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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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Soluble Fas–Fc fusion protein regenerates CTL response  from SIV pJ5-infected macaques. PBMCs were isolated from macaques  (P93) 6 mo after infection and set up for bulk culture CTL in the presence or absence of either Fas–Fc fusion protein (10 μg/ml) or soluble  CD4 (5 μg/ml) for 14 d. After washing the cells, the virus-specific CTL  activities were determined as described in Materials and Methods. The  data are representative of three seperate experiments.
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Figure 7: Soluble Fas–Fc fusion protein regenerates CTL response from SIV pJ5-infected macaques. PBMCs were isolated from macaques (P93) 6 mo after infection and set up for bulk culture CTL in the presence or absence of either Fas–Fc fusion protein (10 μg/ml) or soluble CD4 (5 μg/ml) for 14 d. After washing the cells, the virus-specific CTL activities were determined as described in Materials and Methods. The data are representative of three seperate experiments.

Mentions: We tested this hypothesis with a bulk culture CTL assay in the presence or absence of Fas–Fc fusion protein. No CTL responses were elicited from cells cultured with medium alone or soluble CD4 protein, in agreement with our previous results on the pJ5-infected macaques. However, in the presence of soluble Fas–Fc fusion protein a nef-specific CTL response was established (Fig. 7).


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)

Soluble Fas–Fc fusion protein regenerates CTL response  from SIV pJ5-infected macaques. PBMCs were isolated from macaques  (P93) 6 mo after infection and set up for bulk culture CTL in the presence or absence of either Fas–Fc fusion protein (10 μg/ml) or soluble  CD4 (5 μg/ml) for 14 d. After washing the cells, the virus-specific CTL  activities were determined as described in Materials and Methods. The  data are representative of three seperate experiments.
© Copyright Policy
Related In: Results  -  Collection

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

Figure 7: Soluble Fas–Fc fusion protein regenerates CTL response from SIV pJ5-infected macaques. PBMCs were isolated from macaques (P93) 6 mo after infection and set up for bulk culture CTL in the presence or absence of either Fas–Fc fusion protein (10 μg/ml) or soluble CD4 (5 μg/ml) for 14 d. After washing the cells, the virus-specific CTL activities were determined as described in Materials and Methods. The data are representative of three seperate experiments.
Mentions: We tested this hypothesis with a bulk culture CTL assay in the presence or absence of Fas–Fc fusion protein. No CTL responses were elicited from cells cultured with medium alone or soluble CD4 protein, in agreement with our previous results on the pJ5-infected macaques. However, in the presence of soluble Fas–Fc fusion protein a nef-specific CTL response was established (Fig. 7).

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