EVASION OF CYTOTOXIC T-LYMPHOCYTE (CTL) RESPONSES BY NEF-DEPENDENT INDUCTION OF FAS LIGAND (CD95L) EXPRESSION ON SIMIAN IMMUNODEFICIENCY VIRUS-INFECTED CELLS

Inoculation of macaques with live attenuated SIV strains has been show n to protect against subsequent challenge with wild-type SIV. The prot ective mechanism(s) remain obscure. To study the effect in more detail , we have investigated the role of virus-specific CTL responses in mac aques infected with an attenuated SIV strain (pC8), which has a four-a mino acid deletion in the nef gene, as compared with the wild-type SIV mac32H clone (pJ5). Cynomolgus macaques infected with pC8 were protect ed against subsequent challenge with pJ5 and did not develop any AIDS- like symptoms in the 12 months after infection. The pC8-induced protec tion was associated with high levels of virus-specific CTL responses t o a variety of viral antigens. In contrast, pJ5-infected macaques had little, if any, detectable CTL response to the viral proteins after th ree months. The latter group of macaques also showed increased Fas exp ression and apoptotic cell, death in both the CD4(+) and CD8(+) popula tions. In vitro, pJ5 but not PC8 leads to an increase in Fast expressi on on infected cells. Thus the expression of Fast may protect infected cells from CTL attack, killing viral-specific CTLs in the process, an d providing a route for escaping the immune response, leading to the i ncreased pathogenicity of pJ5.pC8, on the other hand does not induce F ast expression, allowing the development of a protective CTL response. Furthermore, interruption of the Fas-FasL interaction allows the rege neration of viral-specific CTL responses in pJ5-infected animals. This observation suggests an additional therapeutic approach to the treatm ent of AIDS.