• We are sorry, but NCBI web applications do not support your browser and may not function properly. More information
Logo of nihpaAbout Author manuscriptsSubmit a manuscriptNIH Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
Curr Opin HIV AIDS. Author manuscript; available in PMC Mar 1, 2010.
Published in final edited form as:
PMCID: PMC2718543
NIHMSID: NIHMS111069

The biology of CCR5 and CXCR4

Abstract

Purpose of review

We discuss the current knowledge concerning the biology of CXCR4 and CCR5 and their roles in HIV-1 infection.

Recent findings

Important research findings reported in the last 2 years have advanced our knowledge in the field of HIV coreceptors and pathogenesis. Novel methods have been used to crystallize two new members of the G-protein coupled receptors. It has been demonstrated that expression and stability of the naturally occurring truncated CCR5 protein is critical for resistance to HIV-1. The first stem cell transplantation of donor cells with the CCR5 mutation provided proof of principle. This is far from being a therapeutic option. The Food and Drug Administration approved the first CCR5-based entry inhibitor. New CXCL12 isoforms were discovered, one isoform is a potent X4 inhibitor with weak chemotaxis activity.

Summary

The coreceptor discoveries revealed new insights into host and viral factors influencing HIV transmission and disease. The HIV/coreceptor interaction has become a major target for the development of novel antiviral strategies to treat and prevent HIV infection. The first CCR5-based entry inhibitor has been recently approved. New drugs that promote CCR5 and CXCR4 internalization, independent of cellular signaling, might provide clinical benefits with minimum side effects.

Keywords: CCR5, CXCR4, G-protein coupled receptor, HIV/AIDS

Introduction

Despite the rapid identification of CD4 cell as the ‘primary receptor’ for the AIDS virus, it soon became clear that additional molecules might be involved [1•]. CXCR4 (Fig. 1) was identified as the coreceptor for X4 HIV-1 isolates [2]. Five different groups independently demonstrated that CCR5 is the coreceptor along with CD4 that allows entry of R5 HIV-1 [37]. The discovery of the HIV coreceptors provided a logical explanation for the previously observed tropism of HIV-1 on primary cells and T cell lines (Fig. 2). This review will focus on the recent findings on CCR5 and CXCR4 in terms of their biological functions, including their role in HIV-1 infection.

Figure 1
Schematic ball diagram showing the amino acid sequence and membrane orientation of CXCR4 gr1
Figure 2
Coreceptor usage and HIV-1 tropism gr2

CCR5 and CXCR4 are G-protein coupled receptors

CCR5 and CXCR4 are structurally related chemokine receptors belonging to the superfamily of the seven-transmembrane G-protein coupled receptors (GPCRs) [8•,9,10•]. The GPCRs are activated to induce a signal by small ligands that are either promiscuous or specific for a given receptor. Agonist-activated GPCRs are rapidly phosphorylated at serine and threonine residues within the C-tail and the third intracellular loop [11••]. There are 21 potential phosphorylation sites in CXCR4 (Fig. 1) and only seven in CCR5. Chemokines, small low-molecular weight proteins, are the ligands that activate and signal through CCR5 and CXCR4 to mediate several cellular functions including development, leukocyte trafficking, angiogenesis, and immune response [12•].

Ligand binding to GPCRs induces a change in conformation of the receptor that is transmitted to the cytoplasmic domains of the protein, enabling the protein to couple with an intracellular heterotrimeric G protein [13]. The intracellular G protein acts as an intracellular signal by activating or inhibiting intracellular enzymes. This model of cellular communication became so successful through evolution that GPCRs are used to enable the senses of taste, smell, and vision and control numerous intracellular signaling systems. Nearly, 1000 seven-transmembrane receptors are thought to be present in the human genome [10•]. Diseases such as some forms of blindness, obesity, inflammation, depression, and hypertension, among others, can be linked to malfunctions of GPCRs. It is not surprising that about half of the drug targets in the pharmaceutical industry are GPCRs [9].

The lack of crystallography on CCR5 and CXCR4 is mainly due to the fact that such proteins are highly hydrophobic and cannot be readily purified. Until recently, X-ray crystallography had provided information on only one GPCR, bovine rhodopsin. This is due to the fact that rhodopsin is easily purified in milligram quantities from bovine retinal extracts. Recently, the crystal structures of two other GPCRs were resolved [14••,15••]. The crystal structures of the human A2A adenosine receptor [15••] and β2-adrenergic receptor (β2AR) [14••] were determined by using a T4L fusion strategy, in which most of the third cytoplasmic loop was replaced with lysozyme from T4 bacteriophage, and the carboxy-terminal tail was deleted to improve the likelihood of crystallization. The A2A adenosine ligand bound structure suggested that there is no general, family-conserved receptor binding pocket in which selectivity is achieved through different amino acid side chains. Rather, the pocket itself can vary in position and orientation, yielding more opportunity for receptor diversity and ligand selectivity [15••].

