Effects of CC chemokine receptor 5 (CCR5) inhibitors on the dynamics of CCR5 and CC-chemokine–CCR5 interactions

Nakata, Hirotomo; Kruhlak, Michael J.; Kamata, Wakako; Ogata-Aoki, Hiromi; Li, Jianfeng; Maeda, Kenji; Ghosh, Arun K.; Mitsuya, Hiroaki

doi:10.3851/imp1529

Cited by 4 publications

(3 citation statements)

References 43 publications

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“…As other groups have reported, maraviroc and other CCR5 antagonists inhibit the binding of the natural CCR5 ligands MIP-1a, MIP-1b, and RANTES to CCR5. 28,29 Because CCR5 receptor-ligand complexes are typically internalized by the cell after initial binding, the blockade of the receptor-ligand interaction prevents the internalization of both CCR5 and its ligands, resulting in an increase in CCR5 on the cell surface as well as an increase in circulating levels of CCR5 ligands, 28,29 as we observed in our trial. Presumably, this increase in CCR5 ligands would not have a physiological consequence on CCR5-mediated signaling because the increases in ligand are occurring as a consequence of CCR5 blockade.…”

Section: Discussionsupporting

confidence: 60%

“…Because CCR5 receptor-ligand complexes are typically internalized by the cell after binding, the blockade of the receptor-ligand interaction by maraviroc and other CCR5 inhibitors prevents the internalization of both CCR5 and its natural ligands, resulting in an increase in CCR5 on the cell surface as well as an increase in circulating CCR5 ligands. 28,29 Although increases in CCR5 ligands (MIP-1a, MIP-1b, and regulated on activation normal T expressed and secreted [RANTES]) are unlikely to affect signaling through CCR5 while maraviroc is bound, these ligands also bind other chemokine receptors including CCR3 and CCR4 on T cells, For personal use only. on May 7, 2018.…”

Section: Changes In T-cell Ccr5 Expression and Plasma Ccr5 Ligand Levelsmentioning

confidence: 99%

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The immunologic effects of maraviroc intensification in treated HIV-infected individuals with incomplete CD4+ T-cell recovery: a randomized trial

Hunt

Shulman

Hayes

et al. 2013

Blood

128

123

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Key Points• Maraviroc intensification unexpectedly increases T-cell activation in peripheral blood and rectal mucosa during treated HIV infection.• Maraviroc appears to redistribute CD81 T cells from the gut to peripheral blood during treated HIV infection.The CCR5 inhibitor maraviroc has been hypothesized to decrease T-cell activation in HIVinfected individuals, but its independent immunologic effects have not been established in a placebo-controlled trial. We randomized 45 HIV-infected subjects with CD4 counts <350 cells per mm 3 and plasma HIV RNA levels <48 copies per mL on antiretroviral therapy (ART)to add maraviroc vs placebo to their regimen for 24 weeks followed by 12 weeks on ART alone. Compared with placebo-treated subjects, maraviroc-treated subjects unexpectedly experienced a greater median increase in % CD381HLA-DR1 peripheral blood CD81 T cells at week 24 (12.2% vs 20.7%, P 5 .014), and less of a decline in activated CD41 T cells (P < .001). The % CD381HLA-DR1 CD41 and CD81 T cells increased nearly twofold in rectal tissue (both P < .001), and plasma CC chemokine receptor type 5 (CCR5) ligand (macrophage-inflammatory protein 1b) levels increased 2.4-fold during maraviroc intensification (P < .001). During maraviroc intensification, plasma lipopolysaccharide declined, whereas sCD14 levels and neutrophils tended to increase in blood and rectal tissue. Although the mechanisms explaining these findings remain unclear, CCR5 ligandmediated activation of T cells, macrophages, and neutrophils via alternative chemokine receptors should be explored. These results may have relevance for trials of maraviroc for HIV preexposure prophylaxis and graft-versus-host disease. This trial was registered at www.clinicaltrials.gov as #NCT00735072. (Blood. 2013;121(23):4635-4646)

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Section: Discussionsupporting

confidence: 60%

Section: Changes In T-cell Ccr5 Expression and Plasma Ccr5 Ligand Levelsmentioning

confidence: 99%

The immunologic effects of maraviroc intensification in treated HIV-infected individuals with incomplete CD4+ T-cell recovery: a randomized trial

Hunt

Shulman

Hayes

et al. 2013

Blood

128

123

View full text Add to dashboard Cite

show abstract

“…Drug concentrations that resulted in 50% reduction (IC 50 ) in p24 antigen production were determined. Antiviral assays using MAGI-CCR5 cells (MAGI assay) were conducted as previously reported 16 , 39 . Single-round virus infection assays using TZM-bl cells infected with R5-HIV-1s (HIV-1 YU2 , HIV-1 KP-5pc , and HIV-1 KP-5mvcR ) 10 were also conducted as previously described 25 .…”

Section: Methodsmentioning

confidence: 99%

Activity and structural analysis of GRL-117C: a novel small molecule CCR5 inhibitor active against R5-tropic HIV-1s

Nakata

Maeda

Das

et al. 2019

Sci Rep

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CCR5 is a member of the G-protein coupled receptor family that serves as an essential co-receptor for cellular entry of R5-tropic HIV-1, and is a validated target for therapeutics against HIV-1 infections. In the present study, we designed and synthesized a series of novel small CCR5 inhibitors and evaluated their antiviral activity. GRL-117C inhibited the replication of wild-type R5-HIV-1 with a sub-nanomolar IC50 value. These derivatives retained activity against vicriviroc-resistant HIV-1s, but did not show activity against maraviroc (MVC)-resistant HIV-1. Structural modeling indicated that the binding of compounds to CCR5 occurs in the hydrophobic cavity of CCR5 under the second extracellular loop, and amino acids critical for their binding were almost similar with those of MVC, which explains viral cross-resistance with MVC. On the other hand, one derivative, GRL-10018C, less potent against HIV-1, but more potent in inhibiting CC-chemokine binding, occupied the upper region of the binding cavity with its bis-THF moiety, presumably causing greater steric hindrance with CC-chemokines. Recent studies have shown additional unique features of certain CCR5 inhibitors such as immunomodulating properties and HIV-1 latency reversal properties, and thus, continuous efforts in developing new CCR5 inhibitors with unique binding profiles is necessary.

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Immunological and pharmacological strategies to reactivate HIV-1 from latently infected cells: a possibility for HIV-1 paediatric patients?

Martínez‐Bonet

Clemente

Serramía

et al. 2015

Journal of Virus Eradication

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Effects of CC chemokine receptor 5 (CCR5) inhibitors on the dynamics of CCR5 and CC-chemokine–CCR5 interactions

Cited by 4 publications

References 43 publications

The immunologic effects of maraviroc intensification in treated HIV-infected individuals with incomplete CD4+ T-cell recovery: a randomized trial

The immunologic effects of maraviroc intensification in treated HIV-infected individuals with incomplete CD4+ T-cell recovery: a randomized trial

Activity and structural analysis of GRL-117C: a novel small molecule CCR5 inhibitor active against R5-tropic HIV-1s

Immunological and pharmacological strategies to reactivate HIV-1 from latently infected cells: a possibility for HIV-1 paediatric patients?

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