Antiretroviral therapy inhibits matrix metalloproteinase-9 from blood mononuclear cells of HIV-infected patients

Abstract

The present findings show for the first time that ART can reduce the capacity of PBMC from HIV-infected patients to secrete increased amounts of MMP-9.

A genetic polymorphism of matrix metalloproteinase 9 (MMP-9) affects the changes in circulating MMP-9 levels induced by highly active antiretroviral therapy in HIV patients

“…However, the increased pro-MMP-9/TIMP-1 ratios after HAART apparently contrast with earlier reports on how antiretrovirals may affect MMP-9. For example, antiretroviral therapy reduced the capacity of peripheral-blood mononuclear cells to secrete MMP-9 in HIV-infected patients, 32 and zidovudine and indinavir attenuated the increase in MMP-9 expression induced by exposure of both astrocytes and microglia to lipopolysaccharide. 33 It is possible that major methodological differences between these studies and the present study may explain the apparently conflicting findings.…”

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

“…9,13 It has been demonstrated that a dysregulated balance between MMPs and their inhibitors as a result of HIV infection is important in the progression and pathogenesis of HIV-related diseases; in particular, HIV infection increases T-cell and monocyte secretion of MMP-9, favouring the crossing of basement membrane barriers and allowing the migration and spread of HIV-infected mononuclear cells into tissues, as well as the subsequent evolution of HIV infection. 12 On these bases, the development of therapeutic strategies targeted towards MMP activity could strongly aid in the treatment of HIV-related disorders in which inhibition of proteinase activity could have important clinical benefits.…”

“…These results indicate that anti-retroviral therapy (HAART protocol including zidovudine, lamivudine and efavirenz), in addition to its well-established activity on viral replication, may also show a direct effect on MMP activity. 15 Hence, according to previous data obtained on glial cells and blood mononuclear cells by zidovudine and indinavir, 12 the use of anti-retroviral compounds that can target MMP activity could represent an interesting challenge in the development of further treatments for HIV patients. 9 In this respect, the possibility that the increased susceptibility of HIV-infected patients towards cardiovascular disease may be, in part, due to higher levels of MMP-9 has drawn attention to the effect of HAART on MMP-9 expression in HIV patients.…”

“…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 statins 11 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.…”

“…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.…”