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The Journal of Immunology, 1999, 162: 6263-6267.
Copyright © 1999 by The American Association of Immunologists

T Cell-Tropic HIV gp120 Mediates CD4 and CD8 Cell Chemotaxis through CXCR4 Independent of CD4: Implications for HIV Pathogenesis1

Sujatha Iyengar*,{dagger}, David H. Schwartz* and James E. K. Hildreth2,{dagger}

* Department of Molecular Microbiology and Immunology, School of Hygiene and Public Health, and {dagger} Department of Pharmacology and Molecular Sciences, School of Medicine, Johns Hopkins University, Baltimore, MD 21205


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
HIV entry is determined by one or more chemokine receptors. T cell-tropic viruses bind CXCR4, whereas macrophage-tropic viruses use CCR5 and other CCRs. Infection with CXCR4 and CCR5-tropic HIV requires initial binding to CD4, and chemotaxis induced by the CCR5-tropic envelope has been reported to be strictly dependent on CD4 binding. We demonstrate that, in contrast to CD4-dependent gp120 signaling via CCR5, envelope signaling through CXCR4 is CD4 independent, inducing chemotaxis of both CD4 and CD8 T cells. Signaling by virus or soluble envelope through CXCR4 may affect pathogenesis by attracting and activating target and effector cells.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
The chemokine receptors (CKRs)3 belong to a family of seven transmembrane domain G protein-coupled receptors. Chemokines are chemotactic for leukocytes, monocytes, and lymphocytes recruited during inflammation. The recent discovery of CKRs as coreceptors for HIV (1, 2, 3, 4, 5, 6) has raised a number of questions with respect to their role in HIV entry, pathogenesis, and disease progression. While several early studies found that signal transduction through CKRs was not necessary for HIV-1 entry (7, 8), these experiments used transformed cell lines and may not fully reflect the role of CKR signaling in HIV entry into normal cells. Moreover, the fact that CKR signaling is not required for HIV entry does not exclude a role for HIV-induced signaling through cell surface CKRs in later steps in the life cycle or pathogenesis of HIV.

One potential role has been demonstrated by Weissman et al. (9) who induced CCR5-mediated chemotaxis with HIV envelope glycoprotein gp120. Like fusion and infection, chemotaxis was strictly dependent upon envelope binding to both the CD4 and CCR5 coreceptors. Similarly, Popik et al. (10) have reported that activation of the MEK/ERK kinase pathways could not be triggered by CXCR4 binding to gp120 in the absence of CD4 binding. On the other hand, CD4-independent association of T cell-tropic HIV-1 gp120 with CXCR4 occurs in T cell lines (11) and neuronal cell lines and triggers Ca2+ flux and chemotaxis (12, 13). Even Weissman et al. (9) found that cross-linking of surface membrane CD4 was unnecessary for calcium flux in CD8+ T cells as long as the soluble envelope had been preincubated with soluble CD4. Moreover, Misse et al. (14) recently demonstrated that removal of the conserved first {alpha} helical region of HIV-1IIIB gp120 abrogated CD4 binding and infection, but did not interfere with CXCR4 binding.

These findings suggest that mimicry of stromal-derived factor 1 (SDF-1)-induced CXCR4-mediated chemotaxis may not require CD4 binding at all. Therefore, we examined the ability of CXCR4-tropic HIV-1MN and macrophage- tropic HIV-1BaL virions or various denatured forms of CXCR4-tropic HIV-1IIIB gp120 to induce chemotaxis of human PBMCs. While the use of recombinant envelopes minimizes the possibility of cytokines confounding the interpretation of the results, we felt it was important to initially demonstrate the phenomena with infectious supernatants and purified virions to establish a case for biological relevance.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Cells and reagents

PBMCs were obtained by Ficoll-Hypaque (Sigma, St. Louis, MO) centrifugation. The human CD4+ T cell line PM1 was obtained from the National Institutes of Health AIDS Research and Reference Reagent Program (Rockville, MD). Clinical use GMP grade, endotoxin-free HIV-1IIIB rgp120, rcmgp120, and soluble CD4-Ig were obtained from Genentech (San Francisco, CA). Gradient-purified HIV-1MN and HIV-1BaL with an infectious titer of 106.5 tissue culture ID50 were obtained from Advanced Biotechnologies (Columbia, MD). CD4 blocking and nonblocking Abs (National Institutes of Health AIDS Research and Reference Reagent Program) and CXCR4 Abs were prepared in our laboratory (15). RANTES, macrophage inflammatory protein 1ß (MIP-1ß), and SDF-1{alpha} were obtained from R&D Systems (Minneapolis, MN).

