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Blood, Vol. 95 No. 10 (May 15), 2000:
pp. 3032-3043
REVIEW ARTICLE
From the Division of Child Health, University of Sheffield,
Sheffield Children's Hospital, Sheffield, United Kingdom.
Chemokines are small peptides that are potent activators and
chemoattractants for leukocyte subpopulations and some nonhemopoietic cells. Their actions are mediated by a family of 7-transmembrane G-protein-coupled receptors, the size of which has grown considerably in recent years and now includes 18 members. Chemokine receptor expression on different cell types and their binding and response to
specific chemokines are highly variable. Significant advances have been
made in understanding the regulation of chemokine receptor expression
and the intracellular signaling mechanisms used in bringing about cell
activation. Chemokine receptors have also recently been implicated in
several disease states including allergy, psoriasis, atherosclerosis,
and malaria. However, most fascinating has been the observation that
some of these receptors are used by human immunodeficiency virus type 1 in gaining entry into permissive cells. This review will discuss
structural and functional aspects of chemokine receptor biology and
will consider the roles these receptors play in inflammation and in
infectious diseases.
(Blood. 2000;95:3032-3043)
Phagocytic leukocytes of the immune system undergo
rapid and directed movements in chemoattractant gradients, a property
that enables them to serve as the first line of cell-mediated host defense against infection. The interaction of chemoattractants with
leukocytes initiates a series of coordinated biochemical and cellular
events that includes alterations in ion fluxes, integrin avidity and
transmembrane potential, changes in cell shape, secretion of lysosomal
enzymes, production of superoxide anions, and enhanced locomotion.
Two groups of chemoattractants have been identified and extensively
studied. The "classical" chemoattractants, such as
bacterial-derived N-formyl peptides, complement fragment peptides C5a
and C3a, and lipid molecules such as leukotriene B4 and
platelet-activating factor are all chemoattractants and activators of
leukocytes.1-4 Recently, a number of chemotactic cytokines
in the 8- to 17-kd molecular mass range have been shown to be selective
chemoattractants for leukocyte subpopulations in vitro and to elicit
the accumulation of inflammatory cells in vivo.5,6 These
chemotactic cytokines belong to the chemokine superfamily, which can be
divided into 4 groups (CXC, CX3C, CC, and C) according to
the positioning of the first 2 closely paired and highly conserved
cysteines of the amino acid sequence.
The specific effects of chemokines on their target cells are mediated
by members of a family of 7-transmembrane-spanning, G-protein-coupled
receptors.7 These chemokine receptors are part of a much
bigger superfamily of G-protein-coupled receptors that include
receptors for hormones, neurotransmitters, paracrine substances,
inflammatory mediators, certain proteinases, taste and odorant
molecules, and even photons and calcium ions.8
To date 18 human chemokine receptors have been identified (Table
1). Among the 5 receptors that selectively
bind certain CXC chemokines are chemokine receptors CXCR1 to CXCR5,
whereas the CC receptor family consists of 9 receptors, CCR1 to CCR9. A
further receptor, designated D6, has been termed CCR10 by 1 research
group, but this has yet to be officially adopted. Recently, receptors
for fractalkine (CX3CR1) and lymphotactin (XCR1) have been
identified. A further chemokine receptor, known as the Duffy antigen
receptor for chemokines (DARC) has been shown to bind promiscuously to
both CXC and CC chemokines. This review describes the characteristics
of chemokine receptor gene and protein structure and includes a
synopsis of each chemokine receptor identified to date. The roles that
chemokine receptors play in inflammation and human disease states are
then discussed.
