Mechanisms of polymorphonuclear neutrophil-mediated induction of HIV-1 replication in macrophages during pulmonary tuberculosis

Yoshihiko Hoshino, Satomi Hoshino, Jeffrey (Jeff) Gold, Bindu Raju, Savita Prabhakar, Richard Pine, William N. Rom, Koh Nakata, Michael Weiden

Research output: Contribution to journalArticle

27 Citations (Scopus)

Abstract

Background. Pulmonary tuberculosis (TB) can present with polymorphonuclear neutrophil (PMN)-predominant alveolitis. TB accelerates acquired immunodeficiency syndrome by increasing human immunodeficiency virus type 1 (HIV-1) replication and mutation in alveolar macrophages. A 16-kDa CCAAAT/enhancer-binding protein β (C/EBPβ) isoform is a strong transcriptional repressor of the HIV long terminal repeat (LTR) in resting alveolar macrophages, leading to latent viral infection; its expression is lost during TB, derepressing the HIV LTR. Methods. Lung segments were sampled from HIV/Mycobacterium tuberculosis - coinfected patients by means of bronchoalveolar lavage. In vitro coculture experiments defined the mechanism of induction of HIV-1 infection in macrophages by PMNs. Results. Lung segments from patients with PMN-predominant TB had a markedly elevated viral load. Direct contact between activated PMNs and macrophages stimulated HIV-1 replication and LTR transcription and down-regulated inhibitory C/EBPβ. Isolated PMN membranes substituted for PMN contact, derepressing the HIV-1 LTR. The lipid raft fraction of PMN membranes expressed CD40 ligand (CD40L), CD28, and leukocyte function-associated antigen 1 (LFA-1 [i.e., CD11a and CD18]), and PMN activation increased lipid raft expression of CD40L and CD28. Blocking antibodies to CD40L, CD28, and LFA-1 inhibited PMN membrane-mediated HIV-1 LTR derepression. Alternately, cross-linking of macrophage receptors for CD40L, CD28, and LFA-1 (CD40, CD80/86, and intercellular adhesion molecule 1) abolished inhibitory C/EBPβ expression. Conclusion. PMN-macrophage contact derepresses the HIV-1 LTR and enhances HIV-1 replication in alveolar macrophages during pulmonary TB. Derepression is mediated through costimulatory molecule signaling.

Original languageEnglish (US)
Pages (from-to)1303-1310
Number of pages8
JournalJournal of Infectious Diseases
Volume195
Issue number9
DOIs
StatePublished - May 1 2007
Externally publishedYes

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HIV Long Terminal Repeat
Virus Replication
Pulmonary Tuberculosis
HIV-1
Neutrophils
Macrophages
Lymphocyte Function-Associated Antigen-1
CD40 Ligand
Alveolar Macrophages
Carrier Proteins
Tuberculosis
Virus Diseases
Membranes
Lipids
Lung
Neutrophil Activation
Blocking Antibodies
Terminal Repeat Sequences
Bronchoalveolar Lavage
Intercellular Adhesion Molecule-1

ASJC Scopus subject areas

  • Public Health, Environmental and Occupational Health
  • Immunology

Cite this

Mechanisms of polymorphonuclear neutrophil-mediated induction of HIV-1 replication in macrophages during pulmonary tuberculosis. / Hoshino, Yoshihiko; Hoshino, Satomi; Gold, Jeffrey (Jeff); Raju, Bindu; Prabhakar, Savita; Pine, Richard; Rom, William N.; Nakata, Koh; Weiden, Michael.

In: Journal of Infectious Diseases, Vol. 195, No. 9, 01.05.2007, p. 1303-1310.

Research output: Contribution to journalArticle

Hoshino, Yoshihiko ; Hoshino, Satomi ; Gold, Jeffrey (Jeff) ; Raju, Bindu ; Prabhakar, Savita ; Pine, Richard ; Rom, William N. ; Nakata, Koh ; Weiden, Michael. / Mechanisms of polymorphonuclear neutrophil-mediated induction of HIV-1 replication in macrophages during pulmonary tuberculosis. In: Journal of Infectious Diseases. 2007 ; Vol. 195, No. 9. pp. 1303-1310.
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AU - Hoshino, Yoshihiko

AU - Hoshino, Satomi

AU - Gold, Jeffrey (Jeff)

AU - Raju, Bindu

AU - Prabhakar, Savita

AU - Pine, Richard

AU - Rom, William N.