Biology of CCR5

CCR5 was first isolated as a functional GPCR that is antagonized by three CC chemokines [16,17]. It was later discovered that several other CC chemokines can bind CCR5 with different affinities and efficiencies in receptor activation [18]. CCL3, CCL4, and CCL5 bind efficiently to CCR5 and are full agonists, whereas CCL7, CCL8, and CCL13 bind less efficiently and exhibit different abilities in receptor activation. Interestingly, MCP-3/CCL7 has been found to bind CCR5 without inducing a signal and has been suggested as a natural antagonist [18]. Among the several CC chemokines that have been demonstrated to bind CCR5, CCL3, CCL4, CCL5, and CCL8 show the most suppressive activities in HIV-1 infection assays [18]. CCL7 binds efficiently to CCR5, but does not induce internalization or block HIV-1 infection [18]. Interestingly, CCL2 binds to CCR5 and acts as a potential enhancer rather than a blocker of HIV-1 replication [19•].

CCR5-deficient (CCR5−/−) mice develop normally, but show reduced efficiency in clearance of Listeria infection and exert a protective effect against lipopolysaccharide (LPS)-induced endotoxemia, reflecting a partial defect in macrophage function [20]. Additionally, CCR5-deficient mice had an enhanced delayed-type hypersensitivity reaction and increased humoral responses to T cell-dependent antigenic challenge, indicating a novel role of CCR5 in downmodulating T cell-dependent immune response [20]. In a murine transplant model with intensive conditioning, the overall effect of absent CCR5 expression on donor cells results in greater graft-versus-host disease (GVHD) and donor T cell expansion [21].

CCR5-deficient (CCR5−/−) Homo sapiens are represented in 2–3% of whites [22]. The lack of CCR5 expression in these individuals is caused by a naturally occurring 32 base pair deletion in the CCR5 gene. Individuals who are homozygous for the mutant CCR5 allele are highly resistant to HIV-1 infection. The mutant allele is not associated with any obvious phenotype. Although homozygosity for CCR5Δ32 mutation is clearly associated with disease resistance, HIV-1 infection has been reported in hemophiliac patients [23] and several CCR5−/− homosexuals [2430], indicating that the protective effect of the CCR5Δ32 mutation is not absolute. In some cases, exclusive use of CXCR4 by the infecting virus isolates or the presence of Env sequences typical of CXCR4-using (X4) viruses was observed. In other cases, dual-tropic (R5X4) HIV-1 isolates have also been identified in three different HIV+CCR5−/− homosexual individuals [26,31].

Our studies suggested that HIV resistance in CCR5Δ32 homozygote might result from both genetic loss of CCR5 on the cell surface as well as active downregulation of CXCR4 expression by the mutant CCR5Δ32 protein [32]. We have recently demonstrated that expression and stability of the truncated CCR5Δ32 protein in CCR5−/− individuals is critical for the resistance phenotype [33••35••]. These studies support the hypothesis that the CCR5Δ32 protein acts as an HIV-suppressive factor by altering the stoichiometry of the molecules involved in HIV-1 entry and provide insight into the development of drugs that mimic the CCR5Δ32 protein interactions [33••35••]. Recently, Hutter et al. [36••] reported the first successful allogeneic stem cell transplantation in an HIV-positive patient with a donor selected to be homozygous for the CCR5Δ32 allele. The patient managed transplantation without any remarkable irregularities and developed a functional reconstitution of his T cell immunity. Although this case provided a proof of principle to the resistance phenotype, the long-term effects of stem cell transplantation remain unknown.

Biology of CXCR4

CXCR4 was originally identified as an orphan receptor called leukocyte-derived seven-transmembrane domain receptor (LESTR) [3741], but did not receive much attention until its isolation as a coreceptor for HIV-1 [2] and the discovery of its natural ligand, SDF-1/CXCL12 [42,43]. The identification of CXCR4 as an HIV coreceptor [2] triggered a wide range of research activities to investigate the biological roles of the CXCL12/CXCR4 axis. CXCL12 is a highly conserved chemokine that has 99% homology between mouse and human, allowing CXCL12 to act across species barriers. Recently, six isoforms have been identified for the CXCL12 [44]. We found that CXCL12γ is a very weak agonist for CXCR4, but is at least 5–6 times more potent than CXCL12α in HIV-blocking assays [45••]. The potent blocking activity of CXCL12γ correlated well with its efficient CXCR4 internalization.

