Mechanisms of polymorphonuclear neutrophil-mediated induction of HIV-1 replication in macrophages during pulmonary tuberculosis.
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.
Hoshino
Yoshihiko
Y
Division of Pulmonary and Critical Care Medicine, Department of Medicine, New York University School of Medicine, New York, NY 10016, USA.
Hoshino
Satomi
S
Gold
Jeffrey A
JA
Raju
Bindu
B
Prabhakar
Savita
S
Pine
Richard
R
Rom
William N
WN
Nakata
Koh
K
Weiden
Michael
M
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
D004279:DNA, Viral; D004268:DNA-Binding Proteins