AU - Nakata, Koh

AU - Weiden, Michael

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N2 - Background. Pulmonary tuberculosis (TB) can present with polymorphonuclear neutrophil (PMN)-predominant alveolitis. TB accelerates acquired immunodeficiency syndrome by increasing human immunodeficiency virus type 1 (HIV-1) replication and mutation in alveolar macrophages. A 16-kDa CCAAAT/enhancer-binding protein β (C/EBPβ) isoform is a strong transcriptional repressor of the HIV long terminal repeat (LTR) in resting alveolar macrophages, leading to latent viral infection; its expression is lost during TB, derepressing the HIV LTR. Methods. Lung segments were sampled from HIV/Mycobacterium tuberculosis - coinfected patients by means of bronchoalveolar lavage. In vitro coculture experiments defined the mechanism of induction of HIV-1 infection in macrophages by PMNs. Results. Lung segments from patients with PMN-predominant TB had a markedly elevated viral load. Direct contact between activated PMNs and macrophages stimulated HIV-1 replication and LTR transcription and down-regulated inhibitory C/EBPβ. Isolated PMN membranes substituted for PMN contact, derepressing the HIV-1 LTR. The lipid raft fraction of PMN membranes expressed CD40 ligand (CD40L), CD28, and leukocyte function-associated antigen 1 (LFA-1 [i.e., CD11a and CD18]), and PMN activation increased lipid raft expression of CD40L and CD28. Blocking antibodies to CD40L, CD28, and LFA-1 inhibited PMN membrane-mediated HIV-1 LTR derepression. Alternately, cross-linking of macrophage receptors for CD40L, CD28, and LFA-1 (CD40, CD80/86, and intercellular adhesion molecule 1) abolished inhibitory C/EBPβ expression. Conclusion. PMN-macrophage contact derepresses the HIV-1 LTR and enhances HIV-1 replication in alveolar macrophages during pulmonary TB. Derepression is mediated through costimulatory molecule signaling.

AB - Background. Pulmonary tuberculosis (TB) can present with polymorphonuclear neutrophil (PMN)-predominant alveolitis. TB accelerates acquired immunodeficiency syndrome by increasing human immunodeficiency virus type 1 (HIV-1) replication and mutation in alveolar macrophages. A 16-kDa CCAAAT/enhancer-binding protein β (C/EBPβ) isoform is a strong transcriptional repressor of the HIV long terminal repeat (LTR) in resting alveolar macrophages, leading to latent viral infection; its expression is lost during TB, derepressing the HIV LTR. Methods. Lung segments were sampled from HIV/Mycobacterium tuberculosis - coinfected patients by means of bronchoalveolar lavage. In vitro coculture experiments defined the mechanism of induction of HIV-1 infection in macrophages by PMNs. Results. Lung segments from patients with PMN-predominant TB had a markedly elevated viral load. Direct contact between activated PMNs and macrophages stimulated HIV-1 replication and LTR transcription and down-regulated inhibitory C/EBPβ. Isolated PMN membranes substituted for PMN contact, derepressing the HIV-1 LTR. The lipid raft fraction of PMN membranes expressed CD40 ligand (CD40L), CD28, and leukocyte function-associated antigen 1 (LFA-1 [i.e., CD11a and CD18]), and PMN activation increased lipid raft expression of CD40L and CD28. Blocking antibodies to CD40L, CD28, and LFA-1 inhibited PMN membrane-mediated HIV-1 LTR derepression. Alternately, cross-linking of macrophage receptors for CD40L, CD28, and LFA-1 (CD40, CD80/86, and intercellular adhesion molecule 1) abolished inhibitory C/EBPβ expression. Conclusion. PMN-macrophage contact derepresses the HIV-1 LTR and enhances HIV-1 replication in alveolar macrophages during pulmonary TB. Derepression is mediated through costimulatory molecule signaling.

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