1 Unité de Biologie des Rétrovirus, Département de Virologie, Institut Pasteur, 25 rue du Dr Roux, 75724 Paris Cedex 15, France
2 INSERM U563, Centre de Physiopathologie de Toulouse Purpan, 31059 Toulouse Cedex 3, France
3 INSERM U131, 32 rue des Carnets, 92140 Clamart, France
Correspondence
Elisabeth Menu
emenu{at}pasteur.fr
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ABSTRACT |
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Both authors contributed equally to this work.
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INTRODUCTION |
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In this report, we asked whether acute HIV-1 infection could modulate cell surface expression of HLA-G1. We found that HIV-1 decreases cell surface expression of HLA-G1 through a Nef-independent and Vpu-dependent mechanism, whereas both proteins affect HLA-A2 expression.
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METHODS |
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The human CD4+ lymphoblastoid cell line (CEM) was cultured in RPMI 1640 supplemented with 10 % FCS, 1 % glutamine and antibiotics. Peripheral blood mononuclear cells (PBMCs) or mononuclear cells isolated from umbilical cord blood were from HIV-1- and hepatitis B virus-negative healthy volunteers (Centre de Transfusion Sanguine d'Ile-de France, Rungis, France). Cells were obtained by density-gradient centrifugation using Ficoll Hypaque (Pharmacia Biotech). Phytohaemagglutinin (PHA)-stimulated PBMCs or mononuclear cells isolated from umbilical cord blood were cultured in RPMI 1640 containing 10 % heat-inactivated fetal calf serum, 20 mM glutamine, antibiotics and 5 U IL2 ml1. Cell supernatants of PHA-IL2-stimulated PBMCs were used for mock infections.
Monocyte-derived M were obtained as described previously (Perez-Bercoff et al., 2003
). Briefly, monocytes were cultured for 7 days in RPMI 1640 containing 20 mM glutamine, 100 U penicillin ml1, 100 µg streptomycin ml1, 10 mM HEPES, 10 mM sodium pyruvate, 50 µM
-mercaptoethanol, 1 % MEM vitamins, 1 % essential amino acids (all from Life Technology) and 15 % heat-inactivated human AB serum (Valbiotech). Matured cells were harvested by centrifugation, washed, infected with HIV-1 Bal (m.o.i.=0·001) and cultured for various periods of time in hydrophobic Teflon pockets in media containing 10 % FCS. The purity of the isolated population used in the experiments was greater than 95 %, as determined by M
-specific markers, including CD11b, CD14, CD32 and CD64 (Perez-Bercoff et al., 2003
). LPS content in media and working solutions was less than 10 pg ml1.
Viruses and inoculations.
HIV-1 Bal and LAI use CCR5 and CXCR4, respectively, as a co-receptor and were inoculated onto M and HLA-G1-expressing U87.CD4-CXCR4 cells, respectively. Viruses were grown from laboratory stocks using mononuclear cells isolated from umbilical cord blood for HIV-1 Bal and CEM cells, for HIV-1 LAI. Culture supernatants containing HIV LAI were clarified at 2500 r.p.m. for 20 min and viral particles were concentrated by centrifugation at 17 000 r.p.m. for 3 h. Pellets were resuspended in NTE buffer (0·1 M NaCl, 0·01 M Tris, 0·001 M EDTA pH 7·4) and frozen at 80 °C until use. The infectious titre of each virus was determined by limiting dilution assay on PHA-activated PBMCs and is expressed as 50 % tissue culture infectious dose (TCID50) ml1. TCID50 values calculated for HIV-1 Bal and LAI were 105 ml1 and 1010 ml1, respectively.
Transfections.
Effectene reagent (Qiagen) was used for transfection experiments. In all experiments, endotoxin-free DNAs (12 µg per 106 cells) were used. U87.CD4-CXCR4 glioma cells were seeded in T25 or T75 flasks 23 days before transfection. The following constructs and backbones were used: pcDNA3, pcDNA3-G1 encoding HLA-G*01011, and pLUMC9901 encoding HLA-A*02011 (gift of Dr G. C. Hassink, Leiden, The Netherlands) (Kikkert et al., 2001), pBR322, pNL4-3 HIV-1 provirus (Adachi et al., 1986
) deleted in the nef or vpu gene (pNL4-3/vpuDEL-1; Klimkait et al., 1990
) (referred to as pNL4-3
nef and pNL4-3
vpu), and pcDNA3.1/myc-HuDC-SIGN (Halary et al., 2002
). Plasmid pVpuHAGFP was a personal gift from R. Benarous (Besnard-Guérin et al., 2004
). pCMV-nef has been obtained by subcloning Nef-Lai from pSG-nef (gift from G. Sutter, Munchen, Germany) into the BamHINotI site of pCMV-IntronA (gift from J. Barr, Canada). Plasmid pN3-EGFP (Clontech) was used as a control.
