Schlecht et al Herein we review the role of the CCR5 receptor in HIV-1 infection and potential methods to target it in anti- HIV-1 therapy. We review the various categories of agents and discuss speciﬁc agents that have progressed to clini- cal study. In particular, we discuss in detail the recently approved, ﬁrst in class CCR5 antagonist, maraviroc, and discuss aspects of resistance to CCR5 antagonism and the potential role of CCR5 antagonism in the management of HIV-1 infection. Viral entry and CCR5 The mechanism by which HIV-1 infects cells was a prime target for early HIV-1 researchers. In 1984, the CD4 molecule was identiﬁed as necessary for HIV-1 replication within host cells (Dalgleish et al 1984). Later studies showed that CD4 alone was not sufﬁcient for HIV-1 infection of a host cell and 2 years later, the chemokine receptor CCR5 was identiﬁed as a major co-receptor (Dragic et al 1996). The proteins required for HIV-1 entry into the cell are encoded by the env gene, the product of which is the precursor to both the gp120 and gp41 glycoproteins (Chan et al 1997). Gp120 associates with the CD4 receptor on the surface of the host cell; gp41 spans the viral envelope and mediates viral fusion with the host cell. The two glycoproteins associate non-covalently on the viral envelope as a heterodimer and then further assemble as a trimer to form the fusion mediating structure (Kwong et al 1998). On exposure of the virus to a cell expressing CD4, gp120 interacts with the CD4 molecule, thereby inducing a conformational change in gp120 that enables binding to the chemokine receptor (see Figure 1). Binding of gp120 to the chemokine receptor (either CCR5 or CXCR4) generates a conformational change in gp41, leading to insertion of a lipophilic region of gp41, known as the fusion peptide, into the lipid bilayer of the host cell. A transitional intermediate state is created in which gp41 is inserted into both the viral envelope and the cellular membrane. The virus and the cell are brought together as gp41 folds on itself in a hairpin structure, thereby bringing the viral envelope into close proximity with the cell membrane of the CD4+ host cell. Fusion is initiated, and the viral core contents are spilled into the cytoplasm (Chan et al 1998; Eckert et al 2001). Figure 1 HIV-1 entry via CD4 and coreceptor binding gp120 binds to CD4 (A) and undergoes conformational changes that expose the co-receptor binding site (B) and enable binding to the chemokine receptor (C). Structural changes are then induced in gp41 that extend the helical domains to form a ‘pre-hairpin intermediate’ (D).The hydrophobic fusion peptide inserts into the target cell membrane, causing gp41 to span between the virus and cell membranes.The gp41 helices then fold into a six-helix bundle, bringing together the N-terminal and C-terminal domains and thus the viral and cellular membranes (E). Contact between the membranes allows mixing of the outer leaﬂets followed by the development of a fusion pore (G). gp120 is omitted from panels F and G for the sake of clarity. Reprinted with permission from Starr-Spires LD, Collman RG. 2002. HIV-1 entry and entry inhibitors as therapeutic agents. Clin Lab Med, 22:681–701. Copright 2002 © Elsevier. 474 Therapeutics and Clinical Risk Management 2008:4(2)