All chemokine receptors identified thus far are membrane-bound
molecules composed of 7-transmembrane domains and coupled to G-proteins. Figure 1 shows a diagrammatic
representation of CXCR1 that provides a good example for discussing the
general chemokine receptor structure. Major hallmarks of chemokine
receptors are as follows. They measure approximately 350 amino acids in
length and require the introduction of few gaps in the primary sequence to be aligned to other chemokine receptors; a short extracellular N-terminus is acidic overall and may be sulfated on tyrosine residues and contain N-linked glycosylation sites; an intracellular C-terminus contains serine and threonine residues that act as phosphorylation sites for receptor regulation; 7
CXCR1 and CXCR2
CXCR3
CXCR4 CXCR4 was originally cloned by Loetscher et al28 as an orphan chemokine receptor (that is, a receptor whose ligand has not yet been discovered) and was given the acronym LESTR. The orphan receptor was found to be expressed on neutrophils, myeloid cells, and, in particular, T lymphocytes.28 LESTR was later identified as an essential cofactor for T-tropic human immunodeficiency virus type 1 (HIV-1) and type 2 (HIV-2) env-mediated fusion and entry into CD4+-expressing cells.29 However, it was not until the CXC chemokine SDF-1 was recognized as the biologic ligand for LESTR that the receptor was reclassified as CXCR4.30,31 SDF-1 is a highly efficacious lymphocyte chemoattractant, and it
inhibits HIV-1 infection of permissive CD4+ in accordance
with CXCR4 expression patterns.30,31 Recently, IL-4 was
found to enhance the cell-surface expression of CXCR4 on resting
T-cells, whereas the receptor is down-regulated after T-cell
stimulation by CD28 or CD3 and CD2.32 Mice lacking the CXCR4 gene exhibit impaired B lymphopoiesis, myelopoiesis,
hematopoiesis, derailed cerebellar neurone migration, and defective
formation of large vessels supplying the gastrointestinal
tract.33-35 These findings suggest that SDF-1 and CXCR4
have biologic functions significantly different from those of other
chemokines and chemokine receptors.
CXCR5 The orphan receptor BLR1, which is known to be highly expressed in Burkitt's lymphoma cells and B lymphocytes, was found to have significant homology with other CXC chemokine receptors.36 However, at the time no known CXC chemokines that stimulated B cells had been identified. Legler et al37 recently identified and cloned a novel CXC chemokine with potent B-cell-activating capabilities that has subsequently been termed BCA-1 (B-cell-activating chemokine). Furthermore, on screening BCA-1 against a panel of putative chemokine receptors, the chemokine was found to be highly specific for BLR1.37 Consequently, because BLR1 is the fifth CXC chemokine receptor to be identified, it has been renamed CXCR5.CX3CR1 Fractalkine, a novel class of chemokine with a unique CX3C motif, has been identified and characterized.38 Unlike other chemokines, the molecule exists as a membrane-bound glycoprotein with the chemokine atop an extended mucin-like stalk. Imai et al39 observed that fractalkine bound with high affinity to the orphan chemokine receptor V28 and subsequently renamed the V28 receptor CX3CR1.39 Fractalkine, either attached or detached from its stalk, binds to CX3CR1 and promotes adhesion of monocytes, NK cells, and T lymphocytes to endothelial, epithelial, and dendritic cells.38,40,41CCR1 The high-affinity RANTES/MIP-1 receptor (now termed CCR1), which
was first cloned by Neote et al42 has 33% similarity to CXCR2 and 31% to CXCR1. It is also 33% homologous to the
7-transmembrane cytomegalovirus protein, US28.43 Indeed,
US28 can bind both RANTES and MIP-1 with high affinity, suggesting
that US28 may be a CCR1 homologue acquired by viral
hijack.44 Xenopus oocytes injected with CCR1 cRNA
acquired responsiveness to MIP-1 and RANTES but not to MIP-1 or
any other CC chemokine tested.42 Cells transfected with
CCR1 responded to MIP-1, RANTES, MCP-2, and MCP-3; hence, CCR1 also
binds MCP-2 and MCP-3.45-47 Recently, the novel CC
chemokines MIP-5, HCC-1 (hemofiltrate CC chemokine), and CK8 have
also been shown to bind specifically to CCR1.48,49
CCR2A and CCR2B The monocyte chemotactic proteins function as potent activators and chemoattractants for monocytes, basophils, eosinophils, and T-lymphocyte subsets, but not for neutrophils.5 Direct binding studies with 125I-MCP-1 identified high-affinity binding sites on human monocytes.56 Monocyte, basophil, and eosinophil activation by CC chemokines, including MCP-1, are prevented by pretreatment with Bordetella pertussis toxin, suggesting that the action of MCP-1 is mediated by a G-protein-coupled receptor.57
CCR3 Cross-desensitization experiments using chemokine-induced intracellular calcium mobilization have indicated that eosinophils may have specific receptors for RANTES, MCP-3, and eotaxin and a shared receptor for MIP-1, RANTES, and MCP-3.61,62 MIP-1, RANTES, and MCP-3 can bind to CCR1, and MCP-3 can also bind to CCR2;
however, CCR2 is not expressed by eosinophils. Using this information,
Daugherty et al63 and Kitaura et al64
independently identified and characterized the eosinophil-selective
chemokine receptor CCR3. CCR3 cDNA encodes for a protein that is
expressed predominantly on eosinophils but can also be detected on
basophils and T cells.63,65,66 The receptor has 63%
similarity to CCR1 and 51% to CCR2B and binds several CC chemokines
specifically, including eotaxin, eotaxin-2, RANTES, MCP-3, MCP-4, and
MIP-5, all of which have been implicated in eosinophil recruitment and activation.63,65,67 Eotaxin and eotaxin-2 have the greatest affinity for CCR3 and, accordingly, are the most potent chemokine activators of eosinophils.68 Subsequently, CCR3 has been
implicated in the progression of allergic reactions (discussed below).