Two different ratios (1 : 1 and 1 : 5) of DNA constructs corresponding to pcDNA3-G1 plus empty construct (control cells) or pcDNA3-G1 plus pNL4-3 HIV-1 provirus (HIV-1+ cells) were tested. As a marker of co-transfection efficiency, cells were transfected with one pcDNA3-G1 for every five pcDNA3.1/myc-HuDC-SIGN, a construct encoding another molecule whose expression was detectable at the cell surface. Cell surface expression of HLA-G1, HLA-A2, DC-SIGN (CD209) or control adhesion molecule CD56 was determined by flow cytometry, using specific monoclonal antibodies (mAbs) (Table 1), 24 and 48 h post-transfection (p.t.). For double transfection in JAR cells, combinations of expression vectors in a ratio of 2 : 1 corresponding to pcDNA3-G1 or pLUMC9901 and pVpuHAGFP or pN3-EGFP (control) were used. For triple transfection, JAR cells were transfected with combinations of expression vectors in a ratio of 2 : 2 : 1 corresponding to pcDNA-3-G1 or pLUMC9901 and pCMV-IA-nef and pVpuHAGFP or pN3-EGFP, respectively. Two days later, HLA-A2 or HLA-G1 cell surface expression was analysed by flow cytometry, using specific mAbs (Table 1
).
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Flow cytometry analysis.
U87 and JEG-3 cells were detached using either PBS containing 5 mM EDTA or trypsin EDTA (Gibco-BRL). U87 cells, JEG-3 cells or M were blocked (for 30 min at 4 °C) with human immunoglobulins (Tegeline, Institut Français du Sang, France). After one washing step, the labelled or unlabelled primary antibody (Table 1
) was added at a final concentration of 5 or 10 µg ml1. Isotype control mAbs were used at the same concentration as the primary antibody. Incubation was done on ice for 30 min, followed by one wash. Goat anti-mouse IgG [F(ab')2-PE; 5 µg ml1; DAKO] or the F(ab')2 goat anti-mouse IgG antibody conjugated with cy5-RPE (Coulter-Immunotech) was used as secondary antibody. Samples were analysed by flow cytometry, using either a XL2 EPICS or an EPICS-Elite flow cytometer (Coulter), gated to exclude non-viable cells and to include EGFP-positive cells. Ten-thousand events were analysed for each sample in duplicate. Mean fluorescence intensity (m.f.i.) represents the m.f.i. of all cells. When indicated, m.f.i. represents the m.f.i. of positively stained cells.
Western blot analysis.
Cellular extracts were prepared by incubating 106 cells in 50 µl of chilled (4 °C) lysis buffer containing 500 mM NaCl, 1 mM EDTA, 0·2 % Triton X-100, 200 mM PMSF, 110 mM -mercaptoethanol, a mixture (4 µg ml1) of pepstatin A, aprotinin, chymostatin and antipain, 500 mM sucrose, 0·15 mM spermine, 0·5 mM spermidine and 10 mM HEPES pH 8 for 5 min. Cell extracts were submitted to centrifugation (15 000 r.p.m. for 15 min at 4 °C). Supernatants were collected and frozen at 80 °C with 10 % (v/v) glycerol before use. Protein content in each cellular extract was measured by using Bradford reagent (Bio-Rad). Cellular extracts (20 µg protein per lane) prepared from M
were run through a 12·5 % SDS-polyacrylamide gel next to cellular extracts (20 µg per lane) from choriocarcinoma JEG-3 cells, used as membrane-bound HLA-G1-positive control, and to molecular mass markers. After electrophoretic transfer of proteins on to Immobilon-P (Millipore), blots were incubated in the presence of MEM-G1 at a dose of 5 µg ml1 (primary mAb specific for denatured forms of HLA-G1), followed by horseradish peroxidase (HRP)-conjugated goat anti-mouse antibodies (secondary antibodies). Blots were developed by using enhanced chemiluminescence (ECL) (SuperSignal West Pico Chemiluminescent Substrate; Pierce).
Statistical analyses.
Statistical significance was determined using the non-parametric MannWhitney test or t-test; P values of less than 0·05 were regarded as significant.
