Search

Naomi F Walker,1–3 James Scriven,2–4 Graeme Meintjes,1–3 Robert J Wilkinson1,2,5 1Department of Medicine, Imperial College London, London, UK; 2Clinical Infectious Diseases Research Initiative, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa; 3Department of Medicine, University of Cape Town, Cape Town, South Africa; 4Liverpool School of Tropical Medicine, Liverpool, UK; 5MRC National Institute of Medical Research, London, UK Abstract: Access to antiretroviral therapy (ART) is improving worldwide. Immune reconstitution inflammatory syndrome (IRIS) is a common complication of ART initiation. In this review, we provide an overview of clinical and epidemiological features of HIV-associated IRIS, current understanding of pathophysiological mechanisms, available therapy, and preventive strategies. The spectrum of HIV-associated IRIS is described, with a particular focus on three important pathogen-associated forms: tuberculosis-associated IRIS, cryptococcal IRIS, and Kaposi's sarcoma IRIS. While the clinical features and epidemiology are well described, there are major gaps in our understanding of pathophysiology and as a result therapeutic and preventative strategies are suboptimal. Timing of ART initiation is critical to reduce IRIS-associated morbidity. Improved understanding of the pathophysiology of IRIS will hopefully enable improved diagnostic modalities and better targeted treatments to be developed. Keywords: antiretroviral therapy, tuberculosis, IRIS, diagnosis, complications

Tuberculosis (TB) causes disease worldwide and multi-drug resistance is an increasing problem. Matrix metalloproteinases (MMPs), particularly the collagenase MMP-1, cause lung extracellular matrix destruction which drives disease transmission and morbidity. The role in such tissue damage of the stromelysin MMP-10, a key activator of the collagenase MMP-1, was investigated in direct Mycobacterium tuberculosis (Mtb) infected macrophages and in conditioned medium from Mtb infected monocytes (CoMtb)-stimulated cells. Mtb infection increased MMP-10 secretion from primary human macrophages 29-fold, while CoMtb increased secretion by 4.5-fold from pulmonary epithelial cells and 10.5-fold from fibroblasts. Inhibition of MMP-10 activity decreased collagen breakdown. In two independent cohorts of TB patients from different continents, MMP-10 was increased in both induced sputum and bronchoalveolar lavage fluid compared to controls and patients with other respiratory diseases (both p