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.