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MMP polymorphisms and HIV antiretroviral drugs

Matrix metalloproteinase polymorphisms and HIV anti-retroviral drugs: new implications of pharmacogenomics in therapeutic approaches

The Pharmacogenomics Journal volume 9, pages 355–357 (2009)Cite this article

Matrix metalloproteinases (MMP) are an ever growing family of endopeptidases that have the capacity to degrade almost all the protein components of the extracellular matrix (ECM); in this way, these enzymes are strongly involved in a kaleidoscope of physiological processes, including embryonic development, morphogenesis, stem cell differentiation, tissue repair and apoptosis.1, 2, 3, 4 The MMP family consists of more than 25 members, which, on the bases of their substrate specificity and domain organization, may be classified as collagenases, gelatinases, stromelysins, membrane type, matrilysins and other MMPs.5, 6 All MMPs share three well-conserved structural domains; they are all synthesized as pre-proenzymes, as they contain an N-terminal pre-domain or signal peptide that is removed during translation, leading to the generation of proMMPs. This N-terminal signal domain is followed by the pro-domain, essential for the latency and activation mechanism of all MMPs; it contains the cysteine switch motif reading PRCGXPD, in which an unpaired cysteine residue, through its bond with catalytic zinc ion, maintains the enzyme in a latent zymogenic form. The enzyme reaches its fully active state when this bridge between the cysteine and the zinc ion is disrupted. The catalytic domain of MMPs contains the highly conserved sequence, one catalytic zinc, one structural zinc and three calcium ions; it is characterized by three histidines that bind the zinc ion and a conserved methionine turn that lies under the active site zinc, creating a base to support the structure around the catalytic zinc.5 MMP activity can be inhibited by aspecific inhibitors such as α2-macroglobulin or by specific tissue inhibitors of MMPs (TIMPs), which bind MMP in a non-covalent manner, thereby inactivating the enzyme.1 An uncontrolled or inappropriate expression/activity of MMPs and/or a decrease in TIMP expression contributes to different pathological conditions, including inflammation, tumour growth, cancer cell invasion and infectious diseases.1, 6 In particular, MMPs have key roles in normal immune response to infection through degradation of extracellular matrix, allowing leukocyte migration and modulating the activity of cytokines, chemokines and defensins.7 The loss of regulation on MMP activity after infection may lead to tissue damage, microbial dissemination and associated immune pathologies.7 In this respect, MMPs are involved and also have important roles in human immunodeficiency virus (HIV) infection,8, 9 in which an altered production and secretion of MMPs and TIMPs contributes to dysregulation in T cells, monocyte/macrophage and dendritic cell trafficking, as well as viral dissemination through extracellular matrix degradation.8 To reduce the detrimental effects of MMP overexpression, several approaches have been widely used in clinical therapeutic practice,9 including tetracyclines,10 statins11 and anti-retroviral drugs (in particular HIV protease inhibitors),12 which are gold standards for HIV infection treatment. In particular, it has been demonstrated that anti-retroviral therapy (e.g., nucleoside reverse-transcriptase inhibitors and protease inhibitors) inhibits MMP expression in both glial cells and peripheral blood mononuclear cells, suggesting that the beneficial effects of anti-retroviral therapy in HIV-infected patients may be, at least in part, due to a reduction of MMP secretion and/or expression.9, 12

Highly active anti-retroviral therapy (HAART) is the standard of care for HIV infection; however, pharmacogenomic approaches highlighted significant interindividual differences in drug disposition, despite standardized dosing (mainly linked to age, gender, ethnicity, food intake, co-morbidity and genetic variation).13 The most studied and common variants are single-nucleotide polymorphisms in genes involved in anti-retroviral drug transport, metabolism and toxicity,13, 14 but there is a paucity of data with regard to the role of MMP gene polymorphisms in HIV patients.

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  1. Department of Biomolecular Sciences, Section of Clinical Biochemistry, Faculty of Sciences and Technologies, University ‘Carlo Bo’, Via O, Ubaldini 7, Urbino, (PU) 61029, Italy

    F Mannello

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Mannello, F. Matrix metalloproteinase polymorphisms and HIV anti-retroviral drugs: new implications of pharmacogenomics in therapeutic approaches. Pharmacogenomics J 9, 355–357 (2009). https://doi.org/10.1038/tpj.2009.35

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