Class B β-arrestin2-dependent CCR5 signalosome retention with natural antibodies to CCR5

Venuti, Assunta; Pastori, Claudia; Pennisi, Rosamaria; Riva, Agostino; Sciortino, Maria Teresa; Lopalco, Lucia

doi:10.1038/srep39382

Cited by 12 publications

(40 citation statements)

References 55 publications

(101 reference statements)

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“…Second and more important, the long-lasting internalization of CCR5 with natural anti-CCR5 Abs seems to be a unique mechanism not demonstrated for other CCR5 modulating molecules so far. Indeed, by using monoclonal antibodies (mAbs) that recognize the N-terminus and the second loop of CCR5, it has been shown a differentially modulation of receptor activity; thus suggesting that each CCR5 extramembrane region can display different properties ( 65 , 77 , 78 ).…”

Section: Ccr5 and Its Related Absmentioning

confidence: 99%

“…Homologous desensitization requires phosphorylation of the receptor binding mediated by members of the GPCR kinases (GRK) family ( 91 ). This in turn leads to the association of β-arrestin1/2 with the receptor and to desensitization via uncoupling of the receptor and G protein ( 77 , 92 ); in particular, β-arrestins bound physically with the receptors and initiate endocytosis through clathrin-coated vescicles and also act as scaffold proteins in crosstalk with other signaling pathways ( 93 ). Conversely, heterologous desensitization is traditionally defined as a state of cellular refractoriness to different agonists after receptor phosphorylation sites different from GRK mediated by second messenger-activated protein kinases, such as PKC ( 90 ).…”

Section: Endocytosis and De Novo Synthesis Of Ccr5mentioning

confidence: 99%

“…It is well known that, after endocytosis, the GPCR proteins are also classified in receptors that are recycled, slowly or rapidly, to the cell membrane after their resensitization and those that should be degraded ( 77 , 95 – 97 ). CCR5 is usually recycled after desensitization ( 4 ): after stimulation with natural ligands, CCR5 is internalized into the trans-Golgi network (TGN) via the endosome recycling compartment (ERC) ( 98 ) and, when the resensitization process is complete, it can return to the cell surface ( 4 , 98 ).…”

Section: Endocytosis and De Novo Synthesis Of Ccr5mentioning

confidence: 99%

“…CCR5 is usually recycled after desensitization ( 4 ): after stimulation with natural ligands, CCR5 is internalized into the trans-Golgi network (TGN) via the endosome recycling compartment (ERC) ( 98 ) and, when the resensitization process is complete, it can return to the cell surface ( 4 , 98 ). However, rare examples of post-endocytic sorting for GPCRs mediated by ligands have been reported ( 77 , 99 – 101 ).…”

Section: Endocytosis and De Novo Synthesis Of Ccr5mentioning

confidence: 99%

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The Role of Natural Antibodies to CC Chemokine Receptor 5 in HIV Infection

2017

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The CC chemokine receptor 5 (CCR5) is responsible for immune and inflammatory responses by mediation of chemotactic activity in leukocytes, although it is expressed on different cell types. It has been shown to act as co-receptor for the human and simian immunodeficiency viruses (HIV-1, HIV-2, and SIV). Natural reactive antibodies (Abs) recognizing first loop (ECL1) of CCR5 have been detected in several pools of immunoglobulins from healthy donors and from several cohorts of either HIV-exposed but uninfected subjects (ESN) or HIV-infected individuals who control disease progression (LTNP) as well. The reason of development of anti-CCR5 Abs in the absence of autoimmune disease is still unknown; however, the presence of these Abs specific for CCR5 or for other immune receptors and mediators probably is related to homeostasis maintenance. The majority of anti-CCR5 Abs is directed to HIV binding site (N-terminus and ECL2) of the receptor. Conversely, it is well known that ECL1 of CCR5 does not bind HIV; thus, the anti-CCR5 Abs directed to ECL1 elicit a long-lasting internalization of CCR5 but not interfere with HIV binding directly; these Abs block HIV infection in either epithelial cells or CD4+ T lymphocytes and the mechanism differs from those ones described for all other CCR5-specific ligands. The Ab-mediated CCR5 internalization allows the formation of a stable signalosome by interaction of CCR5, β-arrestin2 and ERK1 proteins. The signalosome degradation and the subsequent de novo proteins synthesis determine the CCR5 reappearance on the cell membrane with a very long-lasting kinetics (8 days). The use of monoclonal Abs to CCR5 with particular characteristics and mode of action may represent a novel mode to fight viral infection in either vaccinal or therapeutic strategies.

