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Evasion of cytotoxic T lymphocyte (CTL) responses by nef-dependent induction of Fas ligand (CD95L) expression on simian immunodeficiency virus-infected cells.

Xu XN, Screaton GR, Gotch FM, Dong T, Tan R, Almond N, Walker B, Stebbings R, Kent K, Nagata S, Stott JE, McMichael AJ - J. Exp. Med. (1997)

Bottom Line: Cynomolgus macaques infected with pC8 were protected against subsequent challenge with pJ5 and did not develop any AIDS-like symptoms in the 12 months after infection.The pC8-induced protection was associated with high levels of virus-specific CTL responses to a variety of viral antigens.Thus the expression of FasL may protect infected cells from CTL attack, killing viral-specific CTLs in the process, and providing a route for escaping the immune response, leading to the increased pathogenicity of pJ5. pC8, on the other hand does not induce FasL expression, allowing the development of a protective CTL response.

View Article: PubMed Central - PubMed

Affiliation: Molecular Immunology, Institute of Molecular Medicine, John Radcliffe Hospital, Oxford OX3 9DU, United Kingdom.

ABSTRACT
Inoculation of macaques with live attenuated SIV strains has been shown to protect against subsequent challenge with wild-type SIV. The protective mechanism(s) remain obscure. To study the effect in more detail, we have investigated the role of virus-specific CTL responses in macaques infected with an attenuated SIV strain (pC8), which has a four-amino acid deletion in the nef gene, as compared with the wild-type SIVmac32H clone (pJ5). Cynomolgus macaques infected with pC8 were protected against subsequent challenge with pJ5 and did not develop any AIDS-like symptoms in the 12 months after infection. The pC8-induced protection was associated with high levels of virus-specific CTL responses to a variety of viral antigens. In contrast, pJ5-infected macaques had little, if any, detectable CTL response to the viral proteins after three months. The latter group of macaques also showed increased Fas expression and apoptotic cell death in both the CD4(+) and CD8(+) populations. In vitro, pJ5 but not pC8 leads to an increase in FasL expression on infected cells. Thus the expression of FasL may protect infected cells from CTL attack, killing viral-specific CTLs in the process, and providing a route for escaping the immune response, leading to the increased pathogenicity of pJ5. pC8, on the other hand does not induce FasL expression, allowing the development of a protective CTL response. Furthermore, interruption of the Fas-FasL interaction allows the regeneration of viral-specific CTL responses in pJ5-infected animals. This observation suggests an additional therapeutic approach to the treatment of AIDS.

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(A) Comparison of FasL induction by infection with pC8 or  pJ5 as assessed by staining with the anti-FasL mAb. 24 h after infection  cells were stained with biotinylated anti-human FasL mAb (NOK-1) plus  PE-streptavidin (solid lines). Dotted lines indicate background staining  with PE-streptavidin alone. (B) Staining of infected cells (solid lines) with  anti-nef mAb demonstrates equal infectivity of pC8 and pJ5 infection.  Dotted lines indicate background staining with control mAb.
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Figure 5: (A) Comparison of FasL induction by infection with pC8 or pJ5 as assessed by staining with the anti-FasL mAb. 24 h after infection cells were stained with biotinylated anti-human FasL mAb (NOK-1) plus PE-streptavidin (solid lines). Dotted lines indicate background staining with PE-streptavidin alone. (B) Staining of infected cells (solid lines) with anti-nef mAb demonstrates equal infectivity of pC8 and pJ5 infection. Dotted lines indicate background staining with control mAb.

Mentions: PBMC or CEM cells were infected in vitro with either pC8 or pJ5 and then cocultured with 51Cr-labeled Jurkat cells (Fig. 4). The results for PBMC and CEM are equivalent, and demonstrate that pJ5-infected but not pC8- infected cells induce killing of Jurkat cells which is abrogated by Fas–Fc fusion protein, implying upregulation of FasL in the pJ5-infected cells. To confirm the results of the bioassay we analyzed FasL expression on infected CEM cells, 24 h after infection, with an anti-FasL mAb. As expected FasL was upregulated in the pJ5 infected cells to a greater degree than cells infected with pC8 (Fig. 5 A).


