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1. Mechanisms of HIV-1 evasion to the antiviral activity of chemokine CXCL12 indicate potential links with pathogenesis

Author

Armani-Tourret, Marie, Zhou, Zhicheng, Gasser, Romain, Staropoli, Isabelle, Cantaloube-Ferrieu, Vincent, Benureau, Yann, Garcia-Perez, Javier, Pérez-Olmeda, Mayte, Lorin, Valérie, Puissant-Lubrano, Bénédicte, Assoumou, Lambert, Delaugerre, Constance, Lelièvre, Jean-Daniel, Lévy, Yves, Mouquet, Hugo, Martin-Blondel, Guillaume, Alcami, Jose, Arenzana-Seisdedos, Fernando, Izopet, Jacques, Colin, Philippe, Lagane, Bernard, Institut Toulousain des Maladies Infectieuses et Inflammatoires (Infinity), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Pathogénie Virale, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Instituto de Salud Carlos III [Madrid] (ISC), Immunologie humorale - Humoral Immunology, Institut Pierre Louis d'Epidémiologie et de Santé Publique (iPLESP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Génomes, biologie cellulaire et thérapeutiques (GenCellDi (UMR_S_944)), Collège de France (CdF (institution))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), CHU Henri Mondor, Service des maladies infectieuses et tropicales [Toulouse], Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], Laboratoire de Virologie [Toulouse], This work was supported by Agence Nationale de Recherches sur le SIDA et les hépatites virales (ANRS) (http://www.anrs.fr/fr) (Grants AAP-2013-2 and ECTZ63419 to B.L.), Institut National de la Santé et de la Recherche Médicale (INSERM) (https://www.inserm.fr), Institut Pasteur (https://www.pasteur.fr), Université Paul Sabatier Toulouse III (https://www.univ-tlse3.fr), The Milieu Intérieur Program (ANR-10-LABX-69-01 to H.M.) (http://www.milieuinterieur.fr) and Instituto de Salud Carlos III (projects RD16CIII/0002/0001 and PI19CIIII/0004 to J.A.) (https://www.isciii.es). M.A.-T. was supported by a grant from Sidaction (https://www.sidaction.org/)., ANR-10-LABX-0069,MILIEU INTERIEUR,GENETIC & ENVIRONMENTAL CONTROL OF IMMUNE PHENOTYPE VARIANCE: ESTABLISHING A PATH TOWARDS PERSONALIZED MEDICINE(2010), Agence Nationale de Recherches sur le sida et les hépatites virales (Francia), Institut National de la Santé et de la Recherche Médicale (Francia), Institut Pasteur, Paul Sabatier University (Francia), Milieu Intérieur Program, Instituto de Salud Carlos III, Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Pathogénie Virale - Viral Pathogenesis, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Génomes, biologie cellulaire et thérapeutiques (GenCellDi (U944 / UMR7212)), Collège de France (CdF (institution))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), CHU Henri Mondor [Créteil], Service Maladies infectieuses et tropicales [CHU Toulouse], Pôle Inflammation, infection, immunologie et loco-moteur [CHU Toulouse] (Pôle I3LM Toulouse), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Laboratoire Virologie [CHU Toulouse], Institut Fédératif de Biologie (IFB), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Gestionnaire, Hal Sorbonne Université, Laboratoires d'excellence - GENETIC & ENVIRONMENTAL CONTROL OF IMMUNE PHENOTYPE VARIANCE: ESTABLISHING A PATH TOWARDS PERSONALIZED MEDICINE - - MILIEU INTERIEUR2010 - ANR-10-LABX-0069 - LABX - VALID, Agence Nationale de Recherches sur le SIDA et les Hépatites Virales (France), Institut National de la Santé et de la Recherche Médicale (France), and Université Paul Sabatier Toulouse III

