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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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PBMCs from SIV pJ5-infected macaques kill Fas-sensitive  target are CD4-dependent. PBMCs from pJ5-infected or uninfected  macaques (n = 2 in each group) were stimulated with Con A (5 μg/ml)  for 12 h. After washing three times with RPMI, CD4+ or CD8+ T cells  were depleted by using anti-CD4 or CD8 magnetic beads, respectively.  Cells were then cocultured with 51Cr-labeled Jurkat cells in the presence  or absence of fusion proteins (10 μg/ml) or anti-human FasL mAbs  (5 μg/ml) for 12–16 h. Specific lysis was assayed as described in Fig. 4.
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Figure 6: PBMCs from SIV pJ5-infected macaques kill Fas-sensitive target are CD4-dependent. PBMCs from pJ5-infected or uninfected macaques (n = 2 in each group) were stimulated with Con A (5 μg/ml) for 12 h. After washing three times with RPMI, CD4+ or CD8+ T cells were depleted by using anti-CD4 or CD8 magnetic beads, respectively. Cells were then cocultured with 51Cr-labeled Jurkat cells in the presence or absence of fusion proteins (10 μg/ml) or anti-human FasL mAbs (5 μg/ml) for 12–16 h. Specific lysis was assayed as described in Fig. 4.

Mentions: This phenomenon does not result from a difference in the infectivity of the two viral strains. The percentage of infected cells at 3 d, pC8 (98.3%; 76.5 MFI) and pJ5 (98.1%; 78.8 MFI), are equivalent when assessed with anti- nef (Fig. 5 B). A similar result was obtained with anti-env mAb (data not shown). Moreover, the lysis of Jurkat cells is not due to direct viral invasion as Jurkat cells are resistant to SIV infection (our unpublished observation and others [34]). Similar results were also made with fresh PBMC isolated from macaques 3 mo after infection with pJ5 (Fig. 6). Fractionation of T cells from these macaques demonstrates that although the CD8+ population expresses more Fas, the majority of FasL activity resides in the CD4+ population, probably on SIV-infected cells.


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)

PBMCs from SIV pJ5-infected macaques kill Fas-sensitive  target are CD4-dependent. PBMCs from pJ5-infected or uninfected  macaques (n = 2 in each group) were stimulated with Con A (5 μg/ml)  for 12 h. After washing three times with RPMI, CD4+ or CD8+ T cells  were depleted by using anti-CD4 or CD8 magnetic beads, respectively.  Cells were then cocultured with 51Cr-labeled Jurkat cells in the presence  or absence of fusion proteins (10 μg/ml) or anti-human FasL mAbs  (5 μg/ml) for 12–16 h. Specific lysis was assayed as described in Fig. 4.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2198954&req=5

Figure 6: PBMCs from SIV pJ5-infected macaques kill Fas-sensitive target are CD4-dependent. PBMCs from pJ5-infected or uninfected macaques (n = 2 in each group) were stimulated with Con A (5 μg/ml) for 12 h. After washing three times with RPMI, CD4+ or CD8+ T cells were depleted by using anti-CD4 or CD8 magnetic beads, respectively. Cells were then cocultured with 51Cr-labeled Jurkat cells in the presence or absence of fusion proteins (10 μg/ml) or anti-human FasL mAbs (5 μg/ml) for 12–16 h. Specific lysis was assayed as described in Fig. 4.
Mentions: This phenomenon does not result from a difference in the infectivity of the two viral strains. The percentage of infected cells at 3 d, pC8 (98.3%; 76.5 MFI) and pJ5 (98.1%; 78.8 MFI), are equivalent when assessed with anti- nef (Fig. 5 B). A similar result was obtained with anti-env mAb (data not shown). Moreover, the lysis of Jurkat cells is not due to direct viral invasion as Jurkat cells are resistant to SIV infection (our unpublished observation and others [34]). Similar results were also made with fresh PBMC isolated from macaques 3 mo after infection with pJ5 (Fig. 6). Fractionation of T cells from these macaques demonstrates that although the CD8+ population expresses more Fas, the majority of FasL activity resides in the CD4+ population, probably on SIV-infected cells.

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