HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 ENVELOPE PROTEIN ENDOCYTOSIS MEDIATED BY A HIGHLY CONSERVED INTRINSIC INTERNALIZATION SIGNAL IN THE CYTOPLASMIC DOMAIN OF GP41 IS SUPPRESSED IN THE PRESENCE OF THE PR55(GAG)PRECURSOR PROTEIN

The mechanisms involved in the incorporation of viral glycoproteins in to virions are incompletely understood. For retroviruses, incorporatio n may involve interactions between the Gag proteins of these viruses a nd the cytoplasmic domains of the relevant envelope (Env) glycoprotein s. Recent studies have identified within the cytoplasmic tail of the h uman immunodeficiency virus type 1 (HIV-1) Env protein a tyrosine-cont aining internalization motif similar to those found in the cytoplasmic domains of certain cell surface proteins that undergo rapid constitut ive endocytosis in clathrin-coated pits. Given that surface expression of the HIV-1 Env protein is essential for the production of infectiou s virus, the presence Of this internalization motif is surprising. We show here that in contrast to the rapid rate of Fm protein internaliza tion observed in cells expressing the Env protein in the absence of ot her HIV-1 proteins, the rate of internalization of Env protein from th e surfaces of HIV-l-infected cells is extremely slow. The presence of the Pr55(gag) precursor protein is necessary and sufficient for inhibi tion of Env protein internalization, while a mutant Pr55(gag) that is incapable of mediating Env incorporation into virions is also unable t o inhibit endocytosis of the Env protein. The failure of the Env prote in to undergo endocytosis from the surface of an HIV-1-infected cell m ay reflect the fact that the proposed interaction of the matrix domain of the Gag protein with Env during assembly prevents the interaction of Env with host adaptin molecules that recruit plasma membrane molecu les such as the transferrin receptor into clathrin-coated pits. When t he normal ratio of Gag and Env proteins in the infected cells is alter ed by overexpression of Env protein, this mechanism allows removal of excess Env protein from the cell surface. Taken together, these result s suggest that a highly conserved system to reduce surface levels of t he Env protein functions to remove Env protein that is not associated with Gag and that is therefore not destined for incorporation into vir ions. This mechanism for the regulation of surface levels of Fm protei n may protect infected cells from Env-dependent cytopathic effects or Env-specific immune responses.