Treatment of AIDS-Related Kaposi’s Sarcoma with Recombinant γ-Interferon

Ganser, A.; Brücher, W.; Brodt, Hans-Reinhard; Busch, W; Brandhorst, I.; Helm, E. B.; Hoelzer, Dieter

doi:10.1159/000215998

Cited by 17 publications

(8 citation statements)

References 6 publications

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“…An assessment regarding the in vivo significance of TNFand IFN-synergism on progression of HIV infection is complicated by a dissociation between their direct stimulatory effects on HIV-1 replication and their indirect inhibitory effects on HIV-1 spread by eliminating virus-infected host cells, as it was demonstrated by us and others [16,18,31]. Our in vitro findings, however, argue against the rationale behind therapeutic administration of TNFor IFN-in the treatment of HIV-1 infection or HIV-1-associated opportunistic disorders as previously performed [49][50][51][52]. In fact, intravenous administration of recombinant TNFfor treatment of mucocutaneous Kaposi's sarcoma in HIV-1-infected patients significantly increased their circulating p24 antigen serum levels and worsened the course of their opportunistic neoplasm [50].…”

Section: Discussionmentioning

confidence: 48%

Synergistic stimulatory effects of tumour necrosis factor α and interferon γ on replication of human immunodeficiency virus type 1 and on apoptosis of HIV‐1‐infected host cells

Han

Becker

Degen

et al. 1996

Eur J Clin Investigation

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Differential and sometimes contradictory effects have been described for tumour necrosis factor alpha (TNF-alpha) and interferon gamma (IFN-gamma) on replication of human immunodeficiency virus type 1 (HIV-1). The authors examined individual and coordinate action of these cytokines on HIV-1 expression, and on apoptosis of HIV-1-infected host cells by determination of reverse transcriptase activity in cell culture supernatant, expression of HIV-1-RNA and production of p24 antigen in the promonocytic cell line U937 and its persistently HIV-1-infected clone U1. Apoptosis was demonstrated by typical cleavage of cellular DNA at internucleosomal regions in promonocytic and T-lymphocytic cell lines. TNF-alpha alone markedly stimulated HIV-1 replication in U1 cells at the transcriptional and on the translational level. Exclusive application of IFN-gamma only slightly enhanced HIV-1 expression, whereas it synergistically potentiated stimulatory effects of TNF-alpha. Both cytokines also synergistically induced apoptosis in HIV-1-infected host cells. Co-ordinate action of TNF-alpha and IFN-gamma is suggested to represent an important mechanism for disease progression in HIV infection. These findings demonstrate that cytokine effects on viral expression may vary depending on their single or combined application.

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Section: Discussionmentioning

confidence: 48%

Synergistic stimulatory effects of tumour necrosis factor α and interferon γ on replication of human immunodeficiency virus type 1 and on apoptosis of HIV‐1‐infected host cells

Han

Becker

Degen

et al. 1996

Eur J Clin Investigation

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“…In fact, IFN-␥ alone has proviral effects on KSHV replication, demonstrated by the induction of lytic reactivation of latent KSHV by the addition of IFN-␥ to the growth media of cultured PEL cells (43,88,339) and the promotion of maintenance of persistent KSHV infection by IFN-␥ addition to primary explanted PBLs (155,347,468). In agreement, early attempts to treat KS patients with IFN-␥ were associated with progression of disease (172,271), suggesting that this cytokine promoted viral replication in infected people.…”

Section: Perspectives and Future Directionsmentioning

confidence: 60%

Molecular Genetics of Kaposi's Sarcoma-Associated Herpesvirus (Human Herpesvirus 8) Epidemiology and Pathogenesis

Dourmishev

Palmeri

et al. 2003

Microbiol Mol Biol Rev

309

367

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Kaposi's sarcoma had been recognized as unique human cancer for a century before it manifested as an AIDS-defining illness with a suspected infectious etiology. The discovery of Kaposi's sarcoma-associated herpesvirus (KSHV), also known as human herpesvirus-8, in 1994 by using representational difference analysis, a subtractive method previously employed for cloning differences in human genomic DNA, was a fitting harbinger for the powerful bioinformatic approaches since employed to understand its pathogenesis in KS. Indeed, the discovery of KSHV was rapidly followed by publication of its complete sequence, which revealed that the virus had coopted a wide armamentarium of human genes; in the short time since then, the functions of many of these viral gene variants in cell growth control, signaling apoptosis, angiogenesis, and immunomodulation have been characterized. This critical literature review explores the pathogenic potential of these genes within the framework of current knowledge of the basic herpesvirology of KSHV, including the relationships between viral genotypic variation and the four clinicoepidemiologic forms of Kaposi's sarcoma, current viral detection methods and their utility, primary infection by KSHV, tissue culture and animal models of latent- and lytic-cycle gene expression and pathogenesis, and viral reactivation from latency. Recent advances in models of de novo endothelial infection, microarray analyses of the host response to infection, receptor identification, and cloning of full-length, infectious KSHV genomic DNA promise to reveal key molecular mechanisms of the candidate pathogeneic genes when expressed in the context of viral infection

