ENDOCYTOSIS OF ENDOGENOUSLY SYNTHESIZED HIV-1 ENVELOPE PROTEIN - MECHANISM AND ROLE IN PROCESSING FOR ASSOCIATION WITH CLASS-II MHC

CD4(+) T cell clones specific for the HIV-1 envelope (env) protein are able to recognize not only uninfected APC that have taken up and proc essed exogenous env protein, but also virally infected cells expressin g the env protein. We have evaluated the hypothesis that endocytosis o f endogenously synthesized env protein from the plasma membrane of inf ected cells permits entry of the protein into the MHC class II-restric ted Ag processing pathway. We show here that the env protein of HIV-1 is internalized at a surprisingly high rate through a mechanism that i s dependent upon a tyrosine-containing motif located in the cytoplasmi c domain of the gp41 subunit. Mutation of a critical cytoplasmic tyros ine residue or truncation of the C-terminal portion of the cytoplasmic domain resulted in forms of the env protein that did not undergo rapi d internalization. However, by a variety of assays, these poorly inter nalized forms of the env protein were processed for class II-restricte d Ag presentation as efficiently as wild-type env protein, indicating that internalization by this pathway is not essential for class II-res tricted presentation. In addition, a secreted form of the env protein was presented efficiently by class II MHC under conditions that preven ted re-uptake by endocytosis. Taken together, these results suggest th at although rapid endocytosis from the cell surface is likely to be a major mechanism by which endogenously synthesized env protein is proce ssed for association with class II MHC, an internal pathway may also b e used.