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(Journal of Leukocyte Biology. 2000;68:331-337.)
© 2000 by Society for Leukocyte Biology

HIV-1 replication in CD4+ T cell lines: the effects of adaptation on co-receptor use, tropism, and accessory gene function

Nathalie Dejucq

Wohl Virion Centre, Windeyer Institute of Medical Sciences, London, United Kingdom

Correspondence and current address: Dr. Nathalie Dejucq, GERM-INSERM U435, Campus de Beaulieu, 35 042 Rennes Cedex, France. E-mail: nathalie.dejucq{at}rennes.inserm.fr


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 ADAPTATION OF AN R5...
 DISCUSSION
 REFERENCES
 
We studied the replication of HIV-1 macrophage-tropic CCR5-using strains (R5) in CD4+ T cell lines to better understand the switch in co-receptor use of such strains during disease progression and to assess resulting changes in cell tropism. We found that the majority of R5 strains cannot replicate in CD4+ T cell lines without adaptation by serial passage. A small minority of primary R5 isolates, however, were able to infect two T cell lines, Molt4 and SupT1. This expanded tropism was due to the use of undetectable levels of CCR5 rather than CXCR4 or alternative receptors. In contrast, HIV-1SF162 adaptation for replication in the C8166 T cell line was due to the emergence of variant strains that could use CXCR4. Of two variants, one was dual-tropic and one T-tropic, although both could use CCR5 as well as CXCR4. A single mutation in the start codon of the accessory gene vpu accounted for the T-tropic phenotype of the second variant, indicating that a non-functional vpu impairs macrophage tropism. Thus, in vitro and in the absence of an immune response, R5 strains naturally adapt to infect CXCR4+ T cell lines. Such adaptation resembles the rare R5 to X4 switch that occurs in vivo. Mutations in accessory genes (e.g., vpu) not required for replication in rapidly dividing cell lines may also occur in vitro, abrogating replication in primary cell types such as macrophages. Such mutations, however, are normally selected against in vivo.

Key Words: macrophage and T cell lines tropism • CXCR4 • CCR5 • Vpu


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
ADAPTATION OF AN R5...
 DISCUSSION
 REFERENCES
 
Changes in cellular tropism by HIV-1 strains seem to be a key event in the pathogenesis of HIV disease [1 2 3 4 5 6 ] because in half of HIV-infected individuals the emergence of T cell line tropic variants is associated with the development of AIDS [6 , 7 ]. HIV-1 isolates have been classified into two main types: (1) syncytium-inducing (SI), T cell line tropic (T-tropic), rapid/high strains and (2) non-syncytium-inducing (NSI), macrophage-tropic (M-tropic), slow/low strains. In vitro, NSI viruses infect both macrophages and T cells, which are important cell targets for the virus in vivo, but rarely infect T cell lines. In contrast, SI viruses replicate in a range of transformed CD4+ T cell lines [8 ], while their capacity to infect macrophages has been controversial [4 , 9 10 11 12 13 14 15 ]. During primary acute infection, the majority of HIV-1 isolates are NSI [16 ], whereas SI strains emerge during disease progression in about 50% of AIDS patients [5 ]. This emergence often precedes or coincides with a rapid decline in CD4+ cells in blood [17 ]. The selective pressures that drive or prevent this switch are still poorly understood.

Two receptors are required on the surface of the target cell to trigger HIV entry: the CD4 receptor and a co-receptor [18 19 20 ]. Co-receptors have seven transmembrane domains (7TM) and are either members of, or related to, the chemokine receptor family. At least 12 7TM receptors have been shown to act as co-receptors for entry of different HIV-1 strains in vitro [see 21– 24 for reviews]. All HIV-1 strains studied so far, however, use CCR5, CXCR4, or both [14 , 25 ]. The discovery of HIV co-receptors has mainly explained the NSI/ M-tropic versus SI/T-tropic phenotype, by showing that the former strains use CCR5 [19 , 20 , 26 27 28 ], a receptor for CC chemokines RANTES, macrophage inflammatory protein (MIP)-1{alpha}, MIP-1ß, and monocyte chemotactic protein-2 (MCP-2) [29 30 31 32 ], whereas the latter use CXCR4 [18 ], a receptor for the CXC chemokine stromal cell-derived factor 1 (SDF-1) [33 , 34 ]. A new nomenclature for HIV-1 strains was adopted, with isolates that use CCR5 termed R5 viruses, those using CXCR4 designated X4 viruses, and viruses able to use both co-receptors (dual-tropic) called R5X4 [35 ]. Further co-receptors that support infection of cell lines in vitro by various but usually a minority of isolates have also been identified. These include CCR3 [27 , 28 ], APJ [36 ], CCR2b [28 ], CCR8 [37 38 39 ], CX3CR1 [37 ], CCR9 [36 ], ChemR23 [40 ], STRL-33 [41 42 43 ], GPR15 [42 , 44 ], GPR1 [44 ], US28 [45 ], and Leukotriene B4 [46 ]. CCR5 is predominantly expressed on macrophages [11 , 47 48 49 ], dendritic cells [11 , 50 51 52 ], brain microglial cells [53 54 55 ], and memory T cells [56 ] but absent on most T cell lines. CXCR4 is more widely expressed and present on both naive and memory T cells [56 , 57 ] as well as monocytes, and at lower levels on mature macrophages [58 ]. Thus, the cellular tropism of HIV-1 is largely determined by differential usage of chemokine receptors. This simple picture, however, has several exceptions. Hence, some R5 HIV-1 strains do not infect macrophages, although these cells express high levels of CCR5 [59 , 60 ], whereas many primary X4 strains do not replicate in several cell lines expressing CXCR4 [61 ].