Virus infections

Human blood from normal HIV-negative adult volunteers was layered on a Ficoll-Hypaque gradient, centrifuged, and harvested for PBMCs. PBMCs were activated with 5 µg/ml PHA (Life Technologies, Gaithersburg, MD) for 2 days before infection. PHA-activated PBMCs (50 x 106) were incubated with 5 x 104 tissue culture ID50 HIV-1MN or HIV-1BaL in a total volume of 25 ml at 37°C in RPMI 1640 medium containing 10% FCS plus 2 U/ml IL-2 (Boehringer Mannheim, Indianapolis, IN). After 1 h, the cells were washed three times in PBS and cultured at 2 x 106/ml. HIV-1 p24 Ag in supernatants was assessed at day 7 postinfection by enzyme immunoassay (Organon Teknika, Durham, NC).

Chemotaxis assay

CD4+ and CD8+ cells were isolated by negative depletion using anti-CD4 and anti-CD8 magnetic beads (Dynal, Lake Success, NY) at saturating concentrations. The purity of T cell subsets was determined by flow cytometric analysis of cells immunostained with anti-CD4 and anti-CD8 mAbs (Coulter Immunology, Hialeah, FL) and detected with FITC-conjugated goat anti-mouse IgG (Jackson Immunoresearch Laboratories, Bar Harbor, ME). PHA plus IL-2-activated PBMCs or nonactivated CD4+ and CD8+ cells (20,000/well) incubated for 24 h in 2 U IL-2 were labeled with 5 µM calcein dye (Molecular Probes, Eugene, OR) and placed above filters with 5-µm pores overlying medium, chemokines, HIV-1 envelope protein, or HIV-1 virus in serial dilutions in 96-well microchemotaxis chambers (Neuroprobe, Gaithersburg, MD). After 1 h incubation at 37°C, labeled cells in the lower chamber were read in a fluorescence plate reader at 480EX/530EM. Because absolute numbers of migrating cells can vary substantially by donor and between experimental runs, results are normalized against migrating cells in control media (0.5% FCS, RPMI 1640) and expressed as the ratio of absolute cells or migration index (MI).

Calcium signaling

Cells were loaded with indo-1/acetoxymethylester (Molecular Probes) by incubation for 30 min at 37°C with 4 µM indo-1 per 106 cells in 20 mM HEPES, pH 7.4, containing 136 mM NaCl, 4.8 mM KCl, 1 mM CaCl2, and 5 mM glucose. After centrifugation, loaded cells were resuspended in the same buffer (106 cells/ml) and stimulated with the indicated chemokines or envelope protein at 37°C, and the fluorescence-related changes in intracellular-free calcium concentration ([Ca2+]) were recorded in a specifically designed fluorometer.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Induction of chemotaxis by HIV-infected cell culture supernatants

A human CD4+ T cell line, PM1, permissive for both CXCR4- and CCR5-tropic HIV was infected with HIV-1MN and HIV-1BaL. On day 7, culture supernatants were collected and adjusted to equal virus p24 concentrations after measurement by enzyme immunoassay. The supernatants were then analyzed for their ability to induce chemotaxis of PHA/IL-2-activated PBMCs in a 96-well microchemotaxis chamber assay. Purified recombinant human RANTES was used as a positive control. The greatest migration was stimulated by HIV-1-infected cell culture supernatants, although uninfected PM1 supernatants were also moderately stimulatory: RANTES MI = 7.0; HIV-1MN MI = 6.5; HIV-1BaL MI = 8.0; uninfected supernatant MI = 1.3. Both HIV-1MN- and HIV-1BaL-infected cell supernatants showed chemotactic activity at a p24 concentration of 1 ng/ml, which exceeded maximal chemotaxis induced by RANTES (10 ng/ml).

To extend these findings to the virus grown in primary PBMCs, the experiment was repeated using cell culture supernatants from infected or uninfected activated PBMCs. Both HIV-1MN- and HIV-1BaL-infected cell supernatants again showed chemotactic activity at 1 ng/ml p24 comparable to the maximal chemotactic activity of RANTES at 10 ng/ml (Fig. 1GoA). A dose-response curve of both HIV-1 supernatants showed a peak activity at 10 ng/ml p24 concentration, with a steady increase between 0.1–10 ng/ml and a sharp fall in activity between 100 ng/ml and 1000 ng/ml. The uninfected supernatant had no significant chemoattractant activity.