CXCR4 is functionally expressed on the cell surface of various cancer cells and plays a role in cell proliferation and migration of these cells [46]. CXCL12 and CXCR4 gene-deleted mice displayed an identical, lethal phenotype, indicating a monogamous relation between CXCL12 and CXCR4. Mice lacking CXCR4 die in utero and are defective in vascular development, hematopoiesis, and cardiogenesis [47]. Mice lacking CXCL12/SDF-1 are characterized by deficient B-lymphopoiesis and myelopoiesis and abnormal neuronal and cardiovascular development [48]. The CXCR4-CXCL12 axis is functional in evolutionarily distant organisms such as zebra fish and mice, in which CXCR4 expression is a prerequisite for germ cell migration to CXCL12-expressing gonads during development [49].

Role for CCR5 and CXCR4 in HIV-1 entry

The spikes projecting from the surface of HIV-1 particles are composed of the envelope glycoprotein (Env), whose function is to promote HIV entry by a process of direct fusion between the virion membrane and the plasma membrane of the target cell [50,51]. Env consists of two noncovalently associated subunits derived by proteolytic cleavage of the gp160 biosynthetic precursor: the gp120 external subunit, which is responsible for binding to specific target cell receptors, and the gp41 transmembrane subunit, which catalyzes the fusion reaction and anchors Env to the viral host-derived membrane. Biochemical, genetic, immunochemical, and structural analyses have implicated the sulfated N-terminus and the second extracellular loop of CCR5; on the gp120 side, the bridging sheet and third variable (V3) loop are directly involved, with sequences in the latter domain determining the coreceptor usage phenotype (R5, X4, and R5X5) [52].

In their function as HIV coreceptors, CCR5 and CXCR4 physically associate with CD4-activated gp120, as shown by direct binding and coprecipitation studies [5356] and functional assays [57]. The functional envelope glycoprotein on the surface of the HIV particle or infected cells is organized as a trimer of three gp120-gp41 heterodimers (Fig. 3a). The HIV fusion reaction is initiated by sequential receptor binding of gp120, first to CD4 and then to a specific chemokine receptor, generally CCR5 or CXCR4 [1•]. In the generally accepted model for HIV entry [50,58], gp120 binds to CD4 and is induced to undergo a major conformational change that either creates or facilitates exposure of the coreceptor-binding site; gp120 interaction with coreceptor then triggers the gp41 subunit to promote the fusion reaction via another series of complex conformational changes (Fig. 3). These receptor interactions then trigger gp41 to promote membrane fusion; this reaction is thought to involve extension of the gp41 subunit to allow insertion of its N-terminal ‘fusion peptide’ into the target cell membrane, followed by refolding the prefusion intermediated into an energetically favorable six-helix bundle that brings the two membranes together so that fusion can occur (Fig. 3e).

Figure 3
Mechanism of HIV-1 entry gr3

Despite extensive studies aimed at defining the precise molecular composition of the gp120-coreceptor complex, the details remain obscure [52]. The lack of the coreceptor crystal structure represents a major obstacle; indeed to date, a three-dimensional X-ray crystallographic structure has been obtained for only three GPCRs [14••,15••,59]. It is unfortunate that the coreceptor structure is still absent in high resolution X-ray structures solved for gp120 in its CD4-bound [60] and unbound [61] forms, the postfusion core of gp41 [62,63], and the gp120-binding region of CD4 cell [64,65].

It is generally accepted that R5 viruses appear early in infection and are responsible for virus transmission, whereas X4 strains appear late and have been associated to faster decline of CD4+ T cells [1•]. Coreceptor usage and switching has been analyzed most extensively for clade B isolates, which predominate in North America and Western Europe [66]. Nonclade B viruses cause the vast majority of new HIV-1 infections worldwide and should, therefore, be the major focus of vaccine efforts and drug development efforts. Nonclade B viruses are understudied, and their immunogenic and biological properties remain largely unknown. Rapid depletion of CD4+ T-lymphocytes has been associated with a switch in viral coreceptor usage from CCR5 to CXCR4 in approximately 40–50% of infected individuals [67]. However, the majority of infected individuals who progress to AIDS harbor predominantly CCR5-dependent viral strains [67]. Additionally, CCR5-deficient HIV+CCR5−/− patients progress to AIDS harbouring either X4 or R5X4 isolates [68]. There is evidence to suggest that the late-emerging R5 strains have reduced sensitivity to entry inhibitors and increased ability to cause CD4+ T-lymphocyte loss [69]. Recent studies used a simian immunodeficiency virus model to show that disease progression can be induced by a mucosally transmissible, pathogenic R5 nonclade B simian/human immunodeficiency virus [70••].