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“…Based on these and other observations (15)(16)(17)(18)(19), IFN-3, has been employed as a therapeutic agent both in the treatment of HIV infection and of AIDS-associated Kaposi's sarcoma (reviewed in references 56 and 57) with conflicting results. In some studies reduction of plasma levels of p24 Ag, improvement of immune function, and clinical course have been described (58), whereas exacerbation and progression of disease have also been reported (59). Our in vitro findings suggest that the inductive effects of IFN-3' on HIV-infected MP are complex and that the apparent suppressive effects on virus production may in fact represent merely a diversion of the preferential subcellular site of virion production from the plasma membrane to intracytoplasmic vacuoles.…”

Section: Discussionmentioning

confidence: 99%

Interferon gamma induces the expression of human immunodeficiency virus in persistently infected promonocytic cells (U1) and redirects the production of virions to intracytoplasmic vacuoles in phorbol myristate acetate-differentiated U1 cells.

Biswas

Poli

Kinter

et al. 1992

The Journal of Experimental Medicine

140

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SummaryInterferon "), (IFN-v), a lymphokine that exerts multiple immunoregulatory effects, has been found to be elevated in the plasma, cerebrospinal fluid, and lymph nodes of human immunoddldency virus (HIV)-infected individuals and has shown variable effects on HIV replication in acutely infected cells. In the present study, we have demonstrated that IFN-v is a potent modulator of HIV expression in persistently infected U1 promonocytic cells in which virus production is characterized by a constitutive state of relative latency. Direct stimulation of U1 cells with IFN-'), (10-1,000 U/m1) activated HIV expression, as measured by reverse transcriptase (RT) activity in the culture supernatant and increased levels of cell-associated viral protein and mRNAs. These effects on virus expression were not accounted for by the induction of endogenous TNF-cr secretion, as previously described in U1 cells stimulated with phorbol myristate acetate (PMA). At the ultrastructural level, the stimulatory activity of IFN-v was correlated with HIV particle production in intracytoplasmic vacuoles along with the differentiation of U1 into macrophage-like cells. Furthermore, costimulation of U1 cells with IFN-v and PMA significantly increased the accumulation of vacuole-associated HIV concomitant with decreasing membrane-associated particles and RT activity production, as compared with cells stimulated with PMA alone. No evidence of spontaneous secretion of intracellular vacuole-associated virus was obtained by kinetic analysis of the RT activity released in the supernatants throughout the culture period unless cells were deliberately disrupted, These findings suggest that vacuole-associated virions likely represent a relatively stable intracellular reservoir of HIV, as previously described in primary macrophages infected in vitro or in infected macrophages in the brains of patients with acquired immune deficiency syndrome. The reduced levels of RT activity observed in the culture supernatants of U1 cells stimulated with PMA in the presence of IFN-3' were not indicative of a suppressive effect of IFN-3' on PMA-induced expression of HIV proteins and mRNAs, either directly or mediated by the release of IFN-od/3. This study suggests that IFN-3' may play an important role as an inducer of HIV expression in infected mononuclear phagocytes.

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Treatment of AIDS-Related Kaposi’s Sarcoma with Recombinant γ-Interferon

Cited by 17 publications

References 6 publications

Synergistic stimulatory effects of tumour necrosis factor α and interferon γ on replication of human immunodeficiency virus type 1 and on apoptosis of HIV‐1‐infected host cells

Synergistic stimulatory effects of tumour necrosis factor α and interferon γ on replication of human immunodeficiency virus type 1 and on apoptosis of HIV‐1‐infected host cells

Molecular Genetics of Kaposi's Sarcoma-Associated Herpesvirus (Human Herpesvirus 8) Epidemiology and Pathogenesis

Interferon gamma induces the expression of human immunodeficiency virus in persistently infected promonocytic cells (U1) and redirects the production of virions to intracytoplasmic vacuoles in phorbol myristate acetate-differentiated U1 cells.

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