Besides env, accessory genes can sometimes interfere with cell tropism, at least in vitro. For instance, vpr, vif, and vpu are nonessential HIV-1 genes that are dispensible for infection and replication in established cell lines, yet are required to various extents for replication in primary macrophages and/or peripheral blood mononuclear cells (PBMCs) [62 63 64 ]. Mutations that affect the function of such genes are probably selected against and rare in vivo, however, may accrue during passage in T cell lines in vitro.

Here we review our recent studies assessing the adaptation of primary R5 strains for replication in T cell lines, the effects on co-receptor use, and the resulting effects on envelope and accessory genes.

INFECTION OF CD4+ T CELL LINES VIA LOW LEVELS OF CCR5
The majority of CCR5-using viruses do not infect CD4+ T cell lines, however, some R5 strains can infect two T cell lines, Molt4 and SupT1 [65 ]. These strains include a molecularly cloned variant virus, HIV-1C3 that was derived from HIV1JR-CSF. HIV-1C3 was adapted in vitro for replication in Molt4 cells after multiple passages. Sequencing revealed that a single amino acid change in the V1 loop accounted for HIV-1C3’s extended tropism for both Molt4 and SupT1 cells. Thus, if the V3 loop on gp120 is a major determinant of both cell tropism [66 67 68 69 70 71 72 73 74 ] and more recently of co-receptor usage [75 76 77 ], other envelope elements are also involved [77 78 79 80 81 ]. Several reports have implicated the V1/V2 loops of gp120 [65 , 82 83 84 85 86 87 ]. The V1/V2 domains, in addition to the required V3 domain, influence the efficiency of replication of HIV-1 in primary macrophages [68 , 85 , 88 ] and in Jurkat T cells [86 ]. Groenink et al. [84 ] described the configuration of a hypervariable locus in the V2 domain that appeared to be predictive for a switch from an NSI to an SI phenotype. V1/V2 sequences act in conjunction with a CCR5 tropic V3 loop to confer CCR3 usage to some NSI strains [87 ]. Kwong et al. [89 ] have recently reported the crystal structure of gp120 complexed with CD4 and a neutralizing antibody. This structure shows that the stems of the V1/V2 loops and V3 loop are located, respectively, on inner and outer domains of gp120 and on either side of a bridging sheet that spans these two domains. The co-receptor binding site is thought to contain amino acids in this bridging sheet and probably residues in the V3 loop. In some circumstances, the V1/V2 loops are dispensible for high-affinity binding to co-receptors [90 ] and viral replication [86 ], yet when present on gp120 they can have a profound influence on tropism and co-receptor use.

We showed that, in addition to HIV-1C3, of 10 R5 viruses tested, two further strains (HIV-1BR92 and HIV-1E80) consistently replicated in Molt4 and SupT1, providing evidence that viruses like the HIV-1C3 variant do exist in vivo (Table 1 ) [91 ]. These strains had only been passaged in PBMCs and did not replicate in other T cell lines tested. For one isolate (HIV-1ADA) that failed to infect either Molt4 or SupT1, we prepared pseudotype virus that carried the vesicular stomatitis virus envelope glycoprotein G. This pseudotype efficiently infected both Molt4 and SupT1, thus indicating that the block to infection occurred early in the replication and could be bypassed by virions carrying foreign envelope glycoprotein.


