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.