HIV-1 Coreceptor Use: A Molecular Window into Viral Tropism
Robert W. Doms 1and John P. Moore2
1Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104
2The Aaron Diamond AIDS Research Center, The Rockefeller University, 455 First Avenue, New York, NY 10016
The identification of the chemokine receptors CCR5 and CXCR4 as the major coreceptors for HIV-1 has provided a new framework for understanding viral tropism and pathogenesis at the molecular level. It is now possible to assign molecular designations to virus isolates, based on their coreceptor use, that largely explain viral phenotype (reviewed in Berger97a, 3Border97,8Doms9 7,15Moore9731). The need to accurately describe viral phenotype arises because HIV-1 strains can exhibit distinct cellular tropisms that have important implications for viral pathogenesis and disease progression. Generally, virus strains that are transmitted between individuals are able to infect both macrophages and primary CD4+ T-cells, but are unable to replicate in transformed T-cell lines (Connor93,11Roos92,37Schuitemaker92,41Zhu9352). As a result, they fail to form syncytia when grown in MT-2 cells or in certain other commonly used cell lines. Viruses with these properties have been referred to both as macrophage tropic (M-tropic) due to their ability to infect macrophages, non-syncytium inducing (NSI) due to their inability to form syncytia on T-cell lines, or slow-low (SL) in reference to their replication kinetics in culture (Fenyo88,22Schuitemaker9241) . With time, typically about 4-5 years after infection, virus strains evolve in some individuals (about 50) which can infect T-cell lines in addition to primary T-cells (Tersmette88,43Tersmette8944). While this shift in tropism can sometimes be accompanied by a loss of ability to infect macrophages, more often primary isolates retain this property and so are referred to as dual-tropic (Collman9210). Viruses able to infect T-cell lines have been variously referred to as T-tropic, syncytium-inducing (SI), or rapid-high (RH) according to the nomenclature schemes mentioned above. The emergence of these virus types is correlated with accelerated disease progression (Connor9311). Finally, viruses that are well-adapted to grow on transformed cell lines by continual passage are referred to as T-cell line adapted (TCLA). TCLA viruses exhibit greater sensitivity to neutralization by both antibodies and soluble CD4.
The above three systems for classifying viral strains are problematic for several reasons. The M-tropic designation, for example, can be taken incorrectly to mean that a virus is unable to replicate in primary T-cells. Likewise, T-tropic viruses have been described that retain the ability to infect macrophages. The NSI designation is also misleading, as it suggests that there is something inherently wrong with the env protein from these virus strains. It also implies that SI viruses are more fusogenic and cytopathic, which is not necessarily so when they are grown in primary CD4+ T-cells. It is now known that the SI/NSI designation is an artifact resulting from the fact that T-cell lines express CXCR4 but not CCR5; the env proteins from NSI viruses are perfectly capable of forming syncytia provided that target cells expressing CCR5 are used. Finally, an additional complication arising from the current classification schemes is that the terms M-tropic, NSI, and SL are often used synonymously, as are T-tropic, SI, and RH. While this is sometimes appropriate, there are many instances in which these terms are not synonymous.
Chemokine Receptors and Viral Tropism
The major determinant of viral tropism is at the level of entry, more specifica lly at the level of membrane fusion with CD4+ cells. This occurs efficiently only if the appropriate coreceptor is present. Thus, M-tropic, NSI viruses use CCR5 in conjunction with CD4 for fusion. Direct interactions between the env glycoprotein and CCR5 have been detected (Trkola96,46Wu9648), and it is likely that this interaction triggers the final conformational changes in env that promote fusion between the viral and cellular membranes. The importance of CCR5 for HIV-1 infection in vivo was shown by the discovery that approximately 1 of Caucasians lack CCR5, and that these individuals are highly resistant but not entirely immune to virus infection (Dean96, 12Liu96,28Michael97,30Samson9640). Thus, CCR5 is the major coreceptor for HIV-1 transmission in vivo. However, while CD4-positive cells obtained from CCR5-negative individuals are resistant to infection by viruses that require this coreceptor, they are readily infectable by viruses which use CXCR4 (Liu96,28Rana97,35Samson96,40Zhang9750). It is not clear why CCR5-negative individuals are only rarely infected by viruses that can use CXCR4 for cellular entry (for some examples see (Balotta97,2Theodorou97,45OBrien97,32Biti975). It appears that viruses which use CXCR4 are inefficient at establishing an infection in a naive host, for unknown reasons.