Receptor internalization and recycling

The mechanism(s) by which chemokines block HIV-1 infection is not well understood. One model proposes that chemokines bind to a receptor domain that overlaps with gp120 receptor-binding domain (i.e. steric blockade). The other model proposes that chemokine-induced internalization of the coreceptor molecules leads to the downmodulation of receptor sites at the cell surface, making the cells invisible for the virus envelope interaction. Several studies demonstrated that chemokine-induced internalization of CCR5 and CXCR4 could contribute to the chemokine-mediated inhibition of HIV-1 entry [7173].

To avoid prolonged activation of the receptors, GPCR complexes are endocytosed and either recycled back to the plasma membrane or sorted into the degradative pathway [11••]. A ubiquitin-associated system is crucial in regulating these processes and involves the conjugation of ubiquitin onto target proteins destined for degradation, mediated by a family of proteins called E3 ubiquitin ligases. A well characterized example is the agonist-dependent degradation of CXCR4, in which ubiquitination mediated by the E3 ubiquitin ligase, AIP4, has been shown to be required at multiple steps in the sorting process. Ubiquitinated CXCR4 is concentrated on HRS-positive microdomains together with AIP4. AIP4 mediates ubiquitination of HRS following CXCR4 activation, which is critical for MVB sorting. CISK phosphorylates and inhibits AIP4 activity and, thereby, inhibits endosomal sorting of CXCR4 and favors the recycling pathway. VPS4 also regulates the ubiquitination status of CXCR4 and MVB sorting. Ubiquitination functions as an endosomal sorting signal and is not required for CXCR4 internalization. Figure 4 outlines CXCR4 trafficking within the endosomal–lysosomal system.

Figure 4
CXCR4 trafficking within the endosomal–lysosomal system gr4

Recent studies on CCR5 intracellular trafficking of both progressive truncation and substitution mutants of the C-terminal domain demonstrated that the C-terminal tip of CCR5 possesses a sequence necessary for recycling, which acts as a postsynaptic density 95/discs-large/zona occludens (PDZ) interacting sequence [74]. PDZ domains are protein-protein recognition modules that bind to C-terminal short, linear PDZ ligand sequences. This sequence is present at the C-terminal tip of CCR5 (Fig. 2), but not CXCR4. The recent findings on CCR5 trafficking strengthened the key role played by PDZ ligands in the intracellular sorting and reinforced the emerging concept that GPCR recycling is a regulated process [11••]. Ligand-induced internalization of CCR5 is believed to involve a similar mechanism described for CXCR4; however, the subsequent fate of CCR5 is not well established. CCR5 shows a constitutive turnover in the absence of ligand with a half time of 6–9 h. Addition of RANTES has little effect on the rate of CCR5 turnover [75].

Conclusion

The HIV coreceptors have created entirely new paradigms for understanding basic mechanisms underlying the transmission and pathogenesis of HIV-1 infection [76]. In the coming years, we will likely witness the development of coreceptor-based antiviral strategies. Indeed, the orally bioavailable CCR5 blocking agent, maraviroc, [77] is the first such therapeutic to be approved by the U.S. Food and Drug Administration. CXCR4-based blocking agents are less attractive due to the crucial role of CXCR4 in many biological processes; however, agents that are aimed at downmodulating CXCR4 expression might provide some benefits for HIV-positive patients. Antagonism of CXCR4 significantly improved survival from lethal infection through enhanced intraparenchymal migration of West Nile Virus (WNV)-specific CD8+ T cells within the brain, leading to reduced viral loads and, surprisingly, decreased immunopathology at this site [78••].

Acknowledgement

I would like to thank Dr. JoAnn Trejo for help in Figure 4. I thank Bashar Alkhatib for editing the manuscript. Some of the work reported here is supported by the NIH grant# R01 A152019-01 for Ghalib Alkhatib.

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • • of special interest
  • •• of outstanding interest

Additional references related to this topic can also be found in the Current World Literature section in this issue (pp. 000–000).