In association with CD4, CCR3 has also been implicated in permitting macrophage-tropic HIV-1 infection of permissive cells.69
CCR4 Power et al70 have identified a novel CC chemokine receptor called CCR4 that shares 49% identity with CCR1 and 47% with CCR2B.70 Initially, it was thought that CCR4 bound RANTES and MIP-1. However, recent studies show that CCR4 specifically binds the CC chemokines TARC (thymus and activation-regulated chemokine) and
MDC (macrophage-derived chemokine).71,72 TARC and MDC have both been shown to be selective activators of T lymphocytes,
particularly CD4+ Th2 cells. These data are in agreement
with the expression of CCR4, which appears to be highly expressed in T
lymphocytes and platelets and weakly expressed in other peripheral
mononuclear cells.70,71 Furthermore, the expression of CCR4
on Th2 cells was transiently increased after T-cell receptor and CD28
engagement. Consequently, the activity of Th2 cells to TARC
was enhanced on receptor activation.73
CCR5 Originally cloned by Samson et al,74 CCR5 was found to bind the CC chemokines MIP-1, RANTES, MIP-1, and MCP-2 specifically using transfected and peripheral blood mononuclear cells.75 These studies were quickly corroborated by Raport et al,76
who also demonstrated CCR5 mRNA expression in lymphoid organs such as
the thymus and spleen and in peripheral T lymphocytes and
macrophages.76 CCR5 is most closely related to CCR2B, with
71% identical amino acid residues. Furthermore, the gene encoding CCR5
is a localized only 18-kb pair downstream of the gene for CCR2 on
chromosome 3p21,74,76 which suggest that these 2 receptors
share an ancestral gene. CCR5 is also homologous to other CC receptors
and shares 55%, 49%, and 48% identity with CCR1, CCR3, and CCR4,
respectively.76 Recently, CCR5 has been shown to be the
major coreceptor in association with CD4 for macrophage-tropic HIV-1
entry into permissive cells.69 The immunosuppressive and
anti-inflammatory cytokine IL-10 selectively up-regulated the
expression of CCR5 in human monocytes by prolonging the mRNA
half-life.55 It appears that this increase in CCR5 expression is regulated by activation of MAP and STAT
kinases.77 IL-15-stimulated T cells also increased their
expression of CCR5,54 indicating that interleukins can act
as modulators of chemokine receptor expression.
CCR6 CCR6 was originally cloned by several groups as an orphan chemokine receptor and was therefore provided with several different acronyms (STRL 22, DRY-6, GPR-CY4, CKR-L3). It was not until Baba et al78 discovered that the CC chemokine MIP-3/LARC (liver and activation-regulated chemokine) specifically bound to the orphan
receptor GPR-CY4 that these orphan receptors were all redesignated as
CCR6. CCR6 has been detected on memory T cells, B lymphocytes, and
dendritic cells but not on any other peripheral blood
leukocyte.79 CCR6 mRNA has been shown to be up-regulated by
treatment with IL-2.78,80 However, recent data contradict
this finding79 and, as a consequence, the effect of IL-2 on
CCR6 expression remains uncertain.
