The Journal of Experimental Medicine
Cytokines in immune regulation
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Published 19 February 2002. doi:10.1084/jem.20011614
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© Rockefeller University Press, 0022-1007/2002/2/495/ $5.00
The Journal of Experimental Medicine, Volume 195, Number 4, February 18, 2002 495-505

Original Article

 Maximal HIV-1 Replication in Alveolar Macrophages during Tuberculosis Requires both Lymphocyte Contact and Cytokines

Yoshihiko Hoshino1, Koh Nakata3, Satomi Hoshino1, Yoshihiro Honda4, Doris B. Tse2, Tatsuo Shioda5, William N. Rom1 and Michael Weiden1

1 Division of Pulmonary and Critical Care Medicine, Department of Medicine, New York University School of Medicine, New York, NY 10016
2 Division of Infectious Disease and Immunology, Department of Medicine, New York University School of Medicine, New York, NY 10016
3 Department of Respiratory Diseases, Research Institute, International Medical Center of Japan, Tokyo 162-8655, Japan
4 Department of Medicine, Sendai Kosei Hospital, Sendai 980-0873, Japan
5 Department of Viral Infections, Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan

Address correspondence to Michael Weiden, Division of Pulmonary and Critical Care Medicine, Department of Medicine, New York University School of Medicine, 550 First Avenue, New York, NY 10016. Phone: 212-263-7889; Fax: 212-263-8501; E-mail: weidem01@gcrc.med.nyu

HIV-1 replication is markedly upregulated in alveolar macrophages (AM) during pulmonary tuberculosis (TB). This is associated with loss of an inhibitory CCAAT enhancer binding protein ß (C/EBPß) transcription factor and activation of nuclear factor (NF)-{kappa}B. Since the cellular immune response in pulmonary TB requires lymphocyte–macrophage interaction, a model system was developed in which lymphocytes were added to AM. Contact between lymphocytes and AM reduced inhibitory C/EBPß, activated NF-{kappa}B, and enhanced HIV-1 replication. If contact between lymphocytes and macrophages was prevented, inhibitory C/EBPß expression was maintained and the HIV-1 long terminal repeat (LTR) was not maximally stimulated although NF-{kappa}B was activated. Antibodies that cross-linked macrophage expressed B-7, and vascular cell adhesion molecule and CD40 were used to mimic lymphocyte contact. All three cross-linking antibodies were required to abolish inhibitory C/EBPß expression. However, the HIV-1 LTR was not maximally stimulated and NF-{kappa}B was not activated. Maximal HIV-1–LTR stimulation required both lymphocyte-derived soluble factors, and cross-linking of macrophage expressed costimulatory molecules. High level HIV-1–LTR stimulation was also achieved when IL-1ß, IL-6, and TNF-ß were added to macrophages with cross-linked costimulatory molecules. Contact between activated lymphocytes and macrophages is necessary to down-regulate inhibitory C/EBPß, thereby derepressing the HIV-1 LTR. Lymphocyte-derived cytokines activate NF-{kappa}B, further enhancing the HIV-1 LTR.

Key Words: infection • cellular immunity • costimulatory molecules • transcription factors • derepression


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