Interferon γ 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

Priscilla Biswas, Guido Poli, Audrey L. Kinter, Jesse S. Justement, Sharilyn K. Stanley, Wendy J. Maury, Peter Bressler, Jan M. Orenstein, Anthony S. Fauci

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Abstract

Interferon γ (IFN-γ), a lymphokine that exerts multiple immunoregulatory effects, has been found to be elevated in the plasma, cerebrospinal fluid, and lymph nodes of human immunodeficiency 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-γ 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-γ (10-1,000 U/ml) 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-α secretion, as previously described in U1 cells stimulated with phorbol myristate acetate (PMA). At the ultrastructural level, the stimulatory activity of IFN-γ 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-γ 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-γ were not indicative of a suppressive effect of IFN-γ on PMA-induced expression of HIV proteins and mRNAs, either directly or mediated by the release of IFN-α/β. This study suggests that IFN-γ may Play an important role as an inducer of HIV expression in infected mononuclear phagocytes.

Original languageEnglish
Pages (from-to)739-750
Number of pages12
JournalJournal of Experimental Medicine
Volume176
Issue number3
Publication statusPublished - Sep 1 1992

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Tetradecanoylphorbol Acetate
Vacuoles
Virion
Interferons
HIV
RNA-Directed DNA Polymerase
Satellite Viruses
Macrophages
Viruses
Human Immunodeficiency Virus Proteins
Messenger RNA
Lymphokines
Viral Proteins
Phagocytes
Virus Replication
Cerebrospinal Fluid
Acquired Immunodeficiency Syndrome
Lymph Nodes
Membranes
Brain

ASJC Scopus subject areas

  • Immunology

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Interferon γ 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, Priscilla; Poli, Guido; Kinter, Audrey L.; Justement, Jesse S.; Stanley, Sharilyn K.; Maury, Wendy J.; Bressler, Peter; Orenstein, Jan M.; Fauci, Anthony S.

In: Journal of Experimental Medicine, Vol. 176, No. 3, 01.09.1992, p. 739-750.

Research output: Contribution to journalArticle

Biswas, Priscilla ; Poli, Guido ; Kinter, Audrey L. ; Justement, Jesse S. ; Stanley, Sharilyn K. ; Maury, Wendy J. ; Bressler, Peter ; Orenstein, Jan M. ; Fauci, Anthony S. / Interferon γ 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. In: Journal of Experimental Medicine. 1992 ; Vol. 176, No. 3. pp. 739-750.
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abstract = "Interferon γ (IFN-γ), a lymphokine that exerts multiple immunoregulatory effects, has been found to be elevated in the plasma, cerebrospinal fluid, and lymph nodes of human immunodeficiency 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-γ 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-γ (10-1,000 U/ml) 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-α secretion, as previously described in U1 cells stimulated with phorbol myristate acetate (PMA). At the ultrastructural level, the stimulatory activity of IFN-γ 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-γ 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-γ were not indicative of a suppressive effect of IFN-γ on PMA-induced expression of HIV proteins and mRNAs, either directly or mediated by the release of IFN-α/β. This study suggests that IFN-γ may Play an important role as an inducer of HIV expression in infected mononuclear phagocytes.",
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AU - Biswas, Priscilla

AU - Poli, Guido

AU - Kinter, Audrey L.

AU - Justement, Jesse S.

AU - Stanley, Sharilyn K.

AU - Maury, Wendy J.

AU - Bressler, Peter

AU - Orenstein, Jan M.

AU - Fauci, Anthony S.

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