Subjects
RNA viruses, CD4-Positive T-Lymphocytes, MESH: CD4-Positive T-Lymphocytes / virology, [SDV]Life Sciences [q-bio], HIV Infections, chemokines, Pathology and Laboratory Medicine, MESH: Viral Envelope Proteins / metabolism, MESH: Virulence Substances, White Blood Cells, Spectrum Analysis Techniques, cell staining, Immunodeficiency Viruses, Viral Envelope Proteins, Animal Cells, Medicine and Health Sciences, Homeostasis, viral tropism, MESH: HIV Infections / physiopathology, Biology (General), Virulence, T Cells, Chemotaxis, MESH: Antiviral Agents / metabolism, Flow Cytometry, MESH: Chemokine CXCL12 / metabolism, [SDV] Life Sciences [q-bio], Cell Motility, Medical Microbiology, Spectrophotometry, MESH: Homeostasis, Viruses, Cytophotometry, Pathogens, Cellular Types, Research Article, Cell Physiology, Receptors, CXCR4, QH301-705.5, Immune Cells, Immunology, cloning, MESH: HIV-1 / physiology, MESH: HIV-1 / pathogenicity, Research and Analysis Methods, Microbiology, Antiviral Agents, MESH: HIV Infections / transmission, MESH: Receptors, CXCR4 / metabolism, Retroviruses, Humans, MESH: HIV Infections / virology, Molecular Biology Techniques, cell binding, Microbial Pathogens, Molecular Biology, Blood Cells, cell fusion, MESH: Humans, Lentivirus, Organisms, Biology and Life Sciences, HIV, Cell Biology, RC581-607, Chemokine CXCL12, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, HIV-1, viral pathogens, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Immunologic diseases. Allergy
Abstract

HIV-1 infects CD4 T lymphocytes (CD4TL) through binding the chemokine receptors CCR5 or CXCR4. CXCR4-using viruses are considered more pathogenic, linked to accelerated depletion of CD4TL and progression to AIDS. However, counterexamples to this paradigm are common, suggesting heterogeneity in the virulence of CXCR4-using viruses. Here, we investigated the role of the CXCR4 chemokine CXCL12 as a driving force behind virus virulence. In vitro, CXCL12 prevents HIV-1 from binding CXCR4 and entering CD4TL, but its role in HIV-1 transmission and propagation remains speculative. Through analysis of thirty envelope glycoproteins (Envs) from patients at different stages of infection, mostly treatment-naïve, we first interrogated whether sensitivity of viruses to inhibition by CXCL12 varies over time in infection. Results show that Envs resistant (RES) to CXCL12 are frequent in patients experiencing low CD4TL levels, most often late in infection, only rarely at the time of primary infection. Sensitivity assays to soluble CD4 or broadly neutralizing antibodies further showed that RES Envs adopt a more closed conformation with distinct antigenicity, compared to CXCL12-sensitive (SENS) Envs. At the level of the host cell, our results suggest that resistance is not due to improved fusion or binding to CD4, but owes to viruses using particular CXCR4 molecules weakly accessible to CXCL12. We finally asked whether the low CD4TL levels in patients are related to increased pathogenicity of RES viruses. Resistance actually provides viruses with an enhanced capacity to enter naive CD4TL when surrounded by CXCL12, which mirrors their situation in lymphoid organs, and to deplete bystander activated effector memory cells. Therefore, RES viruses seem more likely to deregulate CD4TL homeostasis. This work improves our understanding of the pathophysiology and the transmission of HIV-1 and suggests that RES viruses’ receptors could represent new therapeutic targets to help prevent CD4TL depletion in HIV+ patients on cART., Author summary HIV-1 infects immune cells by binding CD4 and a coreceptor, CCR5 or CXCR4. CXCR4-using viruses are thought to accelerate depletion of CD4 T lymphocytes (CD4TL) and AIDS development. This paradigm, while often true, is however not seen in all patients, suggesting heterogeneity in the virulence of viruses. Here, we show that CXCR4-using viruses can be discriminated on the basis of their resistance to the anti-HIV-1 effect of the CXCR4 chemokine CXCL12. Resistant (RES) viruses are found in patients with low CD4TL levels. They are featured by unique properties of their envelope glycoprotein and the way they use CXCR4. Our data also indicate that RES viruses could contribute to CD4TL depletion. They more effectively kill bystander activated effector memory CD4TL, a subset of CD4TL enriched in HIV+ patients, and enter CD4TL subsets surrounded by CXCL12. Resistance could therefore enhance the ability of viruses to target naive cells and their precursors in lymphoid organs where CXCL12 is present, further hindering CD4TL renewal. Beyond presenting a novel view of CXCR4-using HIV-1 pathogenesis, this work also opens new therapeutic perspectives and increases our knowledge of the still debated role of CXCL12 in HIV-1 transmission.