1. Alkhatib G, Berger EA. HIV coreceptors: from discovery and designation to new paradigms and promise. Eur J Med Res. 2007;12(9):375–384. Most recent review on HIV coreceptors. [PubMed]
2. Feng Y, Broder CC, Kennedy PE, Berger EA. HIV-1 entry cofactor: Functional cDNA cloning of a seven-transmembrane, G protein-coupled receptor. Science. 1996;272:872–877. [PubMed]
3. Alkhatib G, Combadiere C, Broder CC, et al. CC CKR5: a RANTES, MIP-1alpha, MIP-1beta receptor as a fusion cofactor for macrophage-tropic HIV-1. Science. 1996;272(5270):1955–1958. [PubMed]
4. Choe H, Farzan M, Sun Y, et al. The beta-chemokine receptors CCR3 and CCR5 facilitate infection by primary HIV-1 isolates. Cell. 1996;85(7):1135–1148. [PubMed]
5. Deng H, Liu R, Ellmeier W, et al. Identification of a major co-receptor for primary isolates of HIV-1 [see comments] Nature. 1996;381(6584):661–666. [PubMed]
6. Doranz BJ, Rucker J, Yi Y, et al. A dual-tropic primary HIV-1 isolate that uses fusin and the beta-chemokine receptors CKR-5, CKR-3, and CKR-2b as fusion cofactors. Cell. 1996;85(7):1149–1158. [PubMed]
7. Dragic T, Litwin V, Allaway GP, et al. HIV-1 entry into CD4(+) cells is mediated by the chemokine receptor CC-CKR-5. Nature. 1996;381:667–673. [PubMed]
8. Allen SJ, Crown SE, Handel TM. Chemokine: receptor structure, interactions, and antagonism. Annu Rev Immunol. 2007;25:787–820. Recent review on chemokines. [PubMed]
9. Schlyer S, Horuk R. I want a new drug: G-protein-coupled receptors in drug development. Drug Discov Today. 2006;11(11–12):481–493. [PubMed]
10. Yeagle PL, Albert AD. G-protein coupled receptor structure. Biochim Biophys Acta. 2007;1768(4):808–824. Recent review on GPCRs. [PubMed]
11. Marchese A, Paing MM, Temple BR, Trejo J. G protein-coupled receptor sorting to endosomes and lysosomes. Annu Rev Pharmacol Toxicol. 2008;48:601–629. A comprehensive review on GPCR endocytosis. [PMC free article] [PubMed]
12. Viola A, Luster AD. Chemokines and their receptors: drug targets in immunity and inflammation. Annu Rev Pharmacol Toxicol. 2008;48:171–197. Most recent review on chemokines and their receptors. [PubMed]
13. Lederman MM, Penn-Nicholson A, Cho M, Mosier D. Biology of CCR5 and its role in HIV infection and treatment. Jama. 2006;296(7):815–826. [PubMed]
14. Hanson MA, Cherezov V, Griffith MT, et al. A specific cholesterol binding site is established by the 2.8 A structure of the human beta2-adrenergic receptor. Structure. 2008;16(6):897–905. This study describes a novel method to obtain the crystal structure of human β2-adrenergic receptor. [PMC free article] [PubMed]
15. Jaakola VP, Griffith MT, Hanson MA, et al. The 2.6 Angstrom Crystal Structure of a Human A2A Adenosine Receptor Bound to an Antagonist. Science. 2008 This study describes a novel method to obtain the crystal structure of human A2A receptor. [PMC free article] [PubMed]
16. Combadiere C, Ahuja SK, Tiffany HL, Murphy PM. Cloning and functional expression of CC CKR5, a human monocyte CC chemokine receptor selective for MIP-1(alpha), MIP-1(beta), and RANTES. J Leukoc Biol. 1996;60(1):147–152. [PubMed]
17. Samson M, Labbe O, Mollereau C, et al. Molecular cloning and functional expression of a new human CC-chemokine receptor gene. Biochemistry. 1996;35(11):3362–3367. [PubMed]
18. Blanpain C, Migeotte I, Lee B, et al. CCR5 binds multiple CC-chemokines: MCP-3 acts as a natural antagonist. Blood. 1999;94(6):1899–1905. [PubMed]
19. Ansari AW, Heiken H, Moenkemeyer M, Schmidt RE. Dichotomous effects of C-C chemokines in HIV-1 pathogenesis. Immunol Lett. 2007;110(1):1–5. This study shows that the CC chemokine CCL2 ehances HIV-1 replication. [PubMed]
20. Zhou Y, Kurihara T, Ryseck RP, et al. Impaired macrophage function and enhanced T cell-dependent immune response in mice lacking CCR5, the mouse homologue of the major HIV-1 coreceptor. J Immunol. 1998;160(8):4018–4025. [PubMed]
21. Welniak LA, Wang Z, Sun K, et al. An absence of CCR5 on donor cells results in acceleration of acute graft-vs-host disease. Exp Hematol. 2004;32(3):318–324. [PubMed]
22. O'Brien SJ, Moore JP. The effect of genetic variation in chemokines and their receptors on HIV transmission and progression to AIDS.[In Process Citation] Immunol Rev. 2000;177:99–111. [PubMed]
