Journal of ISSN: 2373-6453JHVRV

Human Virology & Retrovirology
Mini Review
Volume 2 Issue 5 - 2015
CCR5: A Cellular Doorway for HIV-1 Entry
Latinovic OS1,2*, Redfield RR1,2,3
1Institute of Human Virology, University of Maryland School of Medicine, USA
2Department of Microbiology and Immunology, University of Maryland School of Medicine, USA
3Department of Medicine, University of Maryland School of Medicine, USA
Received:August 05, 2015 | Published: August 24, 2015
*Corresponding author: Olga S Latinovic, Institute of Human Virology, University of Maryland School of Medicine, 725 West Lombard Street, Baltimore, Maryland 21201, Tel: 4107062769; Email:
Citation: Latinovic OS, Redfield RR (2015) CCR5: A Cellular Doorway for HIV-1 Entry. J Hum Virol Retrovirol 2(5): 00056. DOI: 10.15406/jhvrv.2015.02.00056


The CCR5 chemokine receptor plays a crucial role in HIV-1 infection, acting as the principal coreceptor for viral entry and transmission, and as such offers an important potential therapeutic target. Studies have suggested that CCR5 surface density and its conformational changes subsequent to virions engagement are rate limiting for virus entry. Several small molecule antagonists have been developed that target the HIV-1 coreceptor CCR5. CCR5-tropic (R5) viral strains are by far the most prevalent and are the predominant transmitted types. Not all existing CCR5 blockers fully inhibit HIV-1 infection, suggesting a need for more potent reagents. This review will discuss some of the CCR5 blockers, their development, and existing or potential future clinical usage.

Keywords: CCR5; HIV-1 Entry; CCR5 Antagonists; Maraviroc; CCR5 mAbs; Fusion protein


CCR5: C-C Chemokine Receptor Type 5; MVC: Maraviroc; FLSC IgG1: Full Length; Single Chain IgG1


Viruses, unlike fungi and bacteria, require host cells and cellular proteins for infection and replication. HIV-1 requires two cellular proteins for cell entry, the primary receptor CD4 and co receptors CCR5 or CXCR4 [1-3], such cellular targets are attractive for antiviral therapy because they do not readily mutate under therapeutic pressure as viral proteins do [4-6]. Each step during the HIV-1 replication cycle depends upon cellular factors, which are thus potential targets for antiviral therapy. Pharmacology/biotechnology companies have developed 13 drugs that inhibit reverse transcription, 12 protease inhibitors, and 3 integrate inhibitors, but there has been less development in the area of virus entry inhibition, a potential critical target in anti-viral therapy. New drugs are much needed because of the side effects, costs, and existing drug resistance to current antivirals. There are two entry inhibitors licensed for patients with drug-resistant HIV-1, one virus/cell fusion inhibitor (Enfuvirtide, T-20 [7]) and one CCR5 coreceptor antagonist, Maraviroc [8]. Entry inhibitors target HIV-1 extracellular thereby potentially sparing cells from both viral and drug-induced intracellular toxicities. In addition, these inhibitors are especially attractive since they act at the earliest step of viral life and immobilize HIV-1 within the extracellular environment, where it is accessible to the immune system [9].

 The discovery of the HIV-1 inhibitory activity of the CCR5 β-chemokines [10] led to the identification of CCR5 as the major HIV-1 receptor during virus binding and entry [11-13] and there has since been a strong interest in blocking the coreceptor for infection prevention and treatment. The CCR5 coreceptor is expressed on a number of cells, including activated T lymphocytes, dendritic cells and macrophages [14]. It is one of a family of chemokine receptors within the G protein-coupled receptor family [15], and CCR5-tropic HIV-1 strains are the predominant forms involved in viral transmission [16]. The chemokine receptors consist of seven transmembrane helices, an extracellular N-terminus, and three extracellular loops (ECLs). Elements located in the N-terminus and second ECL of CCR5 is crucial for interactions with HIV-1, making them appealing targets for antiviral therapy; therefore, they are the main targets for blocking HIV-1 entry. This has led to efforts to develop effective antiviral CCR5 inhibitors, including CCR5 antagonists [16-18] and fusion proteins that target the N-terminus and other relevant sites in CCR5 [19], as well as CCR5 antibodies [20-22]. Some CCR5 blockers have achieved remarkable suppression of HIV-1 entry both in vitro and in vivo [16,17,22,23].