While M-tropic NSI viruses use CCR5 for cellular entry, CXCR4 is the coreceptor most commonly used by T-tropic, SI virus strains (Feng9621). Viruses that use CCR5 for entry can evolve to use CXCR4 through mutations in the env glycoprotein, usually but not always in the V3-loop. Despite less than 20 amino acid identity between CCR5 and CXCR4 in their extracellular domains, several viruses are known to efficiently use both coreceptors for cellular entry. Use of CXCR4 is largely dependent upon the first and second extracellular loops of this receptor, which are considerably more anionic than the corresponding domains in CCR5 (Brelot97,7Lu9729). It may be relevant that the V3-loops of T-tropic HIV-1 env proteins tend to be more basic than those found in viruses which use CCR5 as a coreceptor (De Jong92,25Fouchier9223), suggesting a charge-charge interaction may be involved in the gp120-CXCR4 interaction.
In addition to CCR5 and CXCR4, at least nine other chemokine or orphan receptors have been shown to support the cellular entry of one or more virus strains. These include CCR2b, CCR3, CCR8, GPR1, GPR15, STRL33, US28, V28, and ChemR23 (Choe96,9Deng97,13Doranz96,16Farzan97,20Liao97,27Pleskoff97a,33Reeves97,36Rucker97,38Samson9739). Though the in vivo significance of these alternative coreceptors is not clear, it is possible that the use of receptors other than CCR5 and CXCR4 may be important for certain aspects of viral pathogenesis. For example, CCR3 is expressed in microglia, and use of this receptor may be correlated with neurotropism (He9724). A major challenge in this rapidly developing field will be to determine if use of these additional receptors has implications for viral pathogenesis.
A Classification System Based on Coreceptor Use
The importance of viral phenotype for pathogenesis and disease progression coupled with the imprecise nature of the current systems for classifying virus strains calls for the development of a more accurate classification scheme. Recently, a new system based on coreceptor use has been proposed (Berger97b4). In this scheme, virus strains that use CCR5 as a coreceptor are designated R5, while those that use CXCR4 are designated X4. Viruses that use both coreceptors are designated R5X4. Thus, under this system the HIV-1 strains most commonly transmitted would be called R5 viruses. However, this designation makes no assumptions about the cells in which HIV-1 replication must occur (unlike the M-tropic/T-tropic designation), or the rate of virus replication (unlike the SL/RH system). Viruses that evolve the capacity to use CXCR4 in infected individuals with or without concurrent use of CCR5 would now be called R5X4 or X4 viruses, respectively. The primary advantage of this classification system is that it offers a precise molecular description of the major coreceptors used by any given virus strain without assuming that this necessarily results in the ability to efficiently replicate in a particular target cell. Furthermore, this system can be readily modified, taking into account other coreceptors (such as CCR3 by using an R3 designation) if their use proves to be a major determinant of tropism. We have compiled a table listing the coreceptors used by more than 100 HIV-1 strains, and discuss some of the nuances of co-receptor use below.