CCR7 By searching the expressed sequence tag (EST) database, Yoshida et al81 identified a cDNA sequence that codes for a novel CC chemokine, was termed ELC (EBI1-ligand chemokine) or MIP-3. ELC was
then screened against a panel of cells transfected with known and
orphan chemokine receptors to search for its corresponding high-affinity receptor. It was found that ELC bound specifically to the
orphan receptor EBI1,82 which has subsequently been renamed CCR7.81 Recently, the novel CC chemokine 6-C-kine, also
known as SLC (secondary lymphoid-tissue chemokine), has been shown to be a specific agonist for CCR7.83 CCR7 is known to be
expressed on activated T and B lymphocytes and dendritic cells and is
strongly up-regulated in B cells infected with Epstein-Barr virus and
in T cells infected with herpesvirus 6 or 7.81,84
CCR8 The human CC chemokine I-309 is a potent monocyte chemoattractant and inhibits apoptosis in thymic cell lines.85 To identify its cognate chemokine receptor, Roos et al86 used an intracellular calcium mobilization assay with I-309 to test for receptor function in cells transfected with several known orphan receptors. I-309 was found to bind specifically to and to activate cells transfected with the orphan receptor known as either TER1,87 ChemR1,88 or CKR-L1.89 These findings were quickly corroborated by Tiffany et al.90 Consequently, these orphan receptors were collectively renamed CCR8, in accordance with the nomenclature system for chemokine receptors. Strong CCR8 mRNA expression was detected in the thymus and monocytes but not in other peripheral blood leukocytes.90 These data appear to be in agreement with the role of I-309 in monocyte activation and thymic cell survival. Indeed, CCR8 is preferentially expressed on Th2-polarized cells91 and is transiently increased after T-cell receptor and CD28 engagement,73 suggesting that CCR8 plays a role in the control of Th2 responses and that up-regulation of CCR8 after antigen encounter may contribute to the proper positioning of activated T cells within sites of antigenic challenge or specialized areas of lymphoid tissue.73 Recently, CCR8 has been shown to serve as a cofactor, in association with CD4, to permit the infection of permissive cells with T-cell tropic and macrophage-tropic HIV-1 strains.92CCR9 CCR9 is the most recent chemokine receptor to be identified. Zaballos et al93 found that thymus-expressed chemokine (TECK) is a specific agonist for the human orphan receptor GPR-9-6 (EMBL accession number U45 982), which has been renamed CCR9 according to the established nomenclature. CCR9 expression is high in the thymus but low in lymph nodes and spleen, and it appears to be expressed on both immature and mature T cells.93 These data are in agreement with previous results showing that TECK is an activator of dendritic cells and thymocytes, which implicates this CC chemokine in T-cell development.94D6 (CCR10?) D6 was simultaneously cloned by 2 independent groups and displays approximately 30% homology with other CC chemokine receptors at the amino acid level.95,96 It was originally described by Bonini et al95 as CCR10. However, because D6 does not generate an intracellular signal on ligand binding and, therefore, appears not to be functional,96 the receptor has yet to be granted a CCR number. The ligand specificity of D6 is also contentious. Bonini et al95 reported D6 to bind MCP-1 and MCP-3 with high affinity, whereas Nibbs et al96 suggest that D6 is more promiscuous because it is able to bind a number of CC chemokines with similar affinity. Northern blot analysis of several human tissues reveals that D6 is almost exclusively expressed in placenta with weak expression in the liver, lung, and thyroid.95,96 These data suggest that D6 may have a role in placental immunity or hematopoiesis.XCR1 Yoshida et al97 have recently reported the finding that the single C motif chemokine lymphotactin binds specifically to the orphan chemokine receptor previously termed GPR5.98 In keeping with the chemokine receptor nomenclature, this receptor has now been designated XCR1. The lymphotactin receptor is strongly expressed in placenta and weakly expressed in spleen and thymus.97 Because lymphotactin activity is most pronounced against lymphocytes and NK cells,99,100 it is expected that these leukocyte subpopulations will also express XCR1.Duffy antigen receptor for chemokines The transmembrane glycoprotein gpD had long been known to be part of the multimeric protein complex that makes up the antigen for the Duffy blood group system.101,102 However, it was not until Chaudhuri et al103 cloned the cDNA for gpD that it was found to be a 7-transmembrane receptor with significant homology to previously cloned chemokine receptors. This discovery also partly explained the phenomenon that erythrocytes could bind both the CXC chemokine IL-8 and the CC chemokine MCP-1.104,105 DARC (Duffy antigen receptor for chemokines) has also been shown to bind numerous CXC and CC chemokines specifically, including RANTES, I-309, GRO-, MCP-3, MCP-4, and eotaxin,106 and it has been
implicated in the pathogenesis of malaria102 (discussed below).