Among all cellular partners needed for HIV-1 entry, CCR5 has a further advantage as a cellular target because it is relatively dispensable for normal immune function, in contrast with CD4 and the minor viral receptor CXCR4 [24], both of which have important roles in immune function [25,26] that limit their utility as antiviral therapy targets. Individuals homozygous for the Δ32 mutation in CCR5 are highly resistant to HIV-1 infection [27,28]. Heterozygous individuals’ progress to AIDS more slowly than do those homozygous for the wild-type gene [29,30]. Moreover, CCR5 density levels (molecules/cell) on CD4+ T cells correlate with RNA viral load [31] and progression to AIDS [32] in untreated HIV-1-infected individuals. The direct impact of CCR5 surface density on the antiviral activity of CCR5 antagonists was clearly established, showing that CCR5 levels inversely correlate with HIV-1 entry inhibition [33,34], thereby establishing that the potency of entry inhibitors is directly associated with and dependent upon CCR5 surface density [16,22]. All of these and the curative impact seen from Δ-32 mutation hematopoietic stem cells transplantation to the Berlin patient with AIDS and leukemia [35] have given strong stimulus for the use of CCR5 blockers for fighting HIV-1 infection.

Several small molecule CCR5 inhibitors have been developed in the last decade [16,17,22,36] which, unlike natural b–chemokines, do not induce coreceptor internalization. Antagonist bound CCR5 does not signal and stays on the cell surface. One of these, CCR5 antagonist Maraviroc (MVC), is an allosteric, non-competitive inhibitor of the receptor [32,33] and is the only clinically approved CCR5 antagonist (Pfizer, 2007) [8]. It has been licensed for patients infected with only CCR5-tropic HIV-1 [37], due to its novel mechanism of action, excellent tolerance and potent capacity to reduce HIV-1 entry. Oral administration of MVC has yielded dramatic reductions in viral loads [38]. MVC and other small molecules have great in vitro synergy with other CCR5 blockers, including CCR5 monoclonal antibodies (mAbs) [19,21,22,35,39], inhibiting HIV-1 entry into physiologically relevant primary cells. An experimental drug candidate for inhibiting CCR5 receptors, Cenicriviroc, is in the Phase II clinical trials [40]. Ongoing efforts on blocking CCR5 function are related to the Zinc Finger Nuclease (ZFN) proteins that can delete CCR5. Recently, a completed Phase I clinical trial study (March, 2015) had an aim to find out whether "zinc finger" modified CD4+ T-cells are safe to give to humans and find how "zinc finger" modified T-cell affects HIV-1 (

 Resistance to MVC has been reported previously [41-43], and is due to several mechanisms, including selection of pre-existent minor HIV-1 variants that use CXCR4 as a coreceptor [41], selection for mutants that use inhibitor-bound CCR5 for entry [42], and selection for mutations, primarily in the V3 loop of gp120, that switch coreceptor use from CCR5 to CXCR4. The latter has been demonstrated in vitro [43], but is rare in infected patients treated with MVC [39]. A potential solution for this problem is to combine MVC and CCR5 Abs with distinct patterns of resistance and different mechanisms of action. A new potential synergistic partner to MVC targeting CCR5 that has been identified is FLSC IgG1, a fusion protein containing gp120BAL, the D1 and D2 domains of human CD4 [44,45] and the hinge-CH2-CH3 region of human IgG1. Efficiently binding to CCR5, FLSC IgG1 inhibits infection by R5 HIV-1 [45-47]. The IgG1 moiety provides protein dimerization, which confers bivalency (reducing the concentration required for half maximal binding to CCR5 by more than an order of magnitude) [45] and increases protein stability and serum half-life [46-49]. Importantly, FLSC IgG1 does not induce calcium mobilization or chemotaxis subsequent to CCR5 binding [46]. Its binding is inhibited by CCR5 ligands RANTES, MIP-1a, and MIP-1b, which also block R5-gp120 interactions by direct competition [50,51]. It seems possible that FLSC IgG1 represents a potential therapeutic agent to synergistically block HIV-1 entry in combination with MVC, and that it may synergize with other CCR5 blocking agents [52].


The success of the current HAART therapies is limited by the emergence of drug-resistance, potential drug toxicity, the need for sustained adherence and costs. CCR5 blockers have great therapeutic potential for prevention and treatment of HIV-1 infection.


