Maraviroc: a review of its use in HIV infection and beyond

Abstract

The human immunodeficiency virus-1 (HIV-1) enters target cells by binding its envelope glycoprotein gp120 to the CD4 receptor and/or coreceptors such as C-C chemokine receptor type 5 (CCR5; R5) and C-X-C chemokine receptor type 4 (CXCR4; X4), and R5-tropic viruses predominate during the early stages of infection. CCR5 antagonists bind to CCR5 to prevent viral entry. Maraviroc (MVC) is the only CCR5 antagonist currently approved by the United States Food and Drug Administration, the European Commission, Health Canada, and several other countries for the treatment of patients infected with R5-tropic HIV-1. MVC has been shown to be effective at inhibiting HIV-1 entry into cells and is well tolerated. With expanding MVC use by HIV-1-infected humans, different clinical outcomes post-approval have been observed with MVC monotherapy or combination therapy with other antiretroviral drugs, with MVC use in humans infected with dual-R5- and X4-tropic HIV-1, infected with different HIV-1 genotype or infected with HIV-2. This review discuss the role of CCR5 in HIV-1 infection, the development of the CCR5 antagonist MVC, its pharmacokinetics, pharmacodynamics, drug–drug interactions, and the implications of these interactions on treatment outcomes, including viral mutations and drug resistance, and the mechanisms associated with the development of resistance to MVC. This review also discusses available studies investigating the use of MVC in the treatment of other diseases such as cancer, graft-versus-host disease, and inflammatory diseases.

Structural Analysis of Chemokine Receptor–Ligand Interactions

“…15 CCR5 binds CCL2, CCL3, CCL4, CCL5, CCL8, CCL11, CCL13, and CCL14 CC chemokines and is the major HIV-1 coreceptor. 1 The FDA approved CCR5 antagonist 16 (9) is used for the treatment of patients with HIV (R5-tropic HIV-1), and a crystal structure of rubredoxin fused CCR5 bound to 16 (PDB 4MBS, Figures 1d, 3b) has been reported. 12 CCR9 activation by CCL25 plays a key role in leukocyte recruitment to the gut and is a therapeutic target in inflammatory bowel disease.…”

“…8 A variety of proteins, peptides, and small-molecule ligands have been identified that can modulate the activity of chemokine receptors 1 by targeting the minor or major pockets in the 7TM helical bundle or intracellular binding pocket (Figures 1–2). Examples of small nonpeptide ligands are the clinically approved drugs 16 (Maraviroc, CCR5 antagonist, Figures 3 and 11) 9 and 1 (plerixafor/AMD3100, CXCR4 antagonist, Figure 11), 10 used for the treatment of HIV and stem cell mobilization, respectively. Molecular pharmacological, medicinal chemistry, and molecular modeling studies have provided insights into molecular determinants of chemokine receptor modulation 1,2,4 and in the past few years the first high-resolution crystal structures of chemokine receptors have been solved that give more detailed structural information on the interaction of chemokine receptors and their ligands.…”

HEK293T Cells Are Heterozygous for CCR5 Delta 32 Mutation

“…The pathogen of AIDS is HIV [ 1 ]. HIV entry into CD4+ cells is dependent on the receptor CD4 and co-receptors, such as CCR5 (C-C chemokine receptor 5) or CXCR4 (C-X-C chemokine receptor type 4) on the surface of target cells [ 4 , 6 – 9 ]. CCR5-tropic viruses predominate most isolates from human bodies globally and usually found in the early HIV infection.…”

“…CCR5-tropic viruses predominate most isolates from human bodies globally and usually found in the early HIV infection. CXCR4-tropic viruses are fewer, and usually found in the late stage of infection [ 4 , 9 , 10 ]. CCR5 delta 32 mutation is a deletion of 32 base pairs after amino acid position 185, resulting in a premature and non-functional CCR5 receptor [ 9 , 11 ].…”

Bad neighbours cause bad blood

“…One such drug, Maraviroc, is used to treat HIV infection, and also blocks graft versus host disease (a complication of bone marrow transplantation) 9 . The authors find that such agents are more effective at preventing MPN post-transplant than in combatting established JMML in mice.…”