title: Mechanisms of polymorphonuclear neutrophil-mediated induction of HIV-1 replication in macrophages during pulmonary tuberculosis.
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 beta (C/EBP beta ) 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/EBP beta . 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/EBP beta expression.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine, New York University School of Medicine, New York, NY 10016, USA.
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Hoshino
authors.forename: Satomi
authors.initials: S
authors.lastname: Hoshino
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Gold
authors.forename: Bindu
authors.initials: B
authors.lastname: Raju
authors.forename: Savita
authors.initials: S
authors.lastname: Prabhakar
authors.forename: Richard
authors.initials: R
authors.lastname: Pine
authors.forename: William N
authors.initials: WN
authors.lastname: Rom
authors.forename: Koh
authors.initials: K
authors.lastname: Nakata
authors.forename: Michael
authors.initials: M
authors.lastname: Weiden
mesh_terms: D000163:Acquired Immunodeficiency Syndrome / Q000150:complications / Q000821:virology*; D018893:Bronchoalveolar Lavage; D004279:DNA, Viral; D004268:DNA-Binding Proteins / Q000378:metabolism*; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000276:immunology*; D016676:Macrophages, Alveolar / Q000276:immunology / Q000821:virology; D009154:Mutation; D009169:Mycobacterium tuberculosis / Q000502:physiology*; D014397:Tuberculosis, Pulmonary / Q000150:complications / Q000503:physiopathology*; D014779:Virus Replication
chemical_list: D004279:DNA, Viral; D004268:DNA-Binding Proteins