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Clin Infect Dis. 2017 Jul 1;65(1):121-132. doi: 10.1093/cid/cix231.

Matrix Degradation in Human Immunodeficiency Virus Type 1-Associated Tuberculosis and Tuberculosis Immune Reconstitution Inflammatory Syndrome: A Prospective Observational Study.

Author information

1
Wellcome Centre for Infectious Diseases Research in Africa, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Observatory, South Africa.
2
Infectious Diseases and Immunity, and Imperial College Wellcome Trust Centre for Global Health, Imperial College London, United Kingdom.
3
Department of Medicine, University of Cape Town, Observatory, South Africa.
4
Department of Clinical Research, London School of Hygiene and Tropical Medicine, London, UK.
5
Francis Crick Institute, London, United Kingdom
6
National Institute for Health Research Respiratory Biomedical Research Unit, Clinical and Experimental Sciences Academic Unit, Faculty of Medicine, University of Southampton, United Kingdom.
7
Applied Proteomics and Chemical Biology Group, Department of Integrative Biomedical Sciences.
8
Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Observatory.
9
HIV/AIDS, Sexually Transmitted Infections and Tuberculosis Programme, Human Sciences Research Council, Cape Town, South Africa.
10
Department of Medical Statistics, London School of Hygiene and Tropical Medicine, London, UK.
11
Department of Medicine, Imperial College London, United Kingdom.

Abstract

Background:

Extensive immunopathology occurs in human immunodeficiency virus (HIV)/tuberculosis (TB) coinfection, but the underlying molecular mechanisms are not well-defined. Excessive matrix metalloproteinase (MMP) activity is emerging as a key process but has not been systematically studied in HIV-associated TB.

Methods:

We performed a cross-sectional study of matrix turnover in HIV type 1 (HIV-1)-infected and -uninfected TB patients and controls, and a prospective cohort study of HIV-1-infected TB patients at risk of TB immune reconstitution inflammatory syndrome (TB-IRIS), in Cape Town, South Africa. Sputum and plasma MMP concentrations were quantified by Luminex, plasma procollagen III N-terminal propeptide (PIIINP) by enzyme-linked immunosorbent assay, and urinary lipoarabinomannan (LAM) by Alere Determine TB LAM assay. Peripheral blood mononuclear cells from healthy donors were cultured with Mycobacterium tuberculosis and extracellular matrix in a 3D model of TB granuloma formation.

Results:

MMP activity differed between HIV-1-infected and -uninfected TB patients and corresponded with specific TB clinical phenotypes. HIV-1-infected TB patients had reduced pulmonary MMP concentrations, associated with reduced cavitation, but increased plasma PIIINP, compared to HIV-1-uninfected TB patients. Elevated extrapulmonary extracellular matrix turnover was associated with TB-IRIS, both before and during TB-IRIS onset. The predominant collagenase was MMP-8, which was likely neutrophil derived and M. tuberculosis-antigen driven. Mycobacterium tuberculosis-induced matrix degradation was suppressed by the MMP inhibitor doxycycline in vitro.

Conclusions:

MMP activity in TB differs by HIV-1 status and compartment, and releases matrix degradation products. Matrix turnover in HIV-1-infected patients is increased before and during TB-IRIS, informing novel diagnostic strategies. MMP inhibition is a potential host-directed therapy strategy for prevention and treatment of TB-IRIS.

KEYWORDS:

HIV-1; immune reconstitution inflammatory syndrome; matrix metalloproteinase; procollagen III N-terminal propeptide; tuberculosis

PMID:
28475709
PMCID:
PMC5815569
DOI:
10.1093/cid/cix231
[Indexed for MEDLINE]
Free PMC Article

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