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Biomedical subjects

Mette D Hazenberg

Publications and source records attributed to Mette D Hazenberg.

8 recordsLinked to original sources
PubMed2003

Persistent immune activation in HIV-1 infection is associated with progression to AIDS.

BACKGROUND: HIV-1 infection is characterized by chronic generalized CD8 and CD4 T cell hyperactivation, the biological effect of which is not understood. OBJECTIVE: To study the relation between chronic immune activation and CD4 T cell depletion in HIV-1 infection. DESIGN: Prospective cohort study among participants of the Amsterdam Cohort Studies on HIV-1 infection and AIDS who have a known seroconversion date (n = 102). METHODS: CD4 and CD8 T cell activation marker expression was analysed by FACScan before and after seroconversion (1 and 5 years after seroconversion); T cell proliferation and T cell numbers were also measured. Cox proportional hazard analyses were used to study the predictive value of these parameters for progression to AIDS. RESULTS: Preseroconversion low CD4 T cell numbers or elevated levels of CD4 T cell activation were associated with increased risk for development of AIDS after HIV-1 seroconversion. Progression to AIDS was associated with loss of both CD4 and CD8 naive T cells. The predictive value of CD8 T cell activation was confirmed and, in addition, in the course of infection low CD4 T cell counts and increasing proportions of dividing CD4 T cells, dividing CD8 T cells or elevated CD4 T cell activation marker expression became independent predictors of progression to AIDS. CONCLUSIONS: Increased T cell activation has predictive value for HIV-1 disease progression even before seroconversion. These data support the hypothesis that persistent hyperactivation of the immune system may lead to erosion of the naive T cell pool and CD4 T cell depletion.

Acquired Immunodeficiency Syndrome↗
PubMed2003

Depletion of naive CD4 T cells by CXCR4-using HIV-1 variants occurs mainly through increased T-cell death and activation.

OBJECTIVE: Using SCID-Hu mice models and in vitro culture systems, it has been shown that syncytium inducing/CXCR4 using (X4) HIV-1 variants affect thymic function through infection and killing of CXCR4 thymocytes. The effect of X4-emergence on naive, memory and effector T-cell subset kinetics in vivo is, however, not known. DESIGN: Prospective cohort study. METHODS: Analysis of changes in naive, memory and effector CD4 and CD8 T-cell numbers and cell division before and after the emergence of X4 variants. RESULTS: Significantly lower numbers of CD4 T cells in patients with X4 variants (n = 18) compared to patients with non-syncytium inducing/CCR5 using variants (n = 74) were due to increased loss of naive and CD27 memory CD4 T cells. In addition, emergence of X4 variants was associated with a small but significant decline in naive CD8 T-cell numbers and increased proportions of dividing CD4 and CD8 naive, memory and effector T cells. CONCLUSION: Loss of naive T cells may suggest thymic dysfunction, however, such an effect would explain only part of the accelerated naive CD4 T-cell decline because of the longevity of naive T cells. Our data suggest that the accelerated naive CD4 T-cell decline induced by X4 variants is caused mainly by increased death and recruitment to the memory compartment of these cells.

Adult↗
PubMed2003

Early viral load and CD4+ T cell count, but not percentage of CCR5+ or CXCR4+ CD4+ T cells, are associated with R5-to-X4 HIV type 1 virus evolution.

HIV-1 infection is established by CCR5-utilizing (R5) variants, and CXCR4-utilizing (X4) variants emerge in approximately 50% of infected patients. We studied the role of CCR5 and CXCR4 expression before and 1 and 5 years after seroconversion in HIV-1 disease in a prospective study of 102 seroconverters. High percentages of CCR5(+) cells among total cells (relative hazard [RH], 2.55; 95% confidence interval [95% CI], 0.99-6.52), but not among CD45RO(-)CD4(+) and CD45RO(+)CD4(+) cells preseroconversion and among total cells and CD45RO(-)CD4(+) cells (RH, 2.70; 95% CI, 1.06-6.92 and RH, 3.54; 95% CI, 1.27-9.90, respectively) 5 years after seroconversion were associated with more rapid progression to AIDS. One year after seroconversion, high percentages of CXCR4(+) cells among total and CD45RO(-)CD4(+) cells were associated with delayed development of X4 variants (RH, 0.49; 95% CI, 0.20-1.21 and RH, 0.41; 95% CI, 0.17-1.02, respectively), whereas no association was observed for the percentage of CCR5(+) cells. In a larger study population, high early serum viral RNA and low CD4(+) T cell numbers were associated with more rapid development of X4 variants. Our results exclude target cell availability as a driving force for R5-to-X4 virus phenotype evolution.

