New approaches in the treatment of HIV/AIDS – focus on maraviroc and other CCR5 antagonists

REVIEW New approaches in the treatment of HIV/AIDS – focus on maraviroc and other CCR5 antagonists Hans P Schlecht 1 Sarah Schellhorn 2 Bruce J Dezube 3 Jeffrey M Jacobson 1 1 Department of Medicine (Infectious Diseases), Hahnemann University Hospital, Drexel University College of Medicine, Philadelphia, PA, USA; 2 Department of Medicine, 3 Department of Medicine (Hematology/Oncology), Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA Abstract: Treatment of HIV-1 infection has produced dramatic success for many patients. Nevertheless, viral resistance continues to limit the efficacy of currently available agents in many patients. The CCR5 antagonists are a new class of antiretroviral agents that target a necessary coreceptor for viral entry of many strains of HIV-1. Recently, the first agent within this class, maraviroc, was approved by a number of regulatory agencies, including the Food and Drug Administration. 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 clinical study. 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. Keywords: CCR5, HIV-1 tropism, coreceptor, maraviroc, viral entry, chemokine receptor Introduction Correspondence: Hans P Schlecht Drexel University College of Medicine, Mail Stop 461, 245 N. 15th Street, Philadelphia, PA, 19102-1192, USA Tel +1 215 762 6794 Fax +1 215 762 3031 Email The widespread use of highly active antiretroviral therapy (HAART) has profoundly affected the treatment and epidemiology of HIV-1 infection within the developed world, where HIV-1 infection has largely become a chronic illness (Palella et al 1998). HAART’s dramatic success has contributed in saving at least 3 million years of life in the US since 1989 and will aid a patient living with HIV-1 to live more than 13 years longer today than if they had been diagnosed in 1988 (Walensky et al 2006). Despite tremendous impact, patient benefit from HAART is not simple or uniform; 25% of patients starting HAART either do not achieve viral suppression or lose it within 2 to 3 years, frequently due to viral resistance (Bartlett et al 2001; Mocroft et al 2002; Holmberg et al 2003). Moreover, the rate of acquired resistance in patients recently infected with HIV-1 has grown from 13.2% during the period 1995 to 1998 to 24.1% during 2003 to 2004, including some with rapid progression to AIDS (Markowitz et al 2005; Shet et al 2006). In spite of the recalcitrant nature of HIV-1 viral resistance, recent advances have been substantial. The approval of darunavir, a protease inhibitor with potent efficacy against multi-drug resistant strains of HIV-1, has helped shift the emphasis of HIV-1 salvage treatment from preserving immune function to complete suppression of viral replication and immune reconstitution (Hammer et al 2006). With the advent of additional classes of agents such as CCR5 and integrase antagonists, patients with extensive multi-drug resistance will likely be able to achieve an undetectable viral load. Nevertheless, resistance to these new agents has already been seen in vitro and will inevitably arise clinically (Mosley et al 2006; Cooper et al 2007; Steigbigel et al 2007). HIV clinical investigators must be prepared to overcome these defenses by refining the current use of HAART and wisely integrating new agents, such as CCR5 antagonists, in order to minimize the impact of HIV-1 viral resistance on patients and populations (Schooley and Mellors 2007). Therapeutics and Clinical Risk Management 2008:4(2) 473–485 © 2008 Dove Medical Press Limited. All rights reserved 473 Schlecht et al Herein we review the role of the CCR5 receptor in HIV-1 infection and potential methods to target it in antiHIV-1 therapy. We review the various categories of agents and discuss specific agents that have progressed to clinical 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 permissio (...truncated)