HIV/TB interaction in the lung has focused on regulation of HIV-1 replication in alveolar macrophages (AM), the major source of viral replication in tuberculosis (TB). Work performed in this laboratory has demonstrated: 1) Production of inhibitory C/EBPbeta is an interferon (IFN) effect. It is also induced by other innate immune mediators such as SP-a. Once expressed, inhibitory C/EBPbeta suppresses HIV-1 replication and most proinflammatory cytokine promoters in resting AM. 2) As monocytes differentiate to macrophages, they gain the ability to produce a dominant negative C/EBPbeta transcription factor. 3) During TB, contact between lymphocytes and AM drives high-level HIV-1 replication in AM. Both lymphocyte/AM contact and cytokines are required for maximal LTR activation. Lymphocyte/AM contact down-regulates the dominant negative C/EBPbeta, de-repressing the HIV-1 LTR; while cytokines activate NF-kappaB, stimulating the HIV-1 LTR. 4) In mice, CD40 expression is required for de-repression during sepsis. Preliminary data now demonstrate that PU.1 and CREM are expressed in resting AM but not during TB. Both PU.1 and CREM are transcriptional repressors in other systems. In addition, a subset of AIDS patients with TB demonstrates neutrophil (PMN) predominant inflammation. PMN stimulate HIV-1 replication and mutation in vivo and in vitro. Full induction of HIV-1 replication and LTR function requires PMN contact and soluble factors. Like lymphocytes, PMN express CD40L and CD28. Unlike lymphocytes, PMN express LFA- 1, which binds macrophage ICAM-1, and PMN-derived peroxide is a soluble factor that activates NF-kappaB. PMN contact down-regulates inhibitory C/EBPbeta, CREM and PU. 1 in AM. TB patients have elevated levels of soluble ICAM-1, which recruits CD40L to PMN lipid rafts. Antibodies to CD40L, CD28 and CD11a inhibit the activity of PMN lipid rafts. PMN lipid rafts and cross-linking antibodies to CD40, B7 and ICAM-1 aggregate macrophage CD40, B7 and ICAM-1 and abolish inhibitory C/EBPbeta expression. These data led to the hypothesis that inhibitory C/EBPbeta is one of multiple repressors inhibiting HIV LTR activity in resting AM. Further, PMN are a cellular component of the innate immune response that can de-repress the LTR by cellular contact and activate the LTR by soluble factors. This two-step process contributes to high-level HIV-1 replication in AM during opportunistic infection. This proposal will investigate the role of PU. 1 and CREM as inhibitors of HIV-1 replication in AM and the role of PMN in enhancing HIV-1 replication in the lung.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL057879-09
Application #
7244322
Study Section
AIDS-associated Opportunistic Infections and Cancer Study Section (AOIC)
Program Officer
Peavy, Hannah H
Project Start
1999-04-01
Project End
2009-06-30
Budget Start
2007-07-01
Budget End
2008-06-30
Support Year
9
Fiscal Year
2007
Total Cost
$468,819
Indirect Cost
Name
New York University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
121911077
City
New York
State
NY
Country
United States
Zip Code
10016
Segal, Leopoldo N; Clemente, Jose C; Li, Yonghua et al. (2017) Anaerobic Bacterial Fermentation Products Increase Tuberculosis Risk in Antiretroviral-Drug-Treated HIV Patients. Cell Host Microbe 21:530-537.e4
Weiden, Michael D; Kwon, Sophia; Caraher, Erin et al. (2015) Biomarkers of World Trade Center Particulate Matter Exposure: Physiology of Distal Airway and Blood Biomarkers that Predict FEV? Decline. Semin Respir Crit Care Med 36:323-33
Schenck, Edward J; Echevarria, Ghislaine C; Girvin, Francis G et al. (2014) Enlarged pulmonary artery is predicted by vascular injury biomarkers and is associated with WTC-Lung Injury in exposed fire fighters: a case-control study. BMJ Open 4:e005575
Weiden, Michael D; Hoshino, Satomi; Levy, David N et al. (2014) Adenosine deaminase acting on RNA-1 (ADAR1) inhibits HIV-1 replication in human alveolar macrophages. PLoS One 9:e108476
Tsukiji, Jun; Cho, Soo Jung; Echevarria, Ghislaine C et al. (2014) Lysophosphatidic acid and apolipoprotein A1 predict increased risk of developing World Trade Center-lung injury: a nested case-control study. Biomarkers 19:159-65
Cho, Soo Jung; Echevarria, Ghislaine C; Kwon, Sophia et al. (2014) One airway: Biomarkers of protection from upper and lower airway injury after World Trade Center exposure. Respir Med 108:162-70
Nolan, Anna; Kwon, Sophia; Cho, Soo Jung et al. (2014) MMP-2 and TIMP-1 predict healing of WTC-lung injury in New York City firefighters. Respir Res 15:5
Weiden, Michael D; Naveed, Bushra; Kwon, Sophia et al. (2013) Cardiovascular biomarkers predict susceptibility to lung injury in World Trade Center dust-exposed firefighters. Eur Respir J 41:1023-30
Kwon, Sophia; Weiden, Michael D; Echevarria, Ghislaine C et al. (2013) Early elevation of serum MMP-3 and MMP-12 predicts protection from World Trade Center-lung injury in New York City Firefighters: a nested case-control study. PLoS One 8:e76099
Aldrich, Thomas K; Ye, Fen; Hall, Charles B et al. (2013) Longitudinal pulmonary function in newly hired, non-World Trade Center-exposed fire department City of New York firefighters: the first 5 years. Chest 143:791-797

Showing the most recent 10 out of 39 publications