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Section: Ccr5 and Its Related Absmentioning

confidence: 99%

Section: Endocytosis and De Novo Synthesis Of Ccr5mentioning

confidence: 99%

Section: Endocytosis and De Novo Synthesis Of Ccr5mentioning

confidence: 99%

Section: Endocytosis and De Novo Synthesis Of Ccr5mentioning

confidence: 99%

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The Role of Natural Antibodies to CC Chemokine Receptor 5 in HIV Infection

2017

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“…A) First level of protection: xfR5 D+T NP bound on the T-cell surface via CCR5 receptor (xfR5-D+T NP/CCR5 complex) blocks HIV interaction with CCR5 on T-cell surface by two approaches, i.e., first, by blocking HIV from CCR5 binding and the second, providing steric hindrance to HIV virions due to nanoformulation crowding on T-cell surface (red block arrows) (65). B) The xfR5 D+T NP/CCR5 complex triggers the CCR5 trafficking pathway due to anti-CCR5 mAb binding with the CCR5+ T-cells (66), leading to internalization of xfR5 D+T NP. Within the endosome, the low pH induces degradation of polymeric NPs, leading to the release of DTG (INSTI)and TAF (NRTI) into the cytoplasm.…”

Section: Introductionmentioning

confidence: 99%

Targeted immuno-antiretroviral HIV therapeutic approach to provide dual protection and boosts cellular immunity: A proof-of-concept study

Mandal¹,

Prathipati²,

Belshan³

et al. 2020

Preprint

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Human immunodeficiency virus (HIV)-infected active and latent CCR5 expressing long-lived T-cells are the primary barrier to HIV/AIDS eradication. Broadly neutralizing antibodies and latency-reversing agents are the two most promising strategies emerging to achieve ‘functional cure’ against HIV infection. Antiretrovirals (ARVs) have shown to suppress plasma viral loads to non-detectable levels and above strategies have demonstrated a ‘functional cure’ against HIV infection is achievable. Both the above strategies are effective at inducing direct or immune-mediated cell death of latent HIV+ T-cells but have shown respective limitations. In this study, we designed a novel targeted ARVs-loaded nanoformulation that combines the CCR5 monoclonal antibody and antiretroviral drugs (ARV) as a dual protection strategy to promote HIV ‘functional cure’. The modified CCR5 monoclonal antibody (xfR5 mAb) surface-coated dolutegravir (DTG) and tenofovir alafenamide (TAF) loaded nanoformulation (xfR5-D+T NPs) were uniformly sized <250 nm, with 6.5 times enhanced antigen-binding affinity compared to naïve xfR5 mAb, and provided prolonged DTG and TAF intracellular retention (t1/2). The multivalent and sustained drug release properties of xfR5-D+T NPs enhance the protection efficiency against HIV by approximately 12, 3, and 5 times compared to naïve xfR5 mAb, D+T NP alone, and xfR5 NPs, respectively. Further, the nanoformulation demonstrated high binding-affinity to CCR5 expressing CD4+ cells, monocytes, and other HIV prone/latent T-cells by 25, 2, and 2 times, respectively. Further, the xfR5-D+T NPs during short-term pre-exposure prophylaxis induced a protective immunophenotype, i.e., boosted T-helper (Th), temporary memory (TM), and effector (E) sub-population. Moreover, treatment with xfR5-D+T NPs to HIV-infected T-cells induced a defensive/activated immunophenotype i.e., boosted naïve, Th, boosted central memory, TM, EM, E, and activated cytotoxic T-cells population. Therefore, this dual-action targeted mAb-ARV loaded nanoformulation could potentially become a multifactorial/multilayered solution to achieve a “functional cure.”

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Dual CCR5/CCR2 targeting: opportunities for the cure of complex disorders

Fantuzzi

Tagliamonte

Gauzzi

et al. 2019

Cell. Mol. Life Sci.

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100

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The chemokine system mediates acute inflammation by driving leukocyte migration to damaged or infected tissues. However, elevated expression of chemokines and their receptors can contribute to chronic inflammation and malignancy. Thus, great effort has been taken to target these molecules. The first hint of the druggability of the chemokine system was derived from the role of chemokine receptors in HIV infection. CCR5 and CXCR4 function as essential co-receptors for HIV entry, with the former accounting for most new HIV infections worldwide. Not by chance, an anti-CCR5 compound, maraviroc, was the first FDA-approved chemokine receptor-targeting drug. CCR5, by directing leukocytes to sites of inflammation and regulating their activation, also represents an important player in the inflammatory response. This function is shared with CCR2 and its selective ligand CCL2, which constitute the primary chemokine axis driving the recruitment of monocytes/ macrophages to inflammatory sites. Both receptors are indeed involved in the pathogenesis of several immune-mediated diseases, and dual CCR5/CCR2 targeting is emerging as a more efficacious strategy than targeting either receptor alone in the treatment of complex human disorders. In this review, we focus on the distinctive and complementary contributions of CCR5 and CCR2/CCL2 in HIV infection, multiple sclerosis, liver fibrosis and associated hepatocellular carcinoma. The emerging therapeutic approaches based on the inhibition of these chemokine axes are highlighted.

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Class B β-arrestin2-dependent CCR5 signalosome retention with natural antibodies to CCR5

Cited by 12 publications

References 55 publications

The Role of Natural Antibodies to CC Chemokine Receptor 5 in HIV Infection

The Role of Natural Antibodies to CC Chemokine Receptor 5 in HIV Infection

Targeted immuno-antiretroviral HIV therapeutic approach to provide dual protection and boosts cellular immunity: A proof-of-concept study

Dual CCR5/CCR2 targeting: opportunities for the cure of complex disorders

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