Published
2021

2. CCR5 structural plasticity shapes HIV-1 phenotypic properties

Author

Colin, Philippe, Zhou, Zhicheng, Staropoli, Isabelle, Garcia-Perez, Javier, Gasser, Romain, Armani-Tourret, Marie, Benureau, Yann, Gonzalez, Nuria, Jin, Jun, Connell, Bridgette J., Raymond, Stéphanie, Delobel, Pierre, Izopet, Jacques, Lortat-Jacob, Hugues, Alcami, Jose, Arenzana-Seisdedos, Fernando, Brelot, Anne, Lagane, Bernard, Agence Nationale de Recherches sur le sida et les hépatites virales (Francia), Institut National de la Santé et de la Recherche Médicale (Francia), Instituto de Salud Carlos III, Pathogénie Virale - Viral Pathogenesis, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Instituto de Salud Carlos III [Madrid] (ISC), Centre de Physiopathologie Toulouse Purpan (CPTP), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de biologie structurale (IBS - UMR 5075 ), Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), This work was supported by Agence Nationale de Recherche sur le SIDA et les hépatites virales (ANRS) (http://www.anrs.fr/fr), Institut National de la Santé et de la Recherche Médicale (INSERM) (https://www.inserm.fr), Institut Pasteur (https://www.pasteur.fr), Laboratoire d’Excellence 'Integrative Biology of Emerging Infectious Diseases' (Grant ANR-10-LABEX-62-IBEID) (https://research.pasteur.fr/fr/program_project/integrative-biology-of-emerging-infectious-diseases). This work used the platforms of the Grenoble Instruct Centre (ISBG, UMS 3518 CNRS-CEA-UJF-EMBL) (http://www.isbg.fr) with support from FRISBI (ANR-10-INSB-05-02) and GRAL (ANR-10-LABX-49-01) within the Grenoble Partnership for Structural Biology (PSB). JGP was supported by Spanish Ministry of Economy and Competitiveness-ISCIII-FIS No PI16CIII/00034. BJC was supported by a grant from Sidaction (https://www.sidaction.org) and 'la Fondation Pierre Bergé'. ZZ and RG were supported by a grant from ANRS. YB was supported by grants from ANRS and SIDACTION. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript., ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), Pathogénie Virale, Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur [Paris], Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), CHU Toulouse [Toulouse], and Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
RNA viruses, viruses, HIV Infections, Signal transduction, HIV Envelope Protein gp120, Pathology and Laboratory Medicine, Physical Chemistry, Cell Fusion, White Blood Cells, Immunodeficiency Viruses, Animal Cells, Medicine and Health Sciences, Biology (General), Materials, T Cells, virus diseases, Chemistry, Phenotype, Medical Microbiology, Viral Pathogens, Viruses, Physical Sciences, Pathogens, Cellular Types, Dimerization, Coreceptors, Research Article, Protein Binding, Cell Binding, Cell Physiology, Receptors, CCR5, QH301-705.5, Immune Cells, Immunology, Materials Science, Research and Analysis Methods, Microbiology, Retroviruses, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, CCR5 coreceptor, Dimers, Molecular Biology Techniques, Microbial Pathogens, Molecular Biology, Blood Cells, Lentivirus, Organisms, Biology and Life Sciences, HIV, Cell Biology, RC581-607, Virus Internalization, Polymer Chemistry, Chemical Properties, Oligomers, HIV-1, Immunologic diseases. Allergy, Cloning
Abstract