Intracellular signaling by chemokine receptors depends on
coupling to Bordetella pertussis toxin-sensitive
heterotrimeric G-proteins, usually of the Gi-type
(for a more detailed discussion, see Murphy111 and
Bokoch112). G-proteins are inactive when GDP is bound to the G-protein subunit, but they become active when GDP is
exchanged for GTP. During ligand binding, chemokine receptors associate
with G-proteins, facilitating the exchange of guanosine diphosphate
(GDP) for guanosine triphosphate (GTP). In the active state, G-proteins
dissociate into G
Leukocyte activation in acute inflammation To reach sites of inflammation or injury, circulating leukocytes must exit the bloodstream by traversing the endothelium. Leukocytes usually attach to the apical surface of the endothelium of postcapillary venules, where the shear stress is lowest. The first step in the process of leukocyte recruitment at sites of inflammation is the generation of transient selectin-mediated interactions that cause tethering and rolling of flowing leukocytes on the endothelial cell surface.121 The slow velocity of rolling leukocytes on selectins favors encounters with chemokines that are presented on the apical surface of the endothelium by glycosaminoglycans.122 Chemokines bind to their respective chemokine receptors expressed on the leukocyte cell surface, leading to the alteration of2 integrin
avidity, especially CD11b/CD18, on the leukocyte cell surface.123 Then 2 integrins bind to their Ig
counterligands, such as ICAM-1, ICAM-2, and ICAM-3, which have been
up-regulated on the endothelial cell surface by proinflammatory
cytokines. These interactions provide firm attachment of leukocytes to
the endothelium and facilitate leukocyte haptotactic transendothelial migration.123,124 The binding of chemokines to their
respective leukocyte receptors also initiates a series of cellular
events, all of which aim to eradicate the infiltrating inflammatory
agents. These events include changes in cell shape leading to enhanced locomotion, secretion of lysosomal enzymes, and production of superoxide anions. Once leukocytes reach the source of inflammation, a
cytokine-rich milieu is generated that is sustained until the invading
antigen is eliminated. In general, immune responses do not produce
endothelial injury; however, on occasion acute or chronic inflammation
may occur in which the endothelium and surrounding tissues become
damaged (for example, by neutrophil-generated products).
Inflammation resolution and inflammatory disorders After acute infection or injury, blood vessels may be damaged. Part of the mechanism of wound healing, the formation of new blood vessels, known as angiogenesis, is a process tightly regulated by numerous biologic mediators, among them chemokines.125 CXC chemokines, such as IL-8, GRO-, GRO-, PF-4, IP-10, and Mig, have
been implicated in the regulation of keratinocyte and endothelial cell
function, including the stimulation and inhibition of proliferation, angiogenesis, angiostasis, and cell migration.125-131
However, evidence concerning the expression of chemokine receptors by
endothelial cells has been conflicting.132,133 Recent data
now show that endothelial and epithelial cells express several
functional chemokine receptors, in particular CXCR4.134-137
It has been proposed that endothelial proteoglycans can present
chemokines to leukocyte and to endothelial-expressed chemokine
receptors.134,136 This model is analogous to the way in
which basic fibroblast growth factor is thought to bind to endothelial
proteoglycans, facilitating its interaction with high-affinity
fibroblast growth factor receptors on the endothelial cell
surface.138 A low level of expression and responsiveness of
chemokine receptors on endothelial cells may be sufficient to permit
cell activation in the presence of high levels of proteoglycan-bound
chemokine on the adjacent endothelial cell surface. These findings
suggest that chemokines and their receptors may play an important role
in the vascular remodeling and maintenance associated with inflammatory
resolution and, as a consequence, may be implicated in the development
of inflammatory disorders, as discussed below.