23. O'Brien TR, Winkler C, Dean M, et al. HIV-1 infection in a man homozygous for CCR5 delta 32 [letter] [see comments] Lancet. 1997;349(9060):1219. [PubMed]
24. Balotta C, Bagnarelli P, Violin M, et al. Homozygous delta 32 deletion of the CCR-5 chemokine receptor gene in an HIV-1-infected patient. Aids. 1997;11(10):F67–F71. [PubMed]
25. Biti R, Ffrench R, Young J, et al. HIV-1 infection in an individual homozygous for the CCR5 deletion allele [letter; comment] Nature Medicine. 1997;3(3):252–253. [PubMed]
26. Gorry PR, Zhang C, Wu S, et al. Persistence of dual-tropic HIV-1 in an individual homozygous for the CCR5D32 allele. Lancet. 2002;359(9320):1832–1834. [PubMed]
27. Kuipers H, Workman C, Dyer W, et al. An HIV-1-infected individual homozygous for the CCR-5 delta32 allele and the SDF-1 3'A allele. Aids. 1999;13(3):433–434. [PubMed]
28. Michael NL, Nelson JA, KewalRamani VN, et al. Exclusive and persistent use of the entry coreceptor CXCR4 by human immunodeficiency virus type 1 from a subject homozygous for CCR5 delta32. Journal of Virology. 1998;72(7):6040–6047. [PMC free article] [PubMed]
29. Sheppard HW, Celum C, Michael NL, et al. HIV-1 infection in individuals with the CCR5-Delta32/Delta32 genotype: acquisition of syncytium-inducing virus at seroconversion. J Acquir Immune Defic Syndr. 2002;29(3):307–313. [PubMed]
30. Theodorou I, Meyer L, Magierowska M, et al. HIV-1 infection in an individual homozygous for CCR5 delta 32. Seroco Study Group [letter] [see comments] Lancet. 1997;349(9060):1219–1220. [PubMed]
31. Naif HM, Cunningham AL, Alali M, et al. A human immunodeficiency virus type 1 isolate from an infected person homozygous for CCR5Delta32 exhibits dual tropism by infecting macrophages and MT2 cells via CXCR4. J Virol. 2002;76(7):3114–3124. [PMC free article] [PubMed]
32. Agrawal L, Lu X, Qingwen J, et al. Role for CCR5D32 protein in resistance to R5, R5X4, and X4 human immunodeficiency virus type 1 in primary CD4+ cells. J. Virol. 2004;78(5):2277–2287. [PMC free article] [PubMed]
33. Agrawal L, Jin Q, Altenburg J, et al. CCR5Delta32 protein expression and stability are critical for resistance to human immunodeficiency virus type 1 in vivo. J Virol. 2007;81(15):8041–8049. This study is the first to analyze the mechanism of failure of the protective effect of CCR5Δ32 mutation in HIV+CCR5−/− patients. The study concludes that expression and stability of the truncated CCR5Δ32 protein are critical for the resistance phenotype. [PMC free article] [PubMed]
34. Jin Q, Agrawal L, Meyer L, et al. CCR5Δ32 59537-G/A promoter polymorphism is associated with low translational efficiency and the loss of CCR5Δ32 protective effects. J Virol. 2008;82(5):2418–2426. This study shows a strong correlation between polymorphisms in the CCR5 promoter and the efficiency of protein translation. [PMC free article] [PubMed]
35. Jin Q, Marsh J, Cornetta K, Alkhatib G. Resistance to human immunodeficiency virus type 1 (HIV-1) generated by lentivirus vector-mediated delivery of the CCR5{Delta}32 gene despite detectable expression of the HIV-1 co-receptors. J Gen Virol. 2008;89(Pt 10):2611–2621. This study shows that resistance to HIV can be modeled in vitro by continuous and stable expression of the CCR5Δ32 protein. [PMC free article] [PubMed]
36. Hutter G, et al. Treatment of HIV-1 Infection by Allogeneic CCR5-D32/D32 Stem Cell Transplantation: A Promising Approach. 15th Conference on Retroviruses and Opportunistic Infections; Boston, MA. 2008. This study is the first to report the first successful transplanation of CCR5Δ32 stem cells in a HIV+ patient.
37. Federsppiel B, Melhado IG, Duncan AM, et al. Molecular cloning of the cDNA and chromosomal localization of the gene for a putative seven-transmembrane segment (7-TMS) receptor isolated from human spleen. Genomics. 1993;16(3):707–712. [PubMed]
38. Herzog H, Hort YJ, Shine J, Selbie LA. Molecular cloning, characterization, and localization of the human homolog to the reported bovine NPY Y3 receptor: lack of NPY binding and activation. DNA Cell Biol. 1993;12(6):465–471. [PubMed]