Issues Pertaining to Coreceptor Use
As shown in the Table, the major coreceptors used by greater than 100 HIV-1 strains have been determined in little more than a year. All strains listed in the Table have been examined for the ability to use CCR5 or CXCR4, though not necessarily for other coreceptors such as CCR3. From the studies published to date, it is clear that CCR5 and CXCR4 are the major HIV-1 coreceptors since all HIV-1 strains examined thus far use one or both of these receptors. In addition, coreceptor use is phenotype but not genotype dependent. All NSI viruses (irrespective of genetic subtype) studied to date use CCR5 while all SI viruses use CXCR4 (though many also use CCR5). Further, our review of the literature has shown that determining which of these receptors is used by a given virus strain is straightforward and independent of technique or assay. We have found no discrepancies between various virus infection, virus-cell fusion, and cell-cell fusion assays that have been used to determine if virus strains use CCR5 or CXCR4. The only differences concern the relative efficiencies with which R5X4 viruses use CCR5 and CXCR4, but these are relatively insignificant in terms of magnitude. For the purposes of the Table, we have arbitrarily chosen 10 efficiency as the cut-off for relevant coreceptor use. Thus, a virus that uses CCR5 as its most efficient coreceptor is listed as a R5X4 virus if it uses CXCR4 to levels 10 of that observed for CCR5. The efficiency with which different co-receptors are used by some strains is likely to vary between assay systems, and low-level entry via several co-receptors may not be uncommon. Whether this low level of relative efficiency can support virus infection in vivo is not known. As a result, the threshold efficiency for assigning relevance to coreceptor use may have to be raised or lowered in the future.
While many virus strains have been examined for the ability to use CCR5 and CXC R4, only a small number have been tested for use of most of the other viral coreceptors (see Table). Thus, we have not listed coreceptors that are NOT used by a given virus strain. Unlike studies in which use of CCR5 and CXCR4 was examined, we occasionally found discrepancies between different studies with regards to the use of additional coreceptors by some virus strains. The reasons for this are not clear, but may well be due to the fact that use of coreceptors other than CCR5 and CXCR4 tends to be inefficient, thus magnifying assay dependent differences. Perhaps the most significant variable in determining whether a given chemokine or orphan receptor can function as a coreceptor is the level of its expression. Very high levels of CCR3 expression support env-mediated membrane fusion by the majority of HIV-1 strains tested, while at lower levels only a few virus strains could use CCR3 (Rucker9738). Thus, expression levels can strongly influence coreceptor use. Another important variable is the expression level of the coreceptor relative to CD4 (Kozak9726). When CD4 is present on the cell surface at high levels, surprisingly low levels of CCR5 or CXCR4 are needed to support virus entry. However, if CD4 is expressed at low levels, higher expression levels of the coreceptors are needed (Kozak9726). Whether this will hold true for other coreceptors is not known, but clearly both CD4 and coreceptor cell surface expression levels can influence the efficiency of viral entry. As antibodies to additional chemokine and orphan receptors are identified, it will be possible to determine expression levels on relevant target cells. This will make it possible to assess the significance of coreceptor use determined from in vitro assays using cell lines or transient expression systems.
Determining the levels at which various receptors are expressed is but one step in determining their significance in vivo, since it is also important to determine if they are expressed in relevant target cells. In general, this is likely to be limited to CD4-positive cells. However, HIV-1 has been detected in a variety of CD4-negative cells, and several HIV-2 and many SIV strains have been identified that can utilize either CXCR4 or CCR5 for cellular entry in the absence of CD4 (Edinger97,18Endres96,19Reeves9736). In the case of SIV, a number of neurotropic SIV isolates have been shown to infect brain capillary endothelial cells, the principal component of the blood-brain barrier, in a CD4-independent, CCR5-dependent manner (Edinger9718). Thus, expression of an HIV-1 coreceptor in some CD4 negative cells may still have implications for viral pathogenesis. In fact, for many receptors, expression in cells other than T-cells and macrophages may be the only place that they support virus infection, at least during the early stages of disease - it is becoming increasingly clear that the R5 viruses which predominate during the asymptomatic period of the disease fail to infect stimulated PBMCs from individuals who lack CCR5, indicating that receptors such as CCR2b and CCR3 do not play a significant role in supporting virus entry into the primary targets of HIV-1 in vivo (Zhang9750). However, this may not be the case for viruses which emerge later in the course of disease.
