Correlation between Increased Arginase Activity Levels and Disease Severity in HIV-Seropositive Patients

Infection with human immunodeficiency virus (HIV) results in a chronic infection that progressively impairs the immune system. Although depletion of CD4+ T cells is frequently used to explain immunosuppression, chronicity of infection and progressive loss of CD4+ T cells are not sufficient to fully account for immune dysregulation. Arginase-induced L-arginine deprivation is emerging as a key mechanism for the down-regulation of immune responses. Here, we hypothesized that arginase activity levels increase with disease severity in HIV-seropositive patients. We determined the levels of arginase activity in peripheral blood mononuclear cells from HIV-seropositive patients and uninfected control participants. Our results show that peripheral blood mononuclear cells from HIV-seropositive patients with low CD4+ T cell counts expressed statistically significantly higher levels of arginase activity, compared with patients with high CD4+ T cell counts or with uninfected control participants. Furthermore, we found a statistically significant correlation between high arginase activity level and high viral load in HIV-seropositive patients. The pandemic of human immunodeficiency virus (HIV) infection is not declining; more than 39 million people are living with HIV infection and over 2.1 million people died of HIV infection in 2007, according to estimates of the Joint United Nations Programme on HIV/AIDS and the World Health Organization. Major advances have been made in the Reprints or correspondence: Dr P. Kropf, Department of Immunology, or Dr G. Taylor, Department of Genito-Urinary Medicine and Communicable Diseases, Imperial College London, Norfolk Place, London W2 1PG, United Kingdom (p.kropf@imperial.ac.uk; g.p.taylor@imperial.ac.uk). Potential conflicts of interest: none reported. Europe PMC Funders Group Author Manuscript J Infect Dis. Author manuscript; available in PMC 2015 November 30. Published in final edited form as: J Infect Dis. 2010 August 15; 202(3): 374–385. doi:10.1086/653736. E uope PM C Fuders A uhor M ancripts E uope PM C Fuders A uhor M ancripts development of life-prolonging highly active antiretroviral therapy (ART). ART provides substantial benefit to HIV-infected individuals by reducing opportunistic infections and hospitalization and improving quality and duration of life. Chronic HIV infection progressively impairs the immune system. The progressive quantitative and qualitative impairment of CD4+ T cells is well established, and the loss of activated CD4+ T cells starts in the early phases of HIV infection and is accompanied by reduced proliferative responses and altered cytokine secretion [1]. Although the depletion of CD4+ T cells explains much of the immunosuppression, the precise reasons for the onset of immunopathology during HIV infection have not yet been resolved [2]. In particular, although there are ample population-based data correlating clinical outcomes with absolute CD4+ T cell counts, it is also apparent that individual outcomes vary widely at any given CD4+ T cell count. A variety of explanations, ranging from immunological factors to genetic, behavioral, and environmental factors, contribute to the rate of HIV disease progression [3]. The metabolism of L-arginine by arginase is emerging as a crucial mechanism for the regulation of immune responses [4–8]. Arginase 1 impairs T cell responses by modulating the bioavailability of L-arginine. Human peripheral blood polymorphonuclear cells constitutively express high amounts of arginase 1; when released from peripheral blood polymorphonuclear cells, arginase 1 profoundly suppressed the T cell activation [9]. Whereas arginase 1 is constitutively expressed in human peripheral blood polymorphonuclear cells, it is an inducible enzyme in murine granulocytes, as well as in macrophages and dendritic cells [9]. In mouse myeloid cells, high levels of arginase activity coincide with the transport of extracellular L-arginine into the cells, thereby causing a reduction of L-arginine in the microenvironment. In turn, this decrease in L-arginine results in impaired T cell responses [4–6, 9–14]. This T cell dysfunction is directly attributed to Larginine starvation, which arrests cells in the G0–G1 phase of the cell cycle [13]. Arginasemediated L-arginine deprivation has been shown to cause T cell hyporesponsiveness in a variety of physiological and pathological conditions [6, 15, 16]. Moreover, high arginase expression levels have been reported in a variety of infectious diseases, including schistosomiasis [17], trypanosomiasis [18], tuberculosis [19], and leishmaniasis [20]. Arginase hydrolyzes L-arginine to urea and ornithine, the latter being further metabolized into polyamines. Homeostasis of L-arginine depends on dietary arginine intake, protein turnover, L-arginine synthesis, and catabolism. In the present study, we have investigated the levels of arginase activity in peripheral blood mononuclear cells (PBMCs) isolated from the blood of HIV-seropositive patients. MATERIALS AND METHODS