The authors especially thank Drs. Marvin Reitz and Alonso Heredia (IHV, SOM UM) for critical reading of this manuscript.


  1. Kwong PD, Wyatt R, Robinson J, Sweet RW, Sodroski J, et al. (1998) Structure of an HIV gp120 envelope glycoprotein in complex with the CD4 receptor and a neutralizing human antibody. Nature 393(6686): 648-659.
  2. Bachelorized F, Ben Baruch A, Burkhardt AM, Combadiere C, Farber JM, et al. (2014) International Union of Pharmacology. LXXXIX. Update on the extended family of chemokine receptors and introducing a new nomenclature for atypical chemokine receptors. Pharmacologic Rev 66(1): 1-79.
  3. Alkhatib G (2009) The biology of CCR5 and CXCR4. Curr Opin HIV AIDS 4(2): 96-103
  4. Scholz I, Arvidson B, Huseby D, Barklis E (2005) Virus particle core defects caused by mutations in the human immunodeficiency virus capsid N-terminal domain. J Virol 79(3): 1470-1479.
  5. Wacharapornin P, Lauhakirti D, Auewarakul P (2007) The effect of capsid mutations on HIV-1 uncoating. Virology 358(1): 48-54.
  6. Noviello CM, López CS, Kukull B, McNett H, Still A, et al. (2011) Second-site compensatory mutations of HIV-1 capsid mutations. J Virol 85(10): 4730-4738.
  7.  Miyamoto F, Kodama EN (2013) Development of small molecule HIV-1 fusion inhibitors: linking biology to chemistry. Curr Pharm Des 19(10): 1827-1834.
  8. Latinovic O, Kuruppu J, Davis C, Le N, Heredia A (2009) Pharmacotherapy of HIV-1 infection: focus on CCR5 antagonist maraviroc. Clin Med There 1: 1497-1510.
  9. Moore JP, Doms RW (2003) The entry of entry inhibitors: a fusion of science and medicine. Proc Natl Acad Sci USA 100(19): 10598-10602.
  10. Cocchi F, DeVico AL, Garzino-Demo A, Arya SK, Gallo RC, et al. (1995) Identification of RANTES, MIP-1 alpha, and MIP-1 beta as the major HIV-suppressive factors produced by CD8+ T cells. Science 270(5243): 1811-1815.  
  11.  Alkhatib G, Combadiere C, Broder CC, Feng Y, Kennedy PE, et al. (1996) CC CKR5: a RANTES, MIP-1alpha, MIP-1beta receptor as a fusion cofactor for macrophage-tropic HIV-1. Science 272(5270): 1955-1958.
  12.  Choe H, Farzan M, Sun Y, Sullivan N, Rollins B, et al. (1996) The beta-chemokine receptors CCR3 and CCR5 facilitate infection by primary HIV-1 isolates. Cell 85(7): 1135-1148.
  13.  Deng H, Liu R, Ellmeier W, Choe S, Unutmaz D, et al. (1996) Identification of a major co-receptor for primary isolates of HIV-1. Nature 381(6584): 661-666.
  14. Lee B, Sharron M, Montaner LJ, Weissman D, Doms RW (1999) Quantification of CD4, CCR5, and CXCR4 levels on lymphocyte subsets, dendritic cells, and differentially conditioned monocyte-derived macrophages. Proc Natl Acad Sci USA; 96(9): 5215-5220.
  15. Bockaert J and Pin JP (1996) Molecular tinkering of G protein-coupled receptors: an evolutionary success. EMBO J 18(7): 1723-1729.
  16. Latinovic O, Heredia A, Gallo RC, Reitz M, Le N, et al. (2009) Rapamycin enhances Aplaviroc anti-HIV activity: implications for the clinical development of novel CCR5 antagonists. Antiviral Res 83(1): 86-89.
  17. Heredia A, Latinovic O, Gallo RC, Melikyan G, Reitz M, et al. (2008) Reduction of CCR5 with low-dose rapamycin enhances the antiviral activity of vicriviroc against both sensitive and drug-resistant HIV-1. Proc Natl Acad Sci USA 105(51): 20476-20481.
  18. Maeda K, Das D, Yin PD, Tsuchiya K, Ogata-Aoki H, et al. (2008) Involvement of the second extracellular loop and Transmembrane residues of CCR5 in inhibitor binding and HIV-1 fusion: insights into the mechanism of allosteric inhibition. J Mol Biol 381(4): 956-974.