Another important consideration in determining the in vivo relevance of an alternative coreceptor is the number and type of virus strains than can use the coreceptor, and if there is any correlation between viral phenotype and its use. Also, studies of sequential virus isolates may reveal correlations between the acquisition of the ability to use a given coreceptor and clinical aspects of HIV-1 disease, such as the development of neurological symptoms. Ultimately, identification of the ligands for orphan receptors and the development of specific antibodies should make it possible to identify the coreceptors that can be used by HIV-1 to enter various cell types.
The expression of a given coreceptor in conjunction with CD4 is not necessarily sufficient for virus infection. For example, CXCR4 is expressed on the surface of macrophages, which are resistant to infection by virus strains which use this receptor. Interestingly, infection of macrophages obtained from CCR5-negative individuals by a dual-tropic virus isolate, 89.6, is inhibited by the CXCR4 ligand SDF-1, suggesting that CXCR4 can be used as a coreceptor on the surface of macrophages, albeit rarely Yi98 . There are a variety of reasons why CXCR4 may not generally support entry of HIV-1 into macrophages, including differential posttranslational processing, surface expression levels relative to CD4 (as discussed above), and the way in which CXCR4 is presented in relation to CD4. At present, very little is known about the architecture of the fusion site - the number of molecules of env, CD4, and coreceptor that are required for a productive membrane fusion reaction, and their spatial relationships relative to one another.
Summary
The discovery of the HIV-1 coreceptors has important implications for understanding viral tropism and pathogenesis. Identifying which coreceptors are used by particular virus strains, and then determining whether their use correlates with particular aspects of viral pathogenesis, will be of general interest. Thus, a list of coreceptors used by virus strains will be maintained and updated yearly in this database. In addition, this will provide a forum where recent advances in the field can be discussed, particularly with regards as to how coreceptor usage patterns can be determined and our understanding of the significance of receptors other than CCR5 and CXCR4. If other receptors are found to be important for viral pathogenesis, then the classification scheme that we have proposed can be modified to take these new findings into account.
Acknowledgements
The authors thank Satish Pillai and Brian Foley for carefully reviewing.
Strain Proposed Primary Other Designationc Receptord Receptorse References
Accessiona Clade Tropismb
DJ258 L22939 A NSI R5 CCR5 Trkola97
92RW026 NA A NSI R5 CCR5 Trkola97
93KE101 NA A NSI R5 CCR5 Zhang96
93IN103 NA A NSI R5 CCR5 Zhang96
92UG037-8 U51190 A NSI R5 CCR5 CCR8* Bjorndal97,Rucker97
92RW020-5 U08794 A NSI R5 CCR5 Rucker97
92UG31 L34667 A NSI R5 CCR5 Dittmar97
92RW20 U08794 A NSI R5 CCR5 Dittmar97
92UG029 NA A SI X4 CXCR4 Trkola97
92RW009 U88823 A SI R5X4 CXCR4, CCR5 Zhang96
JR-FL U63632 B NSI R5 CCR5 CCR3 Deng97,Farzan97,Rucker97
