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 of processed fragments of viral proteins presented in association with class I MHC molecules on the surfaces of infected cells. Processing begins in the cytosol with the degradation of viral proteins into peptides that are then transported into the endoplasmic reticulum (ER) for association with newly synthesized class I molecules. Transport is mediated by a heterodimer of the MHC-encoded proteins, transporter associated with Ag presentation (TAP)-1 and TAP-2. Uncertainty exists over the site of processing of viral envelope (env) proteins. The extracellular domains of env proteins are not present in the cytosol, the site in which the class I-restricted Ag-processing pathway begins. Rather, the ecto-domains of env proteins are cotranslationally translocated into the ER during biosynthesis. We have analyzed the processing of the HIV-1 env protein by using a large series of env-specific human CD8+ CTL clones. These studies have led to the delineation of two distinct processing pathways. The first pathway permits a subset of class I-restricted epitopes in the ecto-domain of the env protein to be generated efficiently by a TAP-1/2-independent mechanism localized to the ER or a premedial Golgi compartment. A second, more general pathway that is capable 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.
Hammond
S A
SA
Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Johnson
R P
RP
Kalams
S A
SA
Walker
B D
BD
Takiguchi
M
M
Safrit
J T
JT
Koup
R A
RA
Siliciano
R F
RF
D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D000071450:ATP Binding Cassette Transporter, Subfamily B, Member 3; D018528:ATP-Binding Cassette Transporters / Q000502:physiology*; D000595:Amino Acid Sequence; D017951:Antigen Presentation / Q000502:physiology*; D002460:Cell Line; D002999:Clone Cells; D003601:Cytotoxicity Tests, Immunologic; D010450:Endopeptidases / Q000378:metabolism; D000939:Epitopes / Q000276:immunology; D015686:Gene Products, env / Q000276:immunology*; D005822:Genetic Vectors / Q000096:biosynthesis; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D008565:Membrane Proteins; D008969:Molecular Sequence Data; D012697:Serine Endopeptidases; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014616:Vaccinia virus; D014763:Viral Matrix Proteins / Q000502:physiology
D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D000071450:ATP Binding Cassette Transporter, Subfamily B, Member 3; D018528:ATP-Binding Cassette Transporters; C037662:EBV-associated membrane antigen, Epstein-Barr virus; D000939:Epitopes; D015686:Gene Products, env; D008565:Membrane Proteins; C073119:TAP1 protein, human; D014763:Viral Matrix Proteins; C071692:TAP2 protein, human; D010450:Endopeptidases; D012697:Serine Endopeptidases; C026515:type I signal peptidase