Psoriasis The overproduction of CXC and CC chemokines has been associated with many disease states, including arthritis, multiple sclerosis, and lung disorders such as adult respiratory distress syndrome, idiopathic pulmonary fibrosis, and pneumonia.139-142 It was initially noted that large quantities of IL-8, activated neutrophils, and T lymphocytes were present in the epidermis of patients with psoriasis vulgaris.139 Consequently, IL-8 was shown to induce the expression of HLA-DR and to be chemotactic and mitogenic for keratinocytes.129,132 Furthermore, Schulz et al143 demonstrated that CXCR1 and CXCR2 mRNA levels were 10 times more abundant in lesional psoriatic epidermis than in normal epidermis.143 This has led to the suggestion that the overexpression of IL-8 receptors is responsible for the epidermal hyperplasia, leukocyte infiltration, and increased keratinocyte HLA-DR expression seen in psoriasis. Indeed, antipsoriatic drugs such as calcitriol, dithranol, cyclosporin, and FK 506 have been shown to be potent down-regulators of IL-8 receptors on keratinocytes.143,144Atherosclerosis The recruitment of monocytes and the migration, growth, and activation of lipid-laden macrophages, T lymphocytes, and smooth muscle cells during the development of atherosclerotic plaques are critical features of the chronic inflammatory response that typifies atherosclerosis.145 Early studies by Nelken et al146 showed that the CC chemokine MCP-1 is abundantly expressed in macrophage-rich areas of atherosclerotic plaques, suggesting that MCP-1 may be important for monocyte extravasation and for the formation of atherosclerotic lesions.Allergy Recently, chemokines have been implicated in contributing to allergic disorders, in particular to allergic airway inflammation such as allergic rhinitis and asthma.158-160 The long-term effects of these diseases have been attributed, in part, to the infiltrating leukocytes, in particular eosinophils, that surround the bronchus and infiltrate the airway.161
Until recently little attention has been paid to the role of chemokine receptors in infectious diseases. However, it is now known that chemokine receptors participate in several disease states, either by overexpressing receptors or by facilitating viral entry into permissive cells. Malaria Malaria is transmitted by mosquitoes infected with 1 of 4 pathogenic parasites. These parasites bind to and invade erythrocytes eventually causing them to undergo cell lysis. It is this stage of the parasitic life cycle that is associated with clinical illness. Malaria is endemic in most tropical and subtropical areas of the world; however, it is much less prevalent in West Africa. In this geographical area, 95% of the population is resistant to the malaria parasites Plasmodium vivax and Plasmodium knowlesi.110 Miller et al168 note that erythrocytes from humans resistant to P. knowlesi infection do not express the Duffy antigen receptor for chemokines (DARC) on their red blood cells. It was subsequently shown that P. vivax could not invade erythrocytes of DARC-negative patients and that an anti-DARC antibody could block parasite invasion into DARC-positive red blood cells.169,170 A number of studies have since revealed that both P. vivax and P. knowlesi gain entry to erythrocytes by binding specifically to DARC.102,110,171 The genetic difference between persons who are susceptible to P. vivax and P. knowlesi invasion and those who are not corresponds to a single G-to-A nucleotide substitution, producing a Gly44Asp substitution in the polypeptide chain that prevents parasite invasion into erythrocytes.172,173 Interestingly, in some patients DARC is not expressed on red blood cells at all but is expressed on other cell types, including the endothelium.108 It appears that this phenomenon results from a mutation in the DARC promoter region in the erythrocytes of these patients.174 Whether P. vivax or P. knowlesi can gain entry to other cell types that express DARC has yet to be determined. The physiologic roles of DARC remain only partially elucidated (see section on DARC above).Human immunodeficiency virus Perhaps the most exciting development in chemokine receptor-associated pathogenesis comes from the discovery that some chemokines function as HIV-1-suppressive factors.175 Feng et al29 showed that T-cell-tropic HIV-1 isolates used both CD4 and CXCR4 to support Env-mediated cell fusion and HIV-1 infection of permissive cells.29 Further evidence showed that SDF-1 could block HIV-1 entry by binding to CXCR4 expressed by lymphocytes.30,31 These discoveries promoted frantic research in the area of HIV infection. Consequently, it was soon ascertained that CC chemokine receptors CCR2, CCR3, and CCR5 could also serve as cofactors, along with CD4, to permit HIV-1 entry, this time preferentially by macrophage-tropic and dual-tropic strains of HIV-1.69,176-178 Recently, CCR8 has been identified as a cofactor, in association with CD4, to permit the infection of permissive cells either by T-cell tropic or by macrophage-tropic HIV-1 strains.92
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Abstract
Introduction
with 3 intracellular and 3 extracellular connecting loops
composed of hydrophilic amino acids