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  		FIGURE 1. Viruses of differing tropisms and various forms of IIIB rgp120 are chemotactic for activated PBMCs. Calcein-labeled activated PBMCs were spotted at 20,000 per replicate above 5-µm pore filters overlying medium or serially diluted chemokines, HIV-1 envelope protein, or virus in 96-well microchemotaxis chambers. After 1 h at 37°C, 5% CO2, cells in the lower chamber were counted in a fluorometer. MI = [experimental media cell fluorescence]/[media cell fluorescence]. Results are expressed as ± SD for triplicate experiments. A, HIV-1MN or HIV-1BaL at 1 ng/ml p24 induced chemotaxis similar to maximal chemotaxis induced by RANTES at 10 ng/ml. Control supernatants from uninfected cells induced minimal chemotaxis over media alone. B, Heat-denatured (rgp120, 56°C for 2 h) and nondenatured HIV-1IIIB rgp120 are chemotactic for activated PBMCs. RANTES and SDF-1{alpha} were used at optimal concentrations of 10 ng/ml.

 
CD4 independence of chemotaxis induced by noninfectious virions and purified recombinant envelope

To rule out a requirement for virus-induced cytokines or infection of migrating cells, we tested the chemoattractant activity of gradient-purified UV-inactivated HIV-1IIIB. There was potent chemotaxis to inactivated purified virus in a dose-dependent manner, with maximal numbers of cells migrating at 10 ng/ml p24 (not shown). To determine whether the viral envelope gp120 was chemotactic in the absence of secreted cellular factors or additional viral components, experiments were repeated using endotoxin-free purified recombinant gp120 envelope protein from HIV-1IIIB (Genentech), which showed significant chemoattractant activity, rising sharply between 0.01 and 0.1 ng/ml, increasing to maximal at 10 ng/ml, and decreasing between 100-1000 ng/ml. Fig. 1GoB illustrates the responses between 0.1 and 100 ng/ml. Similar CXCR4-mediated dose-response migration was observed with heat-denatured gp120 (Fig. 1GoB) and reduced carboxymethylated IIIB rgp120 (rcmgp120), which does not bind CD4 (Fig. 2GoA). To further rule out an essential role for CD4 in gp120-mediated signaling through CXCR4, a mAb (SIM4) that binds to the same epitope as Leu 3a and blocks HIV CD4 binding and infection was shown to have no inhibitory effect compared with SIM7, a mAb which binds to the same epitope as Leu 3 and does not compete for envelope binding to CD4 (Fig. 2GoA). In addition, gp120-induced chemotaxis of activated PBMC was not blocked by soluble CD4-Ig fusion protein (Fig. 2GoB).



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  		FIGURE 2. Anti-CD4 mAbs and sCD4-Ig do not inhibit chemotaxis of activated PBMCs to various forms of HIV-1IIIB rgp120. A, Cells pretreated with 10 µg/ml blocking mAb (SIM4), nonblocking mAb (SIM7), or medium were placed atop the filter and incubated as for Fig. 1Go. Native rgp120, reduced carboxymethylated rgp120 (rcmgp120), and SDF1{alpha} all induced maximal chemotaxis at 10 ng/ml. B, Soluble rCD4-Ig/rgp120 complex is chemotactic for activated PBMCs. Recombinant gp120 or rcmgp120 were incubated with 10 µg/ml sCD4-Ig. MIP1ß and SDF1{alpha} were used at 10 ng/ml.

 
We found that CXCR4 is not expressed on the surface of T lymphocytes immediately following venipuncture, but is exteriorized to the cell surface from submembrane vesicles within hours of being placed in culture. This is supported by studies by Jourdan, et al. (16) for lymphocytes and by Zaitseva et al. (17) for APC. Freshly isolated (<2 h) PBMCs not expressing surface CXCR4 (Fig. 3GoA) failed to migrate in response to either HIV-1IIIB rgp120 or SDF-1{alpha}. However, as early as 6 h after culture without stimulation, resting PBMCs expressed high levels of surface CXCR4 and responded dramatically to these chemoattractants, albeit with somewhat less migration than seen for activated cells at the 1 ng/ml concentration of rgp120 (Fig. 3GoA). Moreover, pretreatment of PHA/IL-2-activated cells with anti-CXCR4 mAb (FSNM2, mouse IgG2b) blocked chemotaxis induced by rgp120 or SDF-1{alpha}, but not by MIP-1ß, indicating a direct interaction of gp120 with CXCR4 (Fig. 3GoB).