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  		Table 1. SupT1 and Molt4 Infection and Coreceptor Use by R5 Strains

 
The three Molt4/SupT1-tropic viruses used CCR5 predominantly on CD4+ cell lines (Table 1) and did not replicate in CCR5-negative PBMCs derived from individuals homozygous for {Delta}32 CCR5. They did not use CXCR4, nor was any alternative receptor (CCR8, GPR-15, STRL-33, GPR-1, CX3CR1, D6, CCR1, CCR2b, CCR3) used consistently, although low-level infection via CCR3, STRL-33, GPR-15, and CCR8 was noted occasionally. Infection of Molt4 and SupT1 by each of these three strains was potently inhibited by ligands for CCR5 (AOP-RANTES, RANTES, and MIP-1ß) and by a monoclonal antibody specific for CCR5 (2D7; Fig. 1 ). No block of HIV replication was observed using ligands to other co-receptors, e.g., eotaxin (CCR3) and AMD3100 (CXCR4). CCR5 mRNA was present in both Molt4 and SupT1 by reverse transcriptase-polymerase chain reaction (RT-PCR), although CCR5 protein could not be detected on either the cell surface or in intracellular vesicles through the use of either FACScan or confocal microscopy. The expanded tropism of the three strains was therefore not due to adaptation to a new co-receptor but most probably due to their capacity to exploit extremely low levels of CCR5 on Molt4 and SupT1 cells. This could be further tested by using a cell line expressing various amounts of CCR5, such as the one developed by Platt et al. [92 ].



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  		Figure 1. Inhibition of E80 replication in SupT1 by chemokine receptor ligands. SupT1 were treated with virus alone, virus plus chemokine receptor ligand (AOP-Rantes, MIP1ß, AMD3100, eotaxin), or virus plus the CCR5-specific mAb 2D7 or a control anti-CXCR4 mAb. The p24 level detected in presence of inhibitor is represented as a percentage of the maximum p24 value obtained during the time course for the virus alone (100% infectivity). Similar results were obtained on Molt4 (data not shown).

 
The capacity of R5 strains to use low levels of CCR5 could have important significance in vivo by allowing viruses to infect new cell populations and spreading the infection to new body compartments. Adaptation for one cell type, however, may compromise infectivity for others. Like other R5 isolates, HIV-1E80 replicates efficiently in primary macrophages but has consistently failed to infect fetal brain cell cultures containing CCR5+ microglia [93 ]. We are currently assessing whether other Molt4/SupT1 tropic strains (HIV-1C3 and HIV-1BR92) also have a reduced capacity to infect brain microglia.


   ADAPTATION OF AN R5 STRAIN TO USE CXCR4 AND INFLUENCE ON REPLICATION IN MACROPHAGES
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 ABSTRACT
 INTRODUCTION
 ADAPTATION OF AN R5...
DISCUSSION
 REFERENCES
 
HIV-1SF162 variants that replicated in C8166 cells emerged after only a few passages after infection. C8166 cells do not express CCR5 and replicating virus was associated with the production of large syncytia. Two HIV-1SF162 variants were isolated that efficiently infected C8166. One variant retained the ability to infect macrophages and PBMCs, similar to wild-type HIV-1SF162 and was therefore dual-tropic. The second variant became T cell line tropic and replicated poorly in both macrophages and PBMCs (Fig. 2 ).



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  		Figure 2. Cell tropism of SF162 and variants. Infectivity for PBMCs (TCID50/ml), the T cell line C8166 (TCID50/ml), and macrophages (FFU/ml) are shown as Log10 infectivity.

 
Sequence analysis revealed that both T- and dual-tropic variants had two common amino acid substitutions in the V3 loop (IGPGRA to RGPGRV). One of these (I to R) increased the overall positive charge of the V3 loop, a property associated with an SI phenotype and CXCR4 use. Few other amino-acid changes were observed outside the variable regions of env, mostly common to both strains. A single base mutation in the translation initiation codon of vpu (ATG to ATA) was also noted for T-tropic variant, whereas the wild-type and dual-tropic strains retained the ATG codon. C8166 infection was associated with the capacity of the two variants to use CXCR4 as well as CCR5. A role for other co-receptors was not implicated. Chimeric molecular clones were constructed to ascertain the role of the envelope and vpu mutations in the loss of macrophage tropism. Complete envelope genes derived from either the dual-tropic or T-tropic variants conferred macrophage infection, whereas loss of macrophage infection was determined entirely by a single mutation in vpu [N. Dejucq et al., unpublished observations].

In vivo, co-receptor switching for R5 strains to CXCR4 use is apparently rare, with only about half of AIDS patients carrying SI strains. The pressures in vivo that select against CXCR4 use are currently unclear, although immune (neutralizing antibodies) [94 ] and non-immune (SDF-1) mechanisms [95 ] have been suggested. Whatever the selective pressure, it appears to wane late in disease when X4 strains emerge and persist. In vivo, CXCR4 use is associated with acquisition of positively charged amino acids at one (or both) of two specific sites in the V3 loop (e.g., CTRPNNNTRKRIRIGPGRAFYATGKIIGNIRQAHC). T cell line-adapted strains, e.g., the 17.11 variant of HIV-1JR-CSF [96 ] often carry positive amino acids at these sites, however, the HIV-1SF162 variants described here [N. Dejucq et al., unpublished results] contain an additional positive amino acid (I to R change) at a distinct site. Different selection pressures during T cell line adaptation may allow the V3 loop to adopt subtle conformations in vitro, thus allowing positive amino acids at alternative sites to confer CXCR4 use. Cheng-Mayer’s group have also described an HIV-1SF162 variant selected independently for replication in the HUT78 T cell line [97 ]. Coincidently, Cheng-Mayer’s variant contained the same V3 loop amino acid substitutions as our variants, which were shown to confer CXCR4 use and infectivity for HUT78 [59 ].


