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- Title
Mechanisms of Polymorphonuclear Neutrophil—Mediated Induction of HIV-1 Replication in Macrophages during Pulmonary Tuberculosis.
- Authors
Hoshino, Yoshihiko; Hoshino, Satomi; Gold, Jeffrey A.; Raju, Bindu; Prabhakar, Savita; Pine, Richard; Rom, William N.; Nakata, Koh; Weiden, Michael
- 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-κDa 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 downregulated 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.
- Subjects
HIV; VIRAL replication; NEUTROPHILS; GRANULOCYTES; PHAGOCYTES; BRONCHOALVEOLAR lavage; IMMUNODEFICIENCY; IMMUNOSUPPRESSION
- Publication
Journal of Infectious Diseases, 2007, Vol 195, Issue 9, p1303
- ISSN
0022-1899
- Publication type
Article
- DOI
10.1086/513438