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  		FIGURE 3. Chemotaxis induced by HIV-1IIIB rgp120 in PBMC correlates with surface expression of CXCR4 and is inhibited by a mAb against CXCR4. A, Chemotaxis induced by HIV-1IIIB rgp120 in resting PBMCs 1 and 6 h postisolation from blood. No surface expression of CXCR4 on resting PBMCs was detected with anti-CXCR4 mAb by flow cytometry at 1 h; 70% of cells stained positive for CXCR4 at 6 h (data not shown). B, Blocking mAb to CXCR4 inhibits activated PBMC chemotaxis toward IIIB rgp120 and SDF-1{alpha}, but not toward the ß-chemokine MIP-1ß. Control cells were treated with nonblocking Ab against CXCR4.

 
Chemokines induce mobilization of Ca2+ by a G protein-coupled pathway. To determine whether this pathway is also triggered by gp120, PBMCs loaded with the fluorescent Ca2+ indicator indo-1 were exposed to HIV-1IIIB rgp120 or SDF-1{alpha} at 0.01–100 ng/ml. Transient increases in cytosolic free Ca2+ concentration were observed for both gp120 and SDF1{alpha}, peaking at 20 s poststimulation and returning to resting values within 5 min (data not shown). Thus, HIV-1IIIB gp120 can induce Ca2+ mobilization like the physiological chemokine ligands, probably via the G protein-coupled pathway.

Chemotaxis of CD4-CD8+ lymphocytes induced by the CXCR4-tropic envelope and virus

To assess the biological consequences of CD4 independent gp120-CXCR4 interactions, PBMCs were immunomagnetically depleted of CD4+ cells and the remaining cells (<2% CD4+, 85% CD8+) were used in chemotaxis assays with recombinant envelopes and purified virions. Flow cytometry revealed comparable expression by activated CD4 and CD8 cells of CXCR4 or CCR5. This was further confirmed by similar dose-response curves of CD4 and CD8 cells migrating toward SDF-1{alpha} or MIP-1ß. The <2% CD4+ cells remaining in the CD4-depleted population cannot account for the observed high migration indices, as MI > 6 represents migration of more than half of the input cells. Furthermore, significant migration of contaminating CD4+ cells should have been observed equally in response to HIV-1BaL, and this was not seen, as shown in Fig. 4GoB. For both HIV-1IIIB rgp120 and rcmgp120, chemotaxis of CD8 cells was comparable to whole PBMCs (Fig. 4GoA).



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  		FIGURE 4. Chemotaxis of CD4+ and CD4- activated PBMCs to various forms of HIV-1IIIB rgp120 (A) and purified HIV-1 virus isolates (B). The CD4- subset isolated by negative depletion with anti-CD4 magnetic beads contained >85% CD8+ cells and <2% CD4+ cells as determined by flow cytometry. Both cell types expressed comparable levels of CXCR4 and CCR5. In addition, the two cell types had similar migratory dose-response curves to SDF-1{alpha} and MIP-1ß (data not shown).

 
Thus, the T cell-tropic HIV envelope interacting directly with CXCR4 mediated chemotaxis in a CD4-independent manner. Similarly, infectious CXCR4-tropic HIV-1MN induced chemotaxis of both CD4-depleted and undepleted cells (Fig. 4GoB). In contrast, the CCR-5-tropic strain HIV-1BaL induced chemotaxis of the CD4+ group of PBMCs but not of the CD4-depleted PBMCs. This is in agreement with a recent report (9) that macrophage-tropic HIV mediates chemotaxis of T cells through CCR5 only after engaging CD4.


   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
While HIV infection of CD8+ cells in vivo has occasionally been reported (18, 19, 20), its extent and biological significance remains unresolved. Flamand et al. (20) recently reported that activated CD8 cells expressed surface CD4 after several days of stimulation, at which point they became susceptible to infection, in keeping with the paradigm that CD4 is an essential coreceptor on lymphocytes and not replaceable by CD8. We reported that HIV-1MN entry into cells is dependent on cocapping of CXCR4 and CD4 (15). The HIV envelope engagement of CXCR4 on CD8 may not trigger membrane fusion, due to an absence of cocapping between CD4 and CXCR4 or because CXCR4 binding alone is not sufficient to release the gp41 fusion moiety.