39. Jazin EE, Yoo H, Blomqvist AG, et al. A proposed bovine neuropeptide Y (NPY) receptor cDNA clone, or its human homologue, confers neither NPY binding sites nor NPY responsiveness on transfected cells. Regul Pept. 1993;47(3):247–258. [PubMed]
40. Loetscher M, Geiser T, O'Reilly T, et al. Cloning of a human seven-transmembrane domain receptor, LESTR, that is highly expressed in leukocytes. J Biol Chem. 1994;269(1):232–237. [PubMed]
41. Nomura H, Nielsen BW, Matsushima K. Molecular cloning of cDNAs encoding a LD78 receptor and putative leukocyte chemotactic peptide receptors. Int Immunol. 1993;5(10):1239–1249. [PubMed]
42. Bleul CC, Farzan M, Choe H, et al. The lymphocyte chemoattractant SDF-1 is a ligand for LESTR/fusin and blocks HIV-1 entry. Nature. 1996;382(6594):829–833. [PubMed]
43. Oberlin E, Amara A, Bachelerie F, et al. The CXC chemokine SDF-1 is the ligand for LESTR/fusin and prevents infection by T-cell-line-adapted HIV-1. Nature. 1996;382(6594):833–835. [PubMed]
44. Yu L, Cecil J, Peng SB, et al. Identification and expression of novel isoforms of human stromal cell-derived factor 1. Gene. 2006;374:174–179. [PubMed]
45. Altenburg JD, Broxmeyer HE, Jin Q, et al. A Naturally Occurring Splice Variant of CXCL12/Stromal Cell-Derived Factor 1 is a potent HIV-1 Inhibitor with Weak Chemotaxis and Cell Survival Activities. J Virol. 2007;81(15):8140–8148. This is the first study to examine the antiviral activities of the new CXCL12 isoforms. The study identifies CXCL12γ as a potent HIV inhibitor with weak chemotaxis activity. [PMC free article] [PubMed]
46. Burger JA, Kipps TJ. CXCR4: a key receptor in the crosstalk between tumor cells and their microenvironment. Blood. 2006;107(5):1761–1767. [PubMed]
47. Tachibana K, Hirota S, Iizasa H, et al. The chemokine receptor CXCR4 is essential for vascularization of the gastrointestinal tract. Nature. 1998;393(6685):591–594. [PubMed]
48. Nagasawa T, Hirota S, Tachibana K, et al. Defects of B-cell lymphopoiesis and bone-marrow myelopoiesis in mice lacking the CXC chemokine PBSF/SDF-1. Nature. 1996;382(6592):635–638. [PubMed]
49. Nair S, Schilling TF. Chemokine signaling controls endodermal migration during zebrafish gastrulation. Science. 2008;322(5898):89–92. [PMC free article] [PubMed]
50. Eckert DM, Kim PS. Mechanisms of viral membrane fusion and its inhibition. Annu Rev Biochem. 2001;70:777–810. [PubMed]
51. Wyatt R, Sodroski J. The HIV-1 envelope glycoproteins: fusogens, antigens, and immunogens. Science. 1998;280(5371):1884–1888. [PubMed]
52. Dragic T. An overview of the determinants of CCR5 and CXCR4 co-receptor function. J Gen Virol. 2001;82(Pt 8):1807–1814. [PubMed]
53. Bandres JC, Wang QF, O'Leary J, et al. Human immunodeficiency virus (HIV) envelope binds to CXCR4 independently of CD4, and binding can be enhanced by interaction with soluble CD4 or by HIV envelope deglycosylation. J Virol. 1998;72(3):2500–2504. [PMC free article] [PubMed]
54. Lapham CK, Ouyang J, Chandrasekhar B, et al. Evidence for cell-surface association between fusin and the CD4-gp120 complex in human cell lines [see comments] Science. 1996;274(5287):602–605. [PubMed]
55. Trkola A, Dragic T, Arthos J, et al. CD4-dependent, antibody-sensitive interactions between HIV-1 and its co- receptor CCR-5. Nature. 1996;384(6605):184–187. [PubMed]
56. Wu L, Gerard NP, Wyatt R, et al. CD4-induced interaction of primary HIV-1 gp120 glycoproteins with the chemokine receptor CCR-5. Nature. 1996;384(6605):179–183. [PubMed]
57. Salzwedel K, Smith ED, Dey B, Berger EA. Sequential CD4-coreceptor interactions in human immunodeficiency virus type 1 Env function: soluble CD4 activates Env for coreceptor-dependent fusion and reveals blocking activities of antibodies against cryptic conserved epitopes on gp120. J Virol. 2000;74(1):326–333. [PMC free article] [PubMed]
58. Wyatt R, Kwong PD, Desjardins E, et al. The antigenic structure of the HIV gp120 envelope glycoprotein. Nature. 1998;393(6686):705–711. [PubMed]
59. Palczewski K, Kumasaka T, Hori T, et al. Crystal structure of rhodopsin: A G protein-coupled receptor. Science. 2000;289(5480):739–745. [PubMed]
