Immunoregulation by arginase mediated L-arginine metabolism in HIV seropositive patients

Abstract

Infection with HIV results in a chronic infection that progressively impairs the immune system. Although depletion of CD4+ T cells is frequently used to explain the deterioration in immune function, the combination of the chronicity of infection and progressive loss of CD4+ T cells are not sufficient to fully account for the immune dysregulation that occurs during the progression to AIDS. Arginase-induced L-arginine deprivation is emerging as a key mechanism for the downregulation of immune responses. In this thesis it is shown that PBMC arginase activity increases with disease severity in HIV seropositive patients. PBMC arginase activity was found to be associated with both CD4+ T cell count and plasma viral load. However, these associations were not found in the cohort of patients that were taking highly active antiretroviral therapy. HIV seropositive patients with high PBMC arginase activity were also found to have decreased levels of CD3! protein by western blot, a marker of T cell dysregulation caused by arginase mediated L-arginine depletion. The arginase1+ cells in the PBMC fraction were identified as CD15+ CD14- granulocytes and therefore named low-density granulocytes (LDGs). The percentage of LDGs was found to be associated with PBMC arginase activity. LDGs were found to be phenotypically different from neutrophils that co-purify with erythrocytes after density gradient centrifugation (normal density granulocytes – NDGs). LDGs have an increased size, increased expression of the activation markers CD63 and CD66b and a decreased expression of arginase 1 compared to NDGs. This suggests that the LDGs may be a population of activated neutrophils that have degranulated releasing arginase 1. As it has been shown that T cells have an absolute requirement for L-arginine in order to proliferate and express CD3! the results presented in this thesis suggest that arginase-induced L-arginine deprivation might contribute to T cell dysfunction in HIV infection.