hours. Whole blood pH, hematocrit, platelet, and white cell counts remained unchanged. Chemotactic response to formyl methionyl leucyl penylalanine (FMLP) declined from 172.5 +/- 29 units (mean +/- SD) to 125 +/- 48 at 9 hours and 63.6 +/- 48 (p less than 0.05) at 18 hours. Aggregation response to FMLP remained normal for 9 hours but dropped to 15.5 percent of normal after 18 hours. Neutrophil response to cytaxins was maintained for at least 9 hours during storage of whole blood at 4 degrees C but seriously declined within 18 hours. Limiting 4 degrees C storage of whole blood to 9 hours prior to preparing buffy coats may provide flexibility needed for urgent provision of neutrophil transfusions.

Blood Preservation↗