60. Kwong PD, Wyatt R, Robinson J, et al. Structure of an HIV gp120 envelope glycoprotein in complex with the CD4 receptor and a neutralizing human antibody. Nature. 1998;393(6686):648–659. [PubMed]
61. Chen B, Vogan EM, Gong H, et al. Structure of an unliganded simian immunodeficiency virus gp120 core. Nature. 2005;433(7028):834–841. [PubMed]
62. Chan DC, Fass D, Berger JM, Kim PS. Core structure of gp41 from the HIV envelope glycoprotein. Cell. 1997;89(2):263–273. [PubMed]
63. Weissenhorn W, Dessen A, Harrison SC, et al. Atomic structure of the ectodomain from HIV-1 gp41. Nature. 1997;387(6631):426–430. [PubMed]
64. Ryu SE, Kwong PD, Truneh A, et al. Crystal structure of an HIV-binding recombinant fragment of human CD4. Nature. 1990;348(6300):419–426. [PubMed]
65. Wang JH, Yan YW, Garrett TP, et al. Atomic structure of a fragment of human CD4 containing two immunoglobulin-like domains. Nature. 1990;348(6300):411–418. [PubMed]
66. Bazan HA, Alkhatib G, Broder CC, Berger EA. Patterns of CCR5, CXCR4, and CCR3 usage by envelope glycoproteins from human immunodeficiency virus type 1 primary isolates. J.Virol. 1998;72(5):4485–4491. [PMC free article] [PubMed]
67. Gorry PR, Churchill M, Crowe S, et al. Pathogenesis of macrophage tropic HIV-1. Curr HIV Res. 2005;3(1):53–60. [PubMed]
68. Agrawal L, Lu X, Jin Q, Alkhatib G. Anti-HIV therapy: Current and future directions. Curr Pharm Des. 2006;12(16):2031–2055. [PubMed]
69. Karlsson I, Antonsson L, Shi Y, et al. Coevolution of RANTES sensitivity and mode of CCR5 receptor use by human immunodeficiency virus type 1 of the R5 phenotype. J Virol. 2004;78(21):11807–11815. [PMC free article] [PubMed]
70. Humbert M, Rasmussen RA, Song R, et al. SHIV-1157i and passaged progeny viruses encoding R5 HIV-1 clade C env cause AIDS in rhesus monkeys. Retrovirology. 2008;5:94. This study shows AIDS disease progression in a primate model by a pathogenic R5 isolate. [PMC free article] [PubMed]
71. Alkhatib G, Locati M, Kennedy PE, et al. HIV-1 coreceptor activity of CCR5 and its inhibition by chemokines: independence from G protein signaling and importance of coreceptor downmodulation. Virology. 1997;234(2):340–348. [PubMed]
72. Amara A, Gall SL, Schwartz O, et al. HIV coreceptor downregulation as antiviral principle: SDF-1alpha-dependent internalization of the chemokine receptor CXCR4 contributes to inhibition of HIV replication. Journal of Experimental Medicine. 1997;186(1):139–146. [PMC free article] [PubMed]
73. Signoret N, Oldridge J, Pelchen-Matthews A, et al. Phorbol esters and SDF-1 induce rapid endocytosis and down modulation of the chemokine receptor CXCR4. Journal of Cell Biology. 1997;139(3):651–664. [PMC free article] [PubMed]
74. Delhaye M, Gravot A, Ayinde D, et al. Identification of a postendocytic sorting sequence in CCR5. Mol Pharmacol. 2007;72(6):1497–1507. [PubMed]
75. Signoret N, Marsh M. Analysis of chemokine receptor endocytosis and recycling. Methods Mol Biol. 2000;138:197–207. [PubMed]
76. Moore JP, Kitchen SG, Pugach P, Zack JA. The CCR5 and CXCR4 coreceptors–central to understanding the transmission and pathogenesis of human immunodeficiency virus type 1 infection. AIDS Res Hum Retroviruses. 2004;20(1):111–126. [PubMed]
77. Dorr P, Westby M, Dobbs S, et al. Maraviroc (UK-427,857), a potent, orally bioavailable, and selective small-molecule inhibitor of chemokine receptor CCR5 with broad-spectrum anti-human immunodeficiency virus type 1 activity. Antimicrob Agents Chemother. 2005;49(11):4721–4732. [PMC free article] [PubMed]
78. McCandless EE, Zhang B, Diamond MS, Klein RS. CXCR4 antagonism increases T cell trafficking in the central nervous system and improves survival from West Nile virus encephalitis. Proc Natl Acad Sci U S A. 2008;105(32):11270–11275. This study demonstrated that antagonism of CXCR4 significantly improved survival from lethal infection suggesting that targeting CXCR4 may have therapeutic utility for the treatment of acute viral infections of the CNS. [PMC free article] [PubMed]
PubReader format: click here to try

Formats:

Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...

Links

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...