CCR5 plays immune functions and is the coreceptor for R5 HIV-1 strains. It exists in diverse conformations and oligomerization states. We interrogated the significance of the CCR5 structural diversity on HIV-1 infection. We show that envelope glycoproteins (gp120s) from different HIV-1 strains exhibit divergent binding levels to CCR5 on cell lines and primary cells, but not to CD4 or the CD4i monoclonal antibody E51. This owed to differential binding of the gp120s to different CCR5 populations, which exist in varying quantities at the cell surface and are differentially expressed between different cell types. Some, but not all, of these populations are antigenically distinct conformations of the coreceptor. The different binding levels of gp120s also correspond to differences in their capacity to bind CCR5 dimers/oligomers. Mutating the CCR5 dimerization interface changed conformation of the CCR5 homodimers and modulated differentially the binding of distinct gp120s. Env-pseudotyped viruses also use particular CCR5 conformations for entry, which may differ between different viruses and represent a subset of those binding gp120s. In particular, even if gp120s can bind both CCR5 monomers and oligomers, impairment of CCR5 oligomerization improved viral entry, suggesting that HIV-1 prefers monomers for entry. From a functional standpoint, we illustrate that the nature of the CCR5 molecules to which gp120/HIV-1 binds shapes sensitivity to inhibition by CCR5 ligands and cellular tropism. Differences exist in the CCR5 populations between T-cells and macrophages, and this is associated with differential capacity to bind gp120s and to support viral entry. In macrophages, CCR5 structural plasticity is critical for entry of blood-derived R5 isolates, which, in contrast to prototypical M-tropic strains from brain tissues, cannot benefit from enhanced affinity for CD4. Collectively, our results support a role for CCR5 heterogeneity in diversifying the phenotypic properties of HIV-1 isolates and provide new clues for development of CCR5-targeting drugs., Author summary CCR5 regulates host immune responses against pathogens. It also serves as an anchor for R5-tropic strains of HIV-1 to infect immune cells, hence contributing to development of AIDS. CCR5 exists in different forms (e.g. conformations, oligomerization states), but the mechanisms that govern this diversity and its consequences on the physio-/pathophysio-logical functions of the receptor remain unclear. Because genetically diverse viral isolates populate HIV-1 infected individuals, we asked whether divergent viruses differ in the nature of the CCR5 molecules they use, and if so, whether this accounts for differences in their biological properties. Here we answered in the positive to both questions. We also identified CCR5 oligomerization as a key process regulating the receptor conformational diversity, the extent to which HIV-1 envelope glycoproteins bind to target cells and viral entry efficacy. From a functional standpoint, the nature/quantity of the receptor populations that are used by HIV-1 isolates regulates the type of cells they can infect and their ability to escape inhibition by CCR5 ligands. This study thus represents a step forward toward understanding of the mechanisms that regulate CCR5 diversity and its implications on the virus biological properties while opening new avenues for the development of drugs targeting CCR5.

Published
2018

3. CCR5 structural plasticity shapes HIV-1 phenotypic properties.

Author

Zhou, Zhicheng, Staropoli, Isabelle, Benureau, Yann, Jin, Jun, Arenzana-Seisdedos, Fernando, Brelot, Anne, Colin, Philippe, Lagane, Bernard, Garcia-Perez, Javier, Gonzalez, Nuria, Alcami, Jose, Gasser, Romain, Armani-Tourret, Marie, Raymond, Stéphanie, Izopet, Jacques, Delobel, Pierre, Connell, Bridgette J., and Lortat-Jacob, Hugues

Subjects
CHEMOKINE receptors, IMMUNE response, HIV infections, MONOCLONAL antibodies, GLYCOPROTEINS
Abstract

CCR5 plays immune functions and is the coreceptor for R5 HIV-1 strains. It exists in diverse conformations and oligomerization states. We interrogated the significance of the CCR5 structural diversity on HIV-1 infection. We show that envelope glycoproteins (gp120s) from different HIV-1 strains exhibit divergent binding levels to CCR5 on cell lines and primary cells, but not to CD4 or the CD4i monoclonal antibody E51. This owed to differential binding of the gp120s to different CCR5 populations, which exist in varying quantities at the cell surface and are differentially expressed between different cell types. Some, but not all, of these populations are antigenically distinct conformations of the coreceptor. The different binding levels of gp120s also correspond to differences in their capacity to bind CCR5 dimers/oligomers. Mutating the CCR5 dimerization interface changed conformation of the CCR5 homodimers and modulated differentially the binding of distinct gp120s. Env-pseudotyped viruses also use particular CCR5 conformations for entry, which may differ between different viruses and represent a subset of those binding gp120s. In particular, even if gp120s can bind both CCR5 monomers and oligomers, impairment of CCR5 oligomerization improved viral entry, suggesting that HIV-1 prefers monomers for entry. From a functional standpoint, we illustrate that the nature of the CCR5 molecules to which gp120/HIV-1 binds shapes sensitivity to inhibition by CCR5 ligands and cellular tropism. Differences exist in the CCR5 populations between T-cells and macrophages, and this is associated with differential capacity to bind gp120s and to support viral entry. In macrophages, CCR5 structural plasticity is critical for entry of blood-derived R5 isolates, which, in contrast to prototypical M-tropic strains from brain tissues, cannot benefit from enhanced affinity for CD4. Collectively, our results support a role for CCR5 heterogeneity in diversifying the phenotypic properties of HIV-1 isolates and provide new clues for development of CCR5-targeting drugs. [ABSTRACT FROM AUTHOR]

Published
2018
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4. A single-residue change in the HIV-1 V3 loop associated with maraviroc resistance impairs CCR5 binding affinity while increasing replicative capacity.