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 ADAPTATION OF AN R5...
 DISCUSSION
REFERENCES
 
Most primary R5 viruses can readily adapt in vitro to use CXCR4 for infection of T cell lines. We suspect that some strains need few amino acid substitutions to acquire CXCR4 use because they rapidly adapt, whereas others need more extensive passages and must require multiple changes. The potential of R5 strains to acquire an X4 phenotype in vitro is consistent with the presence of unidentified selective pressures that usually prevent CXCR4 use in vivo until late in disease. A minority of R5 viruses can, however, infect particular T cell lines without adaptation to use CXCR4. These strains have the ability to exploit low concentrations of CCR5, which confer them an expanded tropism.

The accidental infection of a laboratory worker by the TCLA CXCR4-using HIV-1 strain, IIIB [98 ] has enabled some insight into the effects of T cell line passage on the in vivo properties of such viruses. Whereas the parental HIV-1IIIB strain is T tropic and infects primary macrophages inefficiently, isolates from the infected worker were macrophage-tropic. Thus, adaptation occurred to allow the virus to infect new cell targets and become more infectious in vivo. Six unique amino acid mutations in the V3 loop region accounted for this increased replication. The change in tropism, however, was not associated with a switch to CCR5 use because the isolates continued to use CXCR4 as the sole co-receptor for entry into PBMCs [99 ]. There are no reports on the current health of this patient to assess the virulence of the HIV-1IIIB strains.

Mutations in vpu have previously been reported to affect macrophage [62 , 63 , 100 , 101 ] and PBMC replication [63 , 100 ]. Vpu has two domains that are responsible for distinct functions. The amino terminus of Vpu forms a transmembrane region that has been implicated as an ion channel [102 ], whereas the cytoplasmic carboxy-terminal domain of the protein interacts CD4 molecules that have formed complexes with viral envelope glycoproteins. CD4 is then redirected into proteosomes for degradation [103 ]. Both Vpu functions contribute to release of virus particles from the cell surface [104 ]. Accessory genes such as vpu and vpr are not required for replication in rapidly dividing T cell lines and thus mutations will simply accumulate in such genes with multiple rounds of replication. However, for macrophage replication where virus particles are predominantly bud into internal vesicles, a defective vpu may seriously affect cell-to-cell spread of infection. Moreover, there could be in vivo situations where mutations in accessory genes may occur and prevail. For instance, when virus is replicating in T cells that are rapidly dividing after immune activation.

Naturally occurring mutations in the start codon of vpu have previously been reported [105 , 106 ]. Schubert et al. described an HIV-1 isolate (AD8) that has evolved a mechanism to compensate for the loss of Vpu function. HIV-2 and SIVs do not have a vpu gene, however, virion release appears to be controlled by determinants in the envelope glycoprotein. HIV-2 envelope can thus complement a vpu-defective HIV-1 strain [107 ]. The AD8 envelope appears to function in the same way, although the mechanisms directed by such envelopes are unclear. The generation of mutations in accessory genes such as vpu is unlikely to reflect events in vivo. Viruses that carry mutations in accessory genes are likely to be attenuated in vivo [108 , 109 ] as shown for SIVmac strains mutated for the loss of up to three accessory genes [110 ]. Such strains may be candidates as live vaccines [111 ].

Although not reflecting the in vivo situation, in vitro experiments show that shifts in cell tropism can result from either envelope change and/or mutations that abrogate accessory gene functions, and are not necessarily linked to a shift in co-receptor usage.


   ACKNOWLEDGEMENTS
 
This work was supported partly by an MRC program grant and partly by an EU Biomed II grant. We thank Robin Weiss for constructive criticism as well as Graham Simmons, Sam Hibbitts, Jackie Reeves, and Aine Mc Knight for help and suggestions. We are particularly grateful to Paul Clapham for his help in preparing the manuscript and for his kind support.


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L. J. Montaner, C.-F. Perno, and S. Crowe
Macrophage infection by HIV-1: focus on viral reservoirs and pathogenesis
J. Leukoc. Biol., September 1, 2000; 68(3): 301 - 302.
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