AN EPITOPE-SELECTIVE, TRANSPORTER ASSOCIATED WITH ANTIGEN PRESENTATION (TAP)-1 2-INDEPENDENT PATHWAY AND A MORE GENERAL TAP-1/2-DEPENDENT ANTIGEN-PROCESSING PATHWAY ALLOW RECOGNITION OF THE HIV-1 ENVELOPE GLYCOPROTEIN BY CD8(+) CTL/

The lysis of virally infected cells by CTLs requires the recognition o f processed fragments of viral proteins presented in association with class I MHC molecules on the surfaces of infected cells. Processing be gins in the cytosol with the degradation of viral proteins into peptid es that are then transported into the endoplasmic reticulum (ER) for a ssociation with newly synthesized class I molecules. Transport is medi ated by a heterodimer of the MHC-encoded proteins, transporter associa ted with Ag presentation (TAP)-1 and TAP-2. Uncertainty exists over th e site of processing of viral envelope (env) proteins. The extracellul ar domains of env proteins are not present in the cytosol, the site in which the class I-restricted Ag-processing pathway begins. Rather, th e ecto-domains of env proteins are cotranslationally translocated into the ER during biosynthesis. We have analyzed the processing of the HI V-1 env protein by using a large series of env-specific human CD8(+) C TL clones. These studies have led to the delineation of two distinct p rocessing pathways. The first pathway permits a subset of class I-rest ricted epitopes in the ectodomain of the env protein to be generated e fficiently by a TAP-1/2-independent mechanism localized to the ER or a premedial Golgi compartment. A second, more general pathway that is c apable of generating all env epitopes uses as a substrate env protein mislocalized to the cytosol and produces peptides that are transported from the cytoplasm to the ER in a TAP-1/2-dependent fashion.