Apoptotic death of lymphocytes in murine acquired immunodeficiency syndrome: Involvement of Fas‐Fas ligand interaction

Abstract

Murine acquired immunodeficiency syndrome (MAIDS) is caused by a defective murine leukemia virus. The disease is characterized by abnormal lymphoproliferation, impaired T and B cell function and aberrant regulation of cytokines. Both T and B lymphocytes show activated phenotypes, but undergo apoptotic death with characteristic DNA fragmentation. These results indicate the presence of a continuous activation death pathway of the lymphocytes in MAIDS. Overexpression of the bcl-2 transgene in lymphocytes showed no effect on the apoptotic cell death or on the development of the disease. In contrast, mice carrying mutations in either Fas or Fas ligand exhibited accelerated progression of the disease upon infection with MAIDS virus. These results suggest the involvement of Fas-Fas ligand system in the pathogenesis of MAIDS.

Apoptosis by CD95 (Fas)-dependent and -independent mechanisms in Peyer's patch lymphocytes in murine retrovirus-induced immunodeficiency syndrome

“…To assess the contribution of the CD95 system to the apoptosis of T and B cells in PP of MAIDS mice, we examined the absolute numbers and percentage of cells in PP from LP-BM5-infected B6 lpr mice in which CD95 is mutant (1). Kanagawa et al have found that murine AIDS is accelerated in CD95 mutant C57BL/6 lpr/lpr mice (23). Consistent with their findings, MAIDS was accelerated in CD95-deficient B6 lpr mice as assessed by mortality, splenomegaly, and increased number of abnormal B220 ϩ T cells (unpublished observation).…”

“…We reported that the level of CD95 is increased on splenocytes in MAIDS mice (15). Recently, Kanagawa et al have demonstrated that lpr mice deficient in CD95 exhibited drastically accelerated disease development, suggesting the involvement of the CD95 system in the regulation of the lymphoproliferation in MAIDS mice (23).…”

“…Westendorp et al have reported that CD95-mediated apoptosis contributes to CD4 ϩ T-cell apoptosis in AIDS (48). These findings, together with a recent report showing the accelerated progression of MAIDS in CD95-mutated B6 lpr mice, indicated that the CD95/CD95 L system also plays a vital role in the host defense mechanism against retrovirus infection through eliminating virus-infected host cells (23). Kanagawa et al have shown that the number of CD4 ϩ and CD8 ϩ T cells, including Thy1 Ϫ CD4 ϩ T cells, increases about sixfold, while non-T cells showed only a twofold increase in number in B6 lpr mice with MAIDS compared with B6 MAIDS mice (23).…”

Possible origin of murine AIDS (MAIDS) virus: conversion of an endogenous retroviral p12gag sequence to a MAIDS-inducing sequence by frameshift mutations

“…Recombination between the defective MAIDS virus and an endogenous sequence has been reported, suggesting that the creation of virus variants by the recombination event may play an important role in the pathogenesis and escape from host immune attack (10,13). However, we observed no such event, although the various changes of nucleotide sequences in p12 gag regions from the inoculated mutant viruses were determined by PCR amplification (data not shown).…”