Activation of the CD95 (APO-1/Fas) system in T cells from human immunodeficiency virus type-1-infected children

Abstract

Increased apoptosis of CD4+ T cells is considered to be involved in CD4+ T-cell depletion in human immunodeficiency virus type-1 (HIV-1)- infected individuals progressing toward acquired immunodeficiency syndrome (AIDS). We have recently shown that CD95 (APO-1/Fas) expression is strongly increased in T cells of HIV-1-infected children. In this report we provide further evidence for a deregulated CD95 system in AIDS. CD95 expression in HIV-1+ children is not restricted to previously activated CD45RO+ T cells but is also increased on freshly isolated naive CD45RA+ T cells. In addition, specific CD95-mediated apoptosis is enhanced in both CD4+ and CD8+ T cells. Furthermore, levels of CD95 ligand mRNA are profoundly increased. Specific T-cell receptor/CD3-triggered apoptosis in HIV-1+ children is more enhanced in CD8+ than in CD4+ T cells. Accelerated activation induced cell death of T cells could partially be inhibited by blocking anti-CD95 antibody fragments. These data suggest an involvement of the CD95 receptor/ligand system in T-cell depletion and apoptosis in AIDS and may open new avenues of rational intervention strategies.

Does HIV cause depletion of CD4+ T cells in vivo by the induction of apoptosis?

“…The increased Fas expression was found by some investigators to be in both CD4 + and CD8 + T cells 57 , 63 , 64 , 65 and, by others, to be restricted to the CD8 + T cell population 60 . T cells isolated from HIV‐infected individuals were more sensitive to Fas receptor agonist‐induced apoptosis, 57 , 61 , 63 , 64 , 66 and both the CD4 + and CD8 + subsets showed this sensitivity 57 , 63 , 64 , 66 …”

“…In addition to the observation that Fas expression is increased in lymphocytes from HIV‐infected individuals, several laboratories have reported that the expression of Fas ligand (FasL) mRNA is also increased in peripheral blood mononuclear cells 66 , 67 . However, whether this results in increased surface levels of FasL has not yet been demonstrated.…”

“…The observations of increased Fas expression and Fas‐mediated apoptosis in T cells, however, raises several questions: (i) is this pathway involved in the increased apoptosis (either spontaneous or activation‐induced) of T cells obtained from HIV‐infected individuals; and (ii) what is the significance of these observations to the pathogenesis of HIV? With respect to the first question, there is disagreement in the field, with some investigators reporting that Fas antagonists block the increased activation‐induced cell death seen in T cells isolated from HIV‐infected individuals, 64 , 66 whereas others report no effect 69 . The latter investigators found that activation‐induced cell death was, instead, inhibited by antagonists of TNF‐related apoptosis‐inducing ligand (TRAIL), a member of the TNF family.…”

“…In an acute in vitro infection model, activation‐induced cell death was also shown to be Fas‐independent 11 . Spontaneous apoptosis of cultured T cells from HIV‐infected individuals has been reported to not involve a Fas‐dependent pathway 66 , 70 …”

T-cell re-population in HIV-infected children on highly active anti-retroviral therapy (HAART)

“…Prior to the initiation of therapy, HIV‐infected children show a substantial up‐regulation of the activation induced apoptotic marker CD95 (APO‐1) [3,4] on their T cells compared with uninfected children. It is conceivable that this contributes significantly to the pathology of the infection [5], decreasing the average life span of the child's T cells and de‐populating the peripheral pool [6,7].…”