Beyond receptor expression: The influence of receptor conformation, density, and affinity in HIV-1 infection

Enveloped animal viruses enter cells via a series of steps that ultimately result in a fusion reaction between the viral membrane and that of the host cell (Hernandez et al., 1996). Discoveries over the pas? 4 years have revealed the identities and in some cases the structures of the proteins involved in entry of human immunodeficiency virus type 1 (HIV-1) at the plasma membrane. Each step of the entry process provides information on viral tropism and pathogenesis, and each step is a real or potential target for antiretroviral agents. The rapid expansion of the AIDS pandemic, the high cost and side effects associated with highly active antiretroviral therapy, and the emergence of drug-resistant virus strains call for the development of new interventional strategies. Virus entry is a particularly attractive target since it involves the exposure, at least transiently, of highly conserved domains in Env and depends on cell surface receptors that can be targets for orally available small molecule inhibitors. Therefore, greater understanding of the entry process can have very practical benefits in addition to elucidating factors that impact viral tropism and pathogenesis. While the molecules involved in HIV-1 entry have been identified, it is clear that there is much more to viral entry than the mere presence of the appropriate receptors on the surface of a target cell. For example, macrophages are an important target cell type in vivo, and they express sufficient levels of the viral CD4 receptor as well as the two major HIV-I coreceptors, CCR5 and CXCR4 (Lee et al., 1999b). However, not all virus strains that require CXCR4 to enter cells can infect macrophages (Rana et al., 1997; Schmidtmayerova et al., 1998; Simmons et al., 1998; Yi et al., 1998). it is not clear why some viruses can utilize CXCR4 expressed on macrophages whereas others cannot. There are other examples of restricted viral entry in either cell lines or primary cell types in which viruses fail to enter cells even though the receptor needed for the membrane fusion reaction are present (Bazan et ai., 1998; Dittmar et ai., 1997; McKnight et al., 1997; Moriuchi et al., 1997; Schmidtmayerova at al., 1998; Verani et ai., 1998; Yi el ai., 1998). In addition, there are examples in which increased viral pathogenicity has been associated with relatively subtle changes in the viral envelope (Env) protein, though the mechanisms that account for this are not readily apparent (Cayabyab et ai., 1999; Karlsson et al., 1998; Liu et ai., 1999; Reimann et al., 1996). Other Env proteins have been described that appear to cause membrane fusion more efficiently than other closely related Env proteins (Etemad-Moghadam et ai., 2000; Shieh et al., 2000). The mechanisms for this are also not clear. In this review, I will discuss recent studies that indicate ways in which viruses may differ from one another in the entry process while essentially using the same molecules for the membrane fusion reaction. Specifically, there is now evidence that entry mediated by the HIV-1 Env protein is a highly cooperative process and that it is affected by receptor density as well as by Env-receptor affinities. In addition, some viral receptors exist in antigenically distinct conformations, not all of which may support virus infection equally well. Thus, it is necessary to go beyond receptor expression to fully understand the early steps of HIV-1 infection.