  19. Huang CC, Lam SN, Acharya P, Tang M, Xiang SH, et al. (2007) Structures of the CCR5 N terminus and of a tyrosine-sulfated antibody with HIV-1 gp120 and CD4. Science 317(5846): 1930-1934.
  20. Ji C, Zhang J, Dioszegi M, Chiu S, Rao E, et al. (2007) CCR5 Small-Molecule antagonists and monoclonal antibodies exert potent synergistic antiviral effects by cobinding to the receptor. Molecular Pharmacology 72(1): 18-28.
  21. Berro R, Klasse PJ, Lascano D, Flegler A, Nagashima KA, et al. (2011) Multiple CCR5 conformations on the cell surface are used differentially by human immunodeficiency viruses resistant or sensitive to CCR5 inhibitors. J Virol 85(16): 8227-8240.
  22.  Lalezari J, Yadavalli GK, Para M, Richmond G, Dejesus E, et al. (2008) Safety, pharmacokinetics, and antiviral activity of HGS004, a novel fully human IgG4 monoclonal antibody against CCR5, in HIV-1 infected patients. J Infect Dis 197(5): 721-727.
  23. Westby M, van der RE (2010) CCR5 antagonists: host-targeted antiviral agents for the treatment of HIV infection, 4 years on. Antivir Chem Chemother 20(5): 179-192.
  24. Berger EA, Murphy PM, Farber JM (1999) Chemokine receptors as HIV-1 co receptors: roles in viral entry, tropism, and disease. Annu Rev Immunol 17: 657-700.
  25. Nagasawa T, Hirota S, Tachibana K, Takakura N, Nishikawa S, et al. (1996) Defects of B-cell lymphopoiesis and bone-marrow myelopoiesis in mice lacking the CXC chemokine PBSF/SDF-1. Nature 382(6592): 635-638.
  26. Zou YR, Kottmann AH, Kuroda M, Taniuchi I, Littman DR (1998) Function of the chemokine receptor CXCR4 in Hematopoiesis and in cerebellar development. Nature 393(6685): 595-599.
  27.  Michael NL, Louie LG, Sheppard HW (1997) CCR5-delta 32 gene deletion in HIV-1 infected patients. Lancet 350(9079): 741-742.
  28.  Liu R, Paxton WA, Choe S, Ceradini D, Martin SR, et al. (1996) Homozygous defect in HIV-1 coreceptor accounts for resistance of some multiply-exposed individuals to HIV-1 infection. Cell 86(3): 367-377.
  29. Paxton WA, Liu R, Kang S, Wu L, Gingeras TR, et al. (1998) Reduced HIV-1 infectability of CD4+ lymphocytes from exposed-uninfected individuals: association with low expression of CCR5 and high production of beta-chemokines. Virology 244(1): 66-73.
  30. De Roda Husman AM, Koot M, Cornelissen M, Keet IP, Brouwer M, et al. (1997) Association between CCR5 genotype and the clinical course of HIV-1 infection. Ann Intern Med 127(10): 882-890.
  31. Reynes J, Portales P, Segondy M, Baillat V, André P, et al. (2000) CD4+ T cell surface CCR5 density as a determining factor of virus load in persons infected with human immunodeficiency virus type 1. J Infect Dis 181(3): 927-932.
  32. Reynes J, Baillat V, Portales P, Clot J, Corbeau P, et al. (2004) Relationship between CCR5 density and viral load after discontinuation of antiretroviral therapy. JAMA 291(1): 46.
  33. Pugach P, Ray N, Klasse PJ, Ketas TJ, Michael E, et al. (2009) Inefficient entry of vicriviroc-resistant HIV-1 via the inhibitor-CCR5 complex at low cell surface CCR5 densities. Virology 387(2): 296-302.  
  34. Anastassopoulou CG, Marozsan AJ, Matet A, Snyder AD, Arts EJ, et al. (2007) Escape of HIV-1 from a small molecule CCR5 inhibitor is not associated with a fitness loss. PLoS Pathog 3(6): e79.
  35. Allers K, Hutter G, Hofmann J, Loddenkemper C, Rieger K (2011) Evidence for the cure of HIV infection by CCR5Delta32/Delta32 stem cell transplantation. Blood 117(10): 2791-2799.