Evasion of cytotoxic T lymphocyte (CTL) responses by nef-dependent induction of Fas ligand (CD95L) expression on simian immunodeficiency virus-infected cells.

Xu XN, Screaton GR, Gotch FM, Dong T, Tan R, Almond N, Walker B, Stebbings R, Kent K, Nagata S, Stott JE, McMichael AJ - J. Exp. Med. (1997)

(A) Comparison of FasL induction by infection with pC8 or  pJ5 as assessed by staining with the anti-FasL mAb. 24 h after infection  cells were stained with biotinylated anti-human FasL mAb (NOK-1) plus  PE-streptavidin (solid lines). Dotted lines indicate background staining  with PE-streptavidin alone. (B) Staining of infected cells (solid lines) with  anti-nef mAb demonstrates equal infectivity of pC8 and pJ5 infection.  Dotted lines indicate background staining with control mAb.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2198954&req=5

Figure 5: (A) Comparison of FasL induction by infection with pC8 or pJ5 as assessed by staining with the anti-FasL mAb. 24 h after infection cells were stained with biotinylated anti-human FasL mAb (NOK-1) plus PE-streptavidin (solid lines). Dotted lines indicate background staining with PE-streptavidin alone. (B) Staining of infected cells (solid lines) with anti-nef mAb demonstrates equal infectivity of pC8 and pJ5 infection. Dotted lines indicate background staining with control mAb.
Mentions: PBMC or CEM cells were infected in vitro with either pC8 or pJ5 and then cocultured with 51Cr-labeled Jurkat cells (Fig. 4). The results for PBMC and CEM are equivalent, and demonstrate that pJ5-infected but not pC8- infected cells induce killing of Jurkat cells which is abrogated by Fas–Fc fusion protein, implying upregulation of FasL in the pJ5-infected cells. To confirm the results of the bioassay we analyzed FasL expression on infected CEM cells, 24 h after infection, with an anti-FasL mAb. As expected FasL was upregulated in the pJ5 infected cells to a greater degree than cells infected with pC8 (Fig. 5 A).

Bottom Line: Cynomolgus macaques infected with pC8 were protected against subsequent challenge with pJ5 and did not develop any AIDS-like symptoms in the 12 months after infection.The pC8-induced protection was associated with high levels of virus-specific CTL responses to a variety of viral antigens.Thus the expression of FasL may protect infected cells from CTL attack, killing viral-specific CTLs in the process, and providing a route for escaping the immune response, leading to the increased pathogenicity of pJ5. pC8, on the other hand does not induce FasL expression, allowing the development of a protective CTL response.

View Article: PubMed Central - PubMed

Affiliation: Molecular Immunology, Institute of Molecular Medicine, John Radcliffe Hospital, Oxford OX3 9DU, United Kingdom.

ABSTRACT
Inoculation of macaques with live attenuated SIV strains has been shown to protect against subsequent challenge with wild-type SIV. The protective mechanism(s) remain obscure. To study the effect in more detail, we have investigated the role of virus-specific CTL responses in macaques infected with an attenuated SIV strain (pC8), which has a four-amino acid deletion in the nef gene, as compared with the wild-type SIVmac32H clone (pJ5). Cynomolgus macaques infected with pC8 were protected against subsequent challenge with pJ5 and did not develop any AIDS-like symptoms in the 12 months after infection. The pC8-induced protection was associated with high levels of virus-specific CTL responses to a variety of viral antigens. In contrast, pJ5-infected macaques had little, if any, detectable CTL response to the viral proteins after three months. The latter group of macaques also showed increased Fas expression and apoptotic cell death in both the CD4(+) and CD8(+) populations. In vitro, pJ5 but not pC8 leads to an increase in FasL expression on infected cells. Thus the expression of FasL may protect infected cells from CTL attack, killing viral-specific CTLs in the process, and providing a route for escaping the immune response, leading to the increased pathogenicity of pJ5. pC8, on the other hand does not induce FasL expression, allowing the development of a protective CTL response. Furthermore, interruption of the Fas-FasL interaction allows the regeneration of viral-specific CTL responses in pJ5-infected animals. This observation suggests an additional therapeutic approach to the treatment of AIDS.

Show MeSH
Related in: MedlinePlus