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F J Staal

Publications and source records attributed to F J Staal.

9 recordsLinked to original sources
PubMed1992

N-acetylcysteine: a new approach to anti-HIV therapy.

Several investigators have implicated depletion of glutathione (GSH) and production of reactive oxygen intermediates (ROIs) in the regulation of the human immunodeficiency virus (HIV). We have shown directly that N-acetylcysteine (NAC) blocks HIV expression in chronic and acute infection models, and HIV replication in normal peripheral blood mononuclear cells. NAC is a cysteine prodrug which maintains intracellular thiol levels during oxidative stress and replenishes depleted GSH. The observed antiviral effect of NAC is due to inhibition of viral stimulation by ROIs, which are produced in response to inflammatory cytokines. We have also shown that HIV-infected individuals have decreased intracellular GSH levels in their circulating T cells. Since GSH is the major protection against the production of ROIs, we hypothesize that the observed decrease is due to a chronic oxidative stress induced by continual exposure to elevated levels of inflammatory cytokines. Together, these results provide a rationale for clinical trials testing the efficacy of GSH-replenishing drugs such as NAC in the treatment of AIDS. NAC is different than many other antiviral drugs in that it inhibits host-mediated stimulation of viral replication arising in normal immune responses, and may thereby extend latency. In addition, it inhibits the action of inflammatory cytokines which may mediate cachexia, thereby raising the possibility that it may alleviate the deleterious wasting that accompanies late stage AIDS.

Acetylcysteine↗
PubMed1992

Intracellular glutathione levels in T cell subsets decrease in HIV-infected individuals.

The authors have shown previously that intracellular glutathione (GSH) plays an important role in the regulation of human immunodeficiency virus (HIV) transcription and replication in vitro, through modulation of signal transduction by inflammatory cytokines. Moreover, intracellular GSH levels are known to regulate T-lymphocyte function. In multiparameter FACS studies presented here, we show that relative GSH levels in CD4+ and CD8+ T cells from HIV+ individuals are significantly lower than in corresponding subsets from uninfected controls. These studies define the relative intracellular glutathione (GSH) levels in CD4+ T cells, CD8+ T cells, B cells, and monocytes from 134 HIV-infected individuals and 31 uninfected controls. The greatest decreases in intracellular GSH occur in subsets of T cells in individuals in the later stages of the HIV infection. In AIDS patients, GSH levels are 63% of normal in CD4+ T cells (p less than 0.0001) and are 62% of normal in CD8+ T cells (p less than 0.0001). Similarly, in AIDS-related complex (ARC) patients, GSH levels are 66% of normal in CD4+ T cells (p less than 0.003) and are 69% of normal in CD8+ T cells (p less than 0.003). These findings suggest that low intracellular GSH levels may be an important factor in HIV infection and in the resulting immunodeficiency.

AIDS-Related Complex↗
PubMed1992

CD20 expression is increased on B lymphocytes from HIV-infected individuals.

In studies presented here, we show that expression of the pan B cell marker CD20 is markedly increased on B lymphocytes from HIV-infected individuals and that this increase tends to be greater in individuals with more advanced disease. By using multiparameter FACS analyses to quantitate surface density of CD20 and intracellular glutathione (GSH) levels simultaneously, we further show that the distribution of intracellular glutathione (GSH) levels in B cells of HIV-infected individuals is more heterogeneous than in uninfected controls. Finally, we show that the intracellular GSH levels correlate with CD20 expression on a per-cell basis in all infected individuals. These findings suggest that CD20 expression, which can be precisely measured, may prove to be a useful surrogate marker for monitoring HIV infection.

Antigens, CD↗
PubMed1991

N-acetylcysteine inhibits latent HIV expression in chronically infected cells.

The progression of the human immunodeficiency virus (HIV) infection from its early latent (asymptomatic) stage to active, late-stage acquired immunodeficiency syndrome (AIDS) apparently begins with the production of inflammatory cytokines that stimulate the expression and replication of the latent virus. We have shown that N-acetylcysteine, a cysteine precursor that is converted intracellularly into glutathione, blocks cytokine-stimulated HIV replication in an acutely infected T-cell line and in acutely infected peripheral blood mononuclear cells from normal individuals. In this report, we show that N-acetylcysteine also inhibits stimulated HIV expression in chronically infected monocyte and T-cell lines which are used as models for latent infection in AIDS. Furthermore, we show that N-acetylcysteine blocks viral production in monocyte cell lines more effectively than it blocks viral production in T cells. Since monocytes are a major reservoir for HIV in infected individuals, these results suggest that N-acetylcysteine may slow the change from latency to the later stages of AIDS in HIV-infected individuals.

Acetylcysteine↗
PubMed1991

CD4 and CD8 T cells with high intracellular glutathione levels are selectively lost as the HIV infection progresses.

Maintenance of intracellular glutathione (GSH) levels has been implicated in blocking cytokine-stimulated HIV replication in vitro, in both acute and latent infection models. We demonstrate here that subsets of human peripheral blood mononuclear cells differ substantially in mean GSH levels, as measured on a cell-by-cell basis with the fluorescence-activated cell sorter (FACS): B cells have the lowest GSH levels; T cells are intermediate; and monocytes and macrophages have the highest levels. Furthermore, GSH levels subdivide the CD4 and CD8 T cell subsets into two classes each: high- and low-GSH cells, which cannot be distinguished by cell size or by currently known surface markers. Significantly, the high-GSH T cells are selectively depleted early during the HIV infection, and are effectively missing in all ARC and AIDS patients.

AIDS-Related Complex↗
PubMed1990

Cytokine-stimulated human immunodeficiency virus replication is inhibited by N-acetyl-L-cysteine.

We show that the stimulation of human immunodeficiency virus (HIV) brought about by tumor necrosis factor alpha and phorbol 12-myristate 13-acetate can be inhibited by adding N-acetyl-L-cysteine (NAC). NAC, which replenishes intracellular glutathione, effectively inhibits the tumor necrosis factor alpha- or phorbol ester-stimulated replication of HIV in acutely infected cell cultures. NAC also inhibits the cytokine-enhanced HIV long terminal repeat-directed expression of beta-galactosidase in in vitro HIV model systems. These results show that intracellular thiol levels influence HIV production. Furthermore, because NAC reverses tumor necrosis factor alpha toxicity both in cells and in animals and is a well-known drug that can be administered orally without known toxicity in humans, these results suggest that NAC is a possible therapeutic agent in AIDS.

Acetylcysteine↗
PubMed1990

Intracellular thiols regulate activation of nuclear factor kappa B and transcription of human immunodeficiency virus.

The activation of nuclear factor kappa B (NF-kappa B) has been implicated in the regulation of transcription of a variety of genes and has been shown to be essential for the expression of genes controlled by the long terminal repeat of human immunodeficiency virus (HIV LTR). We show here that intracellular thiol levels play a key role in regulating this process. That is, stimulation with tumor necrosis factor alpha and/or phorbol 12-myristate 13-acetate activates NF-kappa B and markedly decreases intracellular thiols; N-acetyl-L-cysteine, an efficient thiol source, prevents this thiol decrease and blocks the activation of NF-kappa B; and the lack of activated NF-kappa B prevents the activation of the HIV LTR and the transcription of genes under its control. These findings reveal a previously unrecognized genetic regulatory mechanism in which cytokine-induced shifts in intracellular thiol levels are crucial in the control of NF-kappa B activity and thereby influence the spectrum of genes expressed by cytokine-stimulated cells.

Base Sequence↗