Role of CD4 in the Penetration of Cells by HIV

Abstract

Enveloped viruses penetrate host cells by two distinct. mechanisms: by direct fusion between viral and cell membrane or by receptor-mediated endocytosis. Though not mutually exclusive, it is likely that viruses use one pathway or the other, that one predominates, or even that both occur but only one results in successful infection in the sense that productive infection ensues. Stein et al.¹ and McClure et al.² have shown convincingly that the low pH environment of the endosome is not necessary for infection by HIV. This does not mean that endocytosis does not occur; it may be that HIV is endocytosed but the low pH environment is not required for access of viral material to the cytoplasm. Electron microscopic studies have not been particularly helpful, and one can find examples supporting either mechanism^1,3. Favoring the direct fusion mechanism is the observation that HIV-infected cells fuse with uninfected CD4 cells at neutral pH. The membrane fusion or syncytia phenomenon requires interaction between CD4 and viral envelope glycoprotein gpl20 and its mechanism is likely analagous to infection by cell-free virus. However, the endocytosis mechanism has a certain natural appeal in that the CD4 molecule, the receptor for HIV, has been shown to be internalized in endosomes as a result of T cell activation by mitogen, antigen, or phorbol ester. This occurs as a consequence of protein kinase C (PKC) activation and is associated with phosphorylation of the cytoplasmic segment of CD4^4-7. Bedinger et al.⁸ and Maddon et al.⁷ have made CD4 constructs lacking the cytoplasmic segment of CD4 that are incapable of PKC-induced internalization. Cells expressing these mutant CD4 molecules can be readily infected with HIV ^7,8. However, ligand binding may induce internalization of a receptor independent of mechanisms involving PKC-activated phosphorylation of the cytoplasmic segment of the receptor. The EGF receptor is a case in point. Mutations in the cytoplasmic segment of the EGF receptor rendering it unresponsive to PKC induced internalization do not affect ligand-induced internalization⁹.