TY - JOUR
T1 - Mechanisms of polymorphonuclear neutrophil-mediated induction of HIV-1 replication in macrophages during pulmonary tuberculosis
AU - Hoshino, Yoshihiko
AU - Hoshino, Satomi
AU - Gold, Jeffrey A.
AU - Raju, Bindu
AU - Prabhakar, Savita
AU - Pine, Richard
AU - Rom, William N.
AU - Nakata, Koh
AU - Weiden, Michael
N1 - Funding Information:
Received 1 September 2006; accepted 4 December 2006; electronically published 19 March 2007. Potential conflicts of interest: none reported. Financial support: Japanese Foundation for AIDS Prevention; New York University Center for AIDS Research; National Institutes of Health (grants MO1 RR00096, HL57879, HL 59832, and DA022162). Reprints or correspondence: Dr. Michael Weiden, Div. of Pulmonary and Critical Medicine, Dept. of Medicine, New York University School of Medicine, 550 First Ave., New York, NY 10016 (weidem01@gcrc.med.nyu.edu).
PY - 2007/5/1
Y1 - 2007/5/1
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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U2 - 10.1086/513438
DO - 10.1086/513438
M3 - Article
C2 - 17396999
AN - SCOPUS:34247472531
SN - 0022-1899
VL - 195
SP - 1303
EP - 1310
JO - Journal of Infectious Diseases
JF - Journal of Infectious Diseases
IS - 9
ER -