Role of FAS in HIV Infection

Abstract

Direct cytopathic effects cannot explain the massive CD4+ T cell depletion in acquired immunodeficiency syndrome (AIDS) patients and several indirect mechanisms may be involved. A role has been proposed for apoptosis of uninfected lymphocytes, since lymphocytes from human immunodeficiency virus-1+ (HIV-1) individuals display increased levels of spontaneous apoptosis. This process may be ascribed in part to cell exhaustion by the chronic uncontrolled infection, but can also be directly induced by viral components, such as gp120, tat or nef. A key role is played by the death receptor Fas, but a role can also be played by other death receptors, such as the TNF and TRAIL receptors. By contrast, death of HIV-infected cells seems to be Fas-independent and driven by other viral components such as vpr and HIV proteases. A further role may be played by depletion of CD4+ T cell itself and hence the withdrawal of survival factors such as cytokines. Different ability of HIV strains to induce death of infected and uninfected cells might play a role in the clinical and biological differences displayed by HIV strains. A further variability may be ascribed to the intrinsic resistance of cells to apoptosis, which may depend on the individual genetic background or the use of drugs inhibiting apoptosis. The observation that when progression of HIV infection is slow due to "apoptosis-resistant" genetic backgrounds of the patients, or defective HIV-1 strains, or successful highly active antiretroviral therapy (HAART), generally also T cell apoptosis is low, suggests that HIV-infected subjects may benefit from therapies aimed to inhibit Fas function and/or spontaneous apoptosis.

Morphine aggravates the apoptosis of simian immunodeficiency virus infected CEM x174 cells in the prolonged culture in vitro

“…This result may be partly used to explain the accelerated apoptotic process of lymphocytes in the prolonged viral infection. The works from the other laboratories also indicate that HIV-infected subjects may benefit from therapies aimed to inhibit TNF function [32].…”

Antiviral NK cell responses in HIV infection: II. viral strategies for evasion and lessons for immunotherapy and vaccination

“…Fas/FasL interactions have been implicated in the immunopathogenesis of AIDS in HIV infection (reviewed in ref. [238]). …”

CD4+ T-cell death induced by infectious and noninfectious HIV-1: role of type 1 interferon-dependent, TRAIL/DR5-mediated apoptosis

“…6 Several models showed that CD4 cross-linking and Fas ligation resulted in apoptosis of CD4 ϩ and CD8 ϩ T cells. [7][8][9] However, death mechanisms other than Fas/FasL may contribute to apoptosis of CD4 ϩ T cells during AIDS.…”