  36. Asin-Milan O, Sylla M, El-Far M, Belanger-Jasmin G, Haidara A, et al. (2014) Synergistic combinations of the CCR5 inhibitor VCH-286 with other classes of HIV-1 inhibitors. Antimicrob Agents Chemother 58(12): 7565-7569.
  37. Tsibris AM, Korber B, Arnaout R, Russ C, Lo CC (2009) Quantitative deep sequencing reveals dynamic HIV-1 escape and large population shifts during CCR5 antagonist therapy in vivo. PloS One 4(5): e5683.
  38. Schlecht HP, Schellhorn S, Dezube BJ, Jacobson JM (2008) New approaches in the treatment of HIV/AIDS – focus on maraviroc and other CCR5 antagonists. There Clin Risk Manag 4(2): 473-485
  39. Fouts TR, Tuskan R, Godfrey K, Reitz M, Hone D, et al. (2000) Expression and characterization of a single-chain polypeptide analogue of the human immunodeficiency virus type 1 gp120-CD4 receptor complex. J Virol 74(24): 11427-11436.
  40. Tobira Therapeutics Initiates Phase 2b Trial of Cenicriviroc. (2011) The Body.
  41. Westby M, Smith-Burchell C, Mori J, Lewis M, Mosley M, et al. (2006) Reduced maximal inhibition in phenotypic susceptibility assays indicates that viral strains resistant to the CCR5 antagonist maraviroc utilize inhibitor-bound receptor for entry. J Virol 81(5): 2359-2371.
  42. Nedellec R, Coetzer M, Lederman MM, Offord RE, Hartley O, et al. (2011) Resistance to the CCR5 inhibitor 5P12-RANTES requires a difficult evolution from CCR5 to CXCR4 coreceptor use. PloS One 6(7): e22020.
  43. Westby M, Lewis M, Whitcomb J, Youle M, Pozniak AL (2006) Emergence of CXCR4-using human immunodeficiency virus type (HIV-1) variants in a minority of HIV-1 infected patients following treatment with the CCR5 antagonist maraviroc is from a pretreatment CXCR4-using virus reservoir. J Virol 80(10): 4909-4920.
  44. Vu JR, Fouts T, Bobb K, Burns J, McDermott B, et al. (2006) An immunoglobulin fusion protein based on the gp120-CD4 receptor complex potently inhibits human immunodeficiency virus type 1 in vitro. AIDS Res Hum Retroviruses 22(6): 477-490.
  45. Latinovic O, Schneider K, Szimansky H, Lakowicz J, Heredia A, et al. (2014) Binding of fusion protein FLEC IgG1 to CCR5 is enhanced by CCR5 antagonist Maraviroc. Antiviral Research 112: 80-90.
  46. Latinovic O, Zhang J, Tagaya Y, DeVico AL, Fouts TR, et al. (2015) Synergistic inhibition of R5 HIV-1 by the fusion protein FLSC IgG1 Fc and Maraviroc in primary cells: Implications for prevention and treatment sent for publication.
  47. Latinovic OS, Medina-Moreno S, Schneider K, Gohain N, Zapata J, et al. (2015) Full Length Single Chain Fc Protein (FLSC IgG1) as a Potent Antiviral Therapy Candidate: Implications for In Vivo Studies. AIDS Res Human Retroviruses.
  48. Ashkenazi A, Chamow SM (1997) Immunoadhesins as research tools and therapeutic agents. Curr Opin Immunol 9(2): 195-200.
  49. Trkola A, Dragic T, Arthos J, Binley JM, Olson WC, et al. (1996) CD4-dependent, antibody-sensitive interactions between HIV-1 and its co-receptor CCR-5. Nature 384(6605): 184-187.
  50. Wu L, Gerard NP, Wyatt R, Choe H, Parolin C, et al. (1996) CD4-induced interaction of primary HIV-1 gp120 glycoproteins with the chemokine receptor CCR-5. Nature 384(6605): 179-183.
  51. Platt EJ, Wehrly K, Kuhmann SE, Chesebro B, Kabat D (1998) Effects of CCR5 and CD4 cell surface concentrations on infections by macrophagetropic isolates of human immunodeficiency virus type 1. J Virol 72(4): 2855-2864.
  52. Lahm HW, Stein S (1985) Characterization of recombinant human IL-2 with micromethods. J Chromatogr 326: 357-361.  
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