The process of retroviral entry into a target cell represents the first step in the viral infection cycle. It is characterized by a complex series of events that are initiated through the binding of the viral surface glycoproteins to specific receptor molecules on the cell's outer membrane. This interaction is thought to trigger a conformational change in the viral glycoprotein, which then mediates fusion of the lipid bilayers of the cell and viral membranes and allows the genetic material of the virus to be introduced into the host-cell cytoplasm.

The envelope glycoprotein complex of retroviruses includes two polypeptides, an external, glycosylated hydrophilic polypeptide (SU) and a membrane-spanning protein (TM), that together form an oligomeric knob or knobbed spike on the surface of the virion. Both polypeptides are encoded by the env gene and are synthesized in the form of a polyprotein precursor that is proteolytically cleaved during its transport to the surface of the cell (see Chapter 7). These proteins are not required for the assembly of enveloped viral particles, but they do have an essential role in the entry process. The SU domain binds to a specific receptor molecule on the target cell. This binding event appears to activate the membrane fusion-inducing potential of the TM protein and, by a process that remains largely undefined, the viral and cell membranes then fuse. The specificity of the SU/receptor interaction defines the host range and tissue tropism of a retrovirus; viral particles lacking envelope glycoproteins are noninfectious, and cells lacking a receptor are nonpermissive for viral entry. Viruses may bind weakly to resistant cells through relatively nonspecific interactions, but, in the absence of a specific receptor molecule, they are unable to initiate the infection process.

The receptors for retroviral entry that have been identified and characterized to date appear to be distinct for the different major viral subgroups, and there is no clear association between their normal cell function and their receptor activity. For human and simian immunodeficiency viruses (HIV and SIV), the CD4 antigen found on T-helper cells, macrophages, and a few other cells is a high-affinity receptor molecule involved in cell-cell recognition (Dalgleish et al. 1984; Klatzmann et al. 1984; Maddon et al. 1986), whereas the receptors for mammalian C-type viruses, including the ecotropic (MLV-E) (Albritton et al. 1989) and amphotropic (MLV-A) (Miller et al. 1994; van Zeijl et al. 1994) murine leukemia viruses, the gibbon ape leukemia virus (GALV) (O'Hara et al. 1990), and feline leukemia virus subgroup B (FeLV-B) (Takeuchi et al. 1992), are three different membrane transporter molecules. For the subgroup A avian sarcoma/ leukosis viruses (ASLV-A), the receptor is a small, plasma-membrane protein of unknown function containing a single copy of a sequence repeated multiple times in the receptor for low-density lipoprotein (Bates et al. 1993; Young et al. 1993). The receptor for the closely related subgroup B ASLV is an unrelated protein bearing resemblance to cytokine receptors (J. Brojatsch et al., unpubl.). For bovine leukemia virus (BLV), a novel receptor protein has been cloned with no similarity to other receptors and no known cell function (Ban et al. 1993).

Binding of the viral glycoprotein to its cognate receptor is not by itself necessarily sufficient to trigger viral entry. Activation of the fusion potential of the TM protein requires a functional association between the receptor and SU. The mechanistic aspects of this process are not yet clearly defined, but they may involve conformational changes within the oligomeric glycoprotein complex, as shown for HIV-1 and SIV (Sattentau and Moore 1993; Sattentau et al. 1993). The molecular events involved in the merging of the apposing lipid bilayers also remain to be defined. Nevertheless, it is likely that several glycoprotein/receptor oligomers must associate within the plane of the membrane for an effective “fusion-pore” to form.

This chapter summarizes our current knowledge of the molecules and processes involved in defining retroviral host range and mediating retroviral entry into a target cell.