Our results are consistent with previous observations on the ability of the IIIB envelope to stimulate calcium flux and chemotaxis in neuronal cells in a CXCR4-dependent, CD4-independent manner (13), but would seem to be at odds with the finding of Weissman et al. (9) that IIIB rgp120 and another CXCR4-tropic envelope failed to elicit Ca2+ fluxes even in CD4+ T cells. The differences may be due to our use of either unstimulated or PHA plus IL-2-stimulated cells rather than the anti-CD3 plus IL-2-activated cells used by these authors, as Riley et al. (21) have shown that different stimulation strategies can markedly influence CKR expression. The absence of signal transduction reported by Weissman and colleagues was not confirmed in our published studies demonstrating the ability of IIIB rgp120 to induce actin-mediated cocapping of CD4 and CXCR4 and cap-polarized pseudopod formation typical of chemotaxis (15).

Our experiments have shown that heat-denatured gp120 is capable of signal transduction leading to chemotaxis. This suggests that the amount of unfolding by our heat denaturation is sufficient to retain the signal-transducing property of this protein. Our method of denaturation is mild (56°C) and might still retain enough conformation for CKR binding. Furthermore, the CXCR4 binding residues are recessed in native trimeric gp120, and it is possible that mild heating and denaturation actually increases their exposure and availability for CKR binding. Along these lines, it has been reported previously by Bandres et al. (11) that envelope deglycosylation enhanced envelope binding to CKR. More recently, Misse et al. (14) have demonstrated that a conserved {alpha} helical sequence can be removed from the CXCR4-tropic virus envelope, thereby abrogating CD4 binding and infectivity while preserving CXCR4 binding. Finally, SDF-1 and synthetic ligands have relatively limited terminal regions that effectively engage the CKR.

The advantage to HIV in attracting new infectable CD4+ potential host cells along a chemotactic gradient to loci of infection is obvious. It is less clear that any selective value is conferred on CXCR4-tropic strains by their ability to attract CD8 cells, and it may simply be an epiphenomenon of HIV envelope signaling through CXCR4. Flow analysis performed just before our chemotaxis studies clearly showed an absence of CD4 on the purified CD8+ cells used, as would be predicted by Flamand et al. (20) for cells not stimulated through the TCR. Therefore, expression of surface CD4 during the 1-h migration assay could not account for CXCR4-mediated binding. Also, any such surface expression of CD4 should have rendered the cells responsive to HIV-1BaL as well, and that was not the case. Of course, if the findings of Flamand et al. (20) are generally applicable in vivo, then attracting CD8 cells to lymph nodes where they could become activated and eventually express surface CD4 would provide additional targets for infection, especially late in disease when CD4+ lymphocytes might be rare.

Taking a broader view of viral evolution and pathogenesis, CD8 cells attracted to germinal centers where virus is tethered to follicular dendritic cells in immune complexes (22) may, through direct lysis or indirect release of cytokines, alter the microenvironment in ways that release and disseminate virions throughout the body (23, 24). Coupled with their more rapid rate of replication in T cells, widespread dissemination of CXCR4-tropic virions could represent a significant selective advantage. Alternatively, the ability to attract CD8 cells to sites of infection may be critical for the CXCR4-activated destruction of antiviral CD8 cells by TNF-mediated apoptosis in vivo. Such a mechanism requiring direct contact between macrophages and CD8 cells, has been described and is dramatically up-regulated by the CXCR-tropic envelope (25).


   Acknowledgments
 
We thank Margaret B. Penno and Jennifer C. Hart for help with chemotaxis assays, Gordon W. Weigand for help with calcium flux measurements, and James Mitchell and Richard Hampton for technical help.


   Footnotes
 
1 This work was supported in part by National Institutes of Health Grant 2RO1 AI31806-05 and American Cancer Society Grant IRG 11-36. Back

2 Address correspondence and reprint requests to Dr. James E. K. Hildreth, Department of Pharmacology and Molecular Sciences, School of Medicine, Johns Hopkins University, Room 320A Physiology, 725 North Wolfe Street, Baltimore, MD 21205. E-mail address: Back

3 Abbreviations used in this paper: CKR, chemokine receptor; SDF-1, stromal-derived factor; MIP-1, macrophage inflammatory protein; ERK, extracellular signal-related kinase; MEK, mitogen-activated protein/ERK; MI, migration index. Back

Received for publication December 14, 1998. Accepted for publication February 26, 1999.


   References
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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