JR-CSF M38429 B NSI R5 CCR5 Simmons96,Trkola97,Zhang96
SF162 M65024 B NSI R5 CCR5 STRL33* Liao97,Rucker97
YU2 M93258 B NSI R5 CCR5 CCR3, GPR15 Choe96,Farzan97
ADA AF004394 B NSI R5 CCR5 CCR3, GPR15, Choe96,Farzan97,Rucker97
STRL33*, CCR8
Ba-L M68893 B NSI R5 CCR5 CCR3, STRL33* Deng97,Dragic96,Liao97,Rucker97
92US657 U04908 B NSI R5 CCR5 Trkola97
92US715.6 U08451 B NSI R5 CCR5 Bjorndal97
92Br20-4 U08797 B NSI R5 CCR5 Choe96,Rucker97
91US005.11U27434 B NSI R5 CCR5 Bjorndal97,Rucker97
SL-2 NA B NSI R5 CCR5 Simmons96
92TH014.12U08801 B NSI R5 CCR5 Bjorndal97
CM243 NA B NSI R5 CCR5 GPR15, STRL33 Rucker97
M23 NA B NSI R5 CCR5 Dittmar97
E80 NA B NSI R5 CCR5 Dittmar97
BR92 NA B NSI R5 CCR5 Dittmar97
BR49 NA B NSI R5 CCR5 Dittmar97
BR53 NA B NSI R5 CCR5 Dittmar97
BR90 NA B NSI R5 CCR5 Dittmar97
92HA593g U08444 B SI R5X4 CXCR4, CCR5 Zhang96
92HT593.1gU08444 B NSI R5X4 CXCR4, CCR5 Bjorndal97
2028 NA B SI R5X4 CXCR4, CCR5 CCR3 Dittmar97,Simmons96
2076 NA B SI R5X4 CXCR4, CCR5 Dittmar97,Simmons96,Trkola97
89.6 U39362 B SI R5X4 CXCR4, CCR5 CCR3, CCR2b, Farzan97,Rucker97
CCR8, V28
DH123 NA B SI R5X4 CXCR4, CCR5 Trkola97
Isolate NA B SI R5X4 CXCR4, CCR5 Trkola97
C 7/86
92HA594 U08445 B SI R5X4 CXCR4, CCR5 Zhang96
92HA596 U08446 B SI R5X4 CXCR4, CCR5 Zhang96
M13 NA B SI R5X4 CXCR4, CCR5 Simmons96
2006 NA B SI R5X4 CXCR4, CCR5 Simmons96
2044 NA B SI R5X4 CXCR4, CCR5 Simmons96
2036 NA B SI R5X4 CXCR4, CCR5 Simmons96
2005 NA B SI R5X4 CXCR4, CCR5 Simmons96
92HT599.24U08447 B SI X4 CXCR4 Bjorndal97
BK132 L03697 B SI X4 CXCR4 CCR3*, CCR8* Rucker97
BR65 NA B SI X4 CXCR4 Dittmar97
HC4 NA B SI X4 CXCR4 Trkola97
SF2 K02007 B SI/TCLA R5X4 CXCR4, CCR5 Trkola97
RF M17451 B SI/TCLA R5X4 CXCR4, CCR5 Alkhatib96,Deng97,Rucker97
NL 4-3 M19921 B SI/TCLA X4 CXCR4 Trkola97,Zhang96
LAI X01762 B SI/TCLA X4 CXCR4 Trkola97
HXBc2 K03455 B SI/TCLA X4 CXCR4 Choe96
GUN-1 D34590 B SI/TCLA R5X4 CXCR4, CCR5 Simmons96
BH8 K02011 B SI/TCLA X4 CXCR4 CCR3*, STRL33* Rucker97
92ZW101 NA C NSI R5 CCR5 Zhang96
92BR025.9 U52953 C NSI R5 CCR5 Bjorndal97,Dittmar97
BR28 NA C NSI R5 CCR5 Dittmar97
93MW965.26U08455 C NSI R5 CCR5 Bjorndal97
BR70 NA C NSI R5 CCR5 Dittmar97
JW1 NA C NSI R5 CCR5 Dittmar97
JW4 NA C NSI R5 CCR5 Dittmar97
92ZW102 NA C NSI R5 CCR5 Zhang96
DJ259 L22940 C NSI R5 CCR5 Trkola97
94ZW103 NA C NSI R5 CCR5 Trkola97
94ZW109 NA C NSI R5 CCR5 Trkola97
92ZW106 NA C SI X4 CXCR4 Zhang96
ZAM20 L22956 C SI X4 CXCR4 Trkola97
94ZW106 NA C SI X4 CXCR4 Trkola97
94KE102 NA D NSI R5 CCR5 Trkola97,Zhang96
94KE103 NA D NSI R5 CCR5 Trkola97,Zhang96
92UG046 U08737 D SI X4 CXCR4 Trkola97
UG270 NA D SI X4 CXCR4 Trkola97
92UG024.2 U08726 D SI X4 CXCR4 CCR8*, V28*, Bjorndal97,Rucker97,Trkola97
CCR3f
92UG021.16U27399 D SI X4 CXCR4 Bjorndal97
JW5 NA D SI X4 CXCR4 Dittmar97
NDK M27323 D SI X4 CXCR4 GPR15 Deng97,Pleskoff97b
93ZR001.3 U27419 D NA X4 CXCR4 V28* Rucker97
CM235 NA E NSI R5 CCR5 Trkola97
92TH001 NA E NSI R5 CCR5 Trkola97
M53 NA E NSI R5 CCR5 Dittmar97
92TH22 U09131 E NSI R5 CCR5 Dittmar97
92TH23 NA E NSI R5 CCR5 Dittmar97
C2 NA E NSI R5 CCR5 Dittmar97
93TH305 NA E NSI R5 CCR5 Zhang96
93TH307 NA E NSI R5 CCR5 Zhang96
93TH966.8 U08456 E NSI R5 CCR5 Bjorndal97
93TH976.17U08458 E NA R5 CCR5 Bjorndal97