Author

Garcia-Perez, Javier, Staropoli, Isabelle, Azoulay, Stéphane, Heinrich, Jean-Thomas, Cascajero, Almudena, Colin, Philippe, Lortat-Jacob, Hugues, Arenzana-Seisdedos, Fernando, Alcami, Jose, Kellenberger, Esther, and Lagane, Bernard

Subjects
*MARAVIROC (Drug), *CELL fusion, *VIRAL envelopes, *HIV, *DNA replication, *THERAPEUTICS
Abstract

Background: Maraviroc (MVC) is an allosteric CCR5 inhibitor used against HIV-1 infection. While MVC-resistant viruses have been identified in patients, it still remains incompletely known how they adjust their CD4 and CCR5 binding properties to resist MVC inhibition while preserving their replicative capacity. It is thought that they maintain high efficiency of receptor binding. To date however, information about the binding affinities to receptors for inhibitor-resistant HIV-1 remains limited. Results: Here, we show by means of viral envelope (gp120) binding experiments and virus-cell fusion kinetics that a MVC-resistant virus (MVC-Res) that had emerged as a dominant viral quasispecies in a patient displays reduced affinities for CD4 and CCR5 either free or bound to MVC, as compared to its MVC-sensitive counterpart isolated before MVC therapy. An alanine insertion within the GPG motif (G310_P311insA) of the MVC-resistant gp120 V3 loop is responsible for the decreased CCR5 binding affinity, while impaired binding to CD4 is due to sequence changes outside V3. Molecular dynamics simulations of gp120 binding to CCR5 further emphasize that the Ala insertion alters the structure of the V3 tip and weakens interaction with CCR5 ECL2. Paradoxically, infection experiments on cells expressing high levels of CCR5 also showed that Ala allows MVC-Res to use CCR5 efficiently, thereby improving viral fusion and replication efficiencies. Actually, although we found that the V3 loop of MVC-Res is required for high levels of MVC resistance, other regions outside V3 are sufficient to confer a moderate level of resistance. These sequence changes outside V3, however, come with a replication cost, which is compensated for by the Ala insertion in V3. Conclusion: These results indicate that changes in the V3 loop of MVC-resistant viruses can augment the efficiency of CCR5-dependent steps of viral entry other than gp120 binding, thereby compensating for their decreased affinity for entry receptors and improving their fusion and replication efficiencies. This study thus sheds light on unsuspected mechanisms whereby MVC-resistant HIV-1 could emerge and grow in treated patients. [ABSTRACT FROM AUTHOR]

Published
2015
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5. G Protein-Dependent CCR5 Signaling Is Not Required for Efficient Infection of Primary T Lymphocytes and Macrophages by R5 Human Immunodeficiency Virus Type 1 Isolates.

Author

Amara, Ali, Vidy, Aurore, Boulla, Genevieve, Mollier, Karine, Garcia-Perez, Javier, Alcamí, Jose, Blanpain, Cedric, Parmentier, Marc, Virelizier, Jean-Louis, Charneau, Pierre, and Arenzana-Seisdedos, Fernando

Subjects
*G proteins, *T cells, *HIV
Abstract

The requirement of human immunodeficiency virus (HIV)-induced CCR5 activation for infection by R5 HIV type 1 (HIV-1) strains remains controversial. Ectopic CCR5 expression in CD4[sup +]-transformed cells or pharmacological inhibition of G[sub α]i proteins coupled to CCR5 left unsolved whether CCR5-dependent cell activation is necessary for the HIV life cycle. In this study, we investigated the role played by HIV-induced CCR5dependent cell signaling during infection of primary CD4-expressing leukocytes. Using lentiviral vectors, we restored CCR5 expression in T lymphocytes and macrophages from individuals carrying the homozygous 32-bp deletion of the CCR5 gene (ccr5 Δ32/Δ32). Expression of wild-type (wt) CCR5 in ccr5 Δ32/Δ32 cells permitted infection by R5 HIV isolates. We assessed the capacity of a CCR5 derivative carrying a mutated DRY motif (CCR5-R126N) in the second intracellular loop to work as an HIV-1 coreceptor. The R126N mutation is known to disable G protein coupling and agonist-induced signal transduction through CCR5 and other G proteincoupled receptors. Despite its inability to promote either intracellular calcium mobilization or cell chemotaxis, the inactive CCR5-R126N mutant provided full coreceptor function to several R5 HIV-1 isolates in primary cells as efficiently as wt CCR5. We conclude that in a primary, CCR5-reconstituted CD4[sup +] cell environment, G protein signaling is dispensable for R5 HIV-1 isolates to actively infect primary CD4[sup +] T lymphocytes or macrophages. [ABSTRACT FROM AUTHOR]

Published
2003
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