Adult↗
PubMed2002

Discordant responses during antiretroviral therapy: role of immune activation and T cell redistribution rather than true CD4 T cell loss.

We studied T cell dynamics in four patients who initially responded well to highly active antiretroviral therapy (HAART) but subsequently experienced virological failure. Maintenance of peripheral blood CD4T cell counts was associated with low levels of immune activation. Low reactivity to rebounding virus may preserve normal T lymphocyte distribution over blood and tissues and be associated with stable peripheral blood T cell numbers in virological failures to HAART.

Adult↗
PubMed2002

T-cell receptor excision circle and T-cell dynamics after allogeneic stem cell transplantation are related to clinical events.

It is generally believed that homeostatic responses regulate T-cell recovery after peripheral stem cell transplantation (PSCT). We studied in detail immune recovery in relation to T-cell depletion and clinical events in a group of adult patients who underwent PSCT because of hematologic malignancies. Initially, significantly increased proportions of dividing naive, memory, and effector CD4(+) and CD8(+) T cells were found that readily declined, despite still very low numbers of CD4(+) and CD8(+) T cells. After PSCT, increased T-cell division rates reflected immune activation because they were associated with episodes of infectious disease and graft-versus-host disease (GVHD). T-cell receptor excision circles (TRECs) were measured to monitor thymic output of naive T cells. Mean TREC content normalized rapidly after PSCT, long before naive T-cell numbers had significantly recovered. This is compatible with the continuous thymic production of TREC(+) naive T cells and does not reflect homeostatic increases of thymic output. TREC content was decreased in patients with GVHD and infectious complications, which may be explained by the dilution of TRECs resulting from increased proliferation. Combining TREC and Ki67 analysis with repopulation kinetics led to the novel insight that recovery of TREC content and increased T-cell division during immune reconstitution after transplantation are related to clinical events rather than to homeostatic adaptation to T-cell depletion. (Blood. 2002;99:3449-3453)

Adult↗
PubMed2002

Selective decrease in circulating V alpha 24+V beta 11+ NKT cells during HIV type 1 infection.

CD1d-restricted NKT cells express an invariant TCR and have been demonstrated to play an important regulatory role in a variety of immune responses. Invariant NKT cells down-regulate autoimmune responses by production of type 2 cytokines and can initiate antitumor and antimicrobial immune responses by production of type 1 cytokines. Although defects in the (invariant) Valpha24+Vbeta11+ NKT cell population have been observed in patients with cancer and autoimmune diseases, little is known regarding the protective role of Valpha24+Vbeta11+ NKT cells in human infectious disease. In a cross-sectional study in HIV-1-infected individuals, we found circulating numbers of Valpha24+Vbeta11+ NKT cells to be reduced, independent of CD4+ T cell counts, CD4:CD8 ratios, and viral load. Because a small minority of Valpha24+Vbeta11+ NKT cells of healthy donors expressed HIV-1 (co)receptors and the vast majority of Valpha24+Vbeta11+ NKT cells in HIV-1-infected individuals expressed the Fas receptor, the depletion was more likely due to Fas-mediated apoptosis than to preferential infection of Valpha24+Vbeta11+ NKT cells by HIV-1. A longitudinal cohort study, in which patients were analyzed before seroconversion and 1 and 5 years after seroconversion, demonstrated that a large proportion of the depletion occurred within the first year postseroconversion. In this longitudinal study no evidence was found to support an important role of Valpha24+Vbeta11+ NKT cells in determining the rate of progression during HIV-1 infection.

Adult↗
PubMed2002

Cell turnover and cell tropism in HIV-1 infection.

Early infection with HIV-1 is dominated by CCR5-tropic (R5, non-syncytium-inducing) viruses. The evolution of CXCR4-tropic (X4, syncytium-inducing) viruses occurs later in the infection and is associated with rapid disease progression. Here, we propose that the tropism of X4 viruses for naive CD4+ T cells is disadvantageous in early infection owing to the low division rate of these cells. In healthy individuals, the division rate of memory cells is nearly ten times higher than that of naive cells and thus the memory-cell tropism of R5 viruses could account for their dominance early in infection. As the division rate of naive T cells increases with CD4+ depletion, X4 viruses come to dominate in late disease.

CD4-Positive T-Lymphocytes↗