93TH304 NA E SI R5X4 CXCR4, CCR5 Zhang96
SL6 NA E SI X4 CXCR4 Dittmar97
SL7 NA E SI X4 CXCR4 Dittmar97
SL8 NA E SI X4 CXCR4 Dittmar97
94TH304 NA E SI X4 CXCR4 Trkola97
BR58 NA F SI R5X4 CXCR4, CCR5 CCR3 Dittmar97
BZ162 L22084 F NSI R5 CCR5 Trkola97
R1 NA F NSI R5 CCR5 Trkola97
93BR029.2 U27413 F NA R5 CCR5 Rucker97
92UG975.10U27426 G NSI R5 CCR5 Bjorndal97
CA9 NA O NSI R5 CCR5 Zhang96
MVP5180 L20571 O SI R5X4 CXCR4, CCR5 Zhang96
Footnotes:
a Accession numbers refer to sequences from the described isolate that contain the longest available sequence including Env (full length genome when avaiable, down to a minimum of the V3 region), but may not pertain directly to the sample used to determine the isolate's phenotype. Accession numbers have been deemed "NA" if there are no related locus names in the HIV Database, or if there is insufficient information to conclude that a similarly named locus in the database is referring to the same isolate.
b The tropism for each virus strain is indicated. SI = syncytium inducing; NSI = non syncytium inducing; SI/TCLA = syncytium inducing T-cell line adapted; NA = not available.
c As described in the text, we have proposed that viruses which use CCR5 be termed R5 viruses, viruses that use CXCR4 be termed X4 viruses, and viruses that use both be termed R5X4 viruses. For a virus to be termed an R5X4 virus, CXCR4 must be used at > 10% of the efficiency of CCR5 for viruses that use CCR5 as their primary receptor, or CCR5 must be used at > 10% of the efficiency of CXCR4 for viruses that use CXCR4 as their primary receptor.
d All virus strains in the Table have been tested for the ability to use CCR5 and CXCR4. The receptors used by each strain are indicated. For both receptors to be listed, the least efficiently used receptor must support virus entry by >10% of the levels supported by the most efficiently used receptor. For viruses that use both receptors, CXCR4 is listed first; this does not mean that CXCR4 is used more efficiently than CCR5.
e Receptors other than CCR5 or CXCR4 that are used by the indicated strains are listed. Since most viruses have not yet been tested for the ability to use receptors other than CCR5 and CXCR4, the absence of other receptors used in the Table should not be taken to mean that a virus uses only CCR5 or CXCR4. For example, if CCR3 is not listed as being used by a given virus strain, it may be because it has not yet been tested. Receptors that have been shown by experiments not to be used by a given virus strain are not indicated. Occasionally there are discrepancies in the literature concerning the use of one or more receptors. In these cases, we opted for `majority rules'. If two papers report a positive result and one a negative result, the receptor is shown as being used.
f The virus isolate used CCR3 whereas the cloned env from this isolate did not [Bjorndal97].
*Indicates that coreceptor use was determined only by fusion assays rather than by virus infection.
g 92HT593.1 (cloned env gene) and 92HA593 (whole virus) come from the same isolate and gave slightly different results in references [Dittmar97] and [Zhang96].
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