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RESULTS |
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HIV-1-mediated downregulation of HLA-A2 is Nef- and Vpu-dependent, whereas HIV-1-mediated downregulation of HLA-G1 is Vpu-dependent and Nef-independent
Next, we wanted to determine which HIV-1-encoded protein was responsible for downregulating cell surface expression of HLA-G1. Several viral proteins, including Nef and Vpu, were shown to attenuate the expression of classical MHC-I molecules (Schwartz et al., 1996; Kerkau et al., 1997
). To determine whether these HIV proteins could decrease HLA-G1 expression, we first co-transfected U87 cells with combinations of expression vectors in a ratio of 1 : 5 corresponding to pcDNA-3-G1 and empty construct (control), wild-type pNL4-3, pNL4-3
nef or pNL4-3
vpu. Flow cytometry analysis of two representative experiments are presented in Fig. 1(C)
(left and right panels) and the results obtained in different independent experiments are summarized in Fig. 1(D)
. The results showed that HLA-G1 expression (number of cells expressing HLA-G1 and m.f.i.) was reduced in U87 cells transfected with pNL4-3 or pNL4-3
nef (P<0·001 and P<0·05 as compared to control, respectively) (Fig. 1C, D
). In contrast, HLA-G1 expression in pNL4-3
vpu-transfected cells was similar to that of control cells (Fig. 1C
left panel and 1D). In these experiments, the amount of HIV-1 p24 antigen detected in the supernatant of the different transfectants ranged between 0·2 and 2·1 ng ml1, with comparable amounts of p24 antigen detected in the supernatants of pNL4-3
vpu- (2·1 ng ml1±0·2) and pNL4-3-expressing cells (1·6 ng ml1±0·7). By comparison, analysis of HLA-A2 surface expression in cells transfected with pNL4-3 showed a decrease (P<0·02 as compared to control cells; Fig. 1D
), whereas overall expression of HLA-A2 was similar in control, pNL4-3
nef- and pNL4-3
vpu-transfected cells (Fig. 1D
). Control CD56 surface expression remained unchanged irrespective of the construct transfected and expressed in U87 cells (Fig. 1D
).
Then, JAR cells were co-transfected with plasmids encoding HLA-G1 or HLA-A2 and EGFP, Vpu/EGFP, Nef/EGFP or Nef/Vpu/EGFP. At 48 h p.t., cell surface expression of HLA-G1 or HLA-A2 was analysed by flow cytometry in EGFP-positive cells expressing either Vpu or Nef or both Vpu and Nef, and compared to cell surface expression of HLA-G1 or HLA-A2 in EGFP control positive cells. Results indicated that Vpu downregulated both HLA-G1 and HLA-A2 cell surface expression, in contrast to Nef, which only downregulated HLA-A2 expression (Fig. 2). When cells co-expressed both Vpu and Nef, we observed that the modulation of HLA-G1 was similar to that observed with Vpu only (
40 % decrease). HLA-A2 downregulation was slightly more important in cells expressing both Vpu and Nef than in cells expressing either Nef or Vpu (Fig. 2
).
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Cell-free HIV-1 downregulates HLA-G1 cell surface expression in U87 glioma cells expressing HLA-G1 and in primary culture of M
We then investigated whether cell-free HIV-1 could similarly downregulate the surface expression of HLA-G1. U87.CD4-CXCR4 cells were transfected with pcDNA3-G1 and inoculated, 24 h later, with HIV-1 LAI at an m.o.i. of 1. The results showing that both CD4 and HLA-A2 expression decreased rapidly after viral inoculation, to reach a level below the level of detection for CD4 expression at 48 h after viral inoculation (Fig. 3A), indicated that the majority of cells were infected. At that time after infection (48 h), parallel examination of cell surface expression of HLA-G1 showed that HLA-G1 was significantly downregulated (P<0·05, as compared to mock infection) (Fig. 3B, C
).
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DISCUSSION |
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These latter results were expected since Nef triggers endocytosis of classical MHC-I molecules by direct binding to specific residues present in the cytoplasmic tail (Schwartz et al., 1996; Cohen et al., 1999
; Williams et al., 2002
; Blagoveshchenskaya et al., 2002
) and HLA-G1 lacks these residues due to a short cytoplasmic tail (Geraghty et al., 1987
). In contrast, the present results suggest that HLA-G1 molecules may be degraded before their transport to the membrane, reducing HLA-G1 expression at the cell surface. Indeed, Vpu interacts with various molecules within the endoplasmic reticulum, including CD4, and alters their transport to the membrane by directing them to the degradation pathway (Lenburg & Landau, 1993
; Bour et al., 2001
). In the case of Vpu-mediated CD4 degradation, Vpu interacts with a discrete amino acid sequence in the cytoplasmic tail of CD4 containing a dilysine motif (EKKT) (Lenburg & Landau, 1993
; Bour et al., 1995
). Interestingly, HLA-G contains a dilysine residue (RKKSSD) in positions 4 and 5 from the C terminus (Geraghty et al., 1987
) with which Vpu could interact. Furthermore, this particular motif is determinant for HLA-G trafficking within the different intracellular compartments, regulating its transport from the endoplasmic reticulum to the cis-Golgi network and its export to the membrane upon binding of high-affinity peptides to HLA-G1 (Park et al., 2001
). Alternatively, Vpu could affect an early step in the biosynthesis of HLA-G1, resulting in a decrease of cell surface expression, as described previously for classical MHC-I molecules (Kerkau et al., 1997
).
The present results indicate that both Nef and Vpu can reduce the expression level of HLA-A2 at the cell surface. Discordant results have been described in the literature. Cohen et al. (1999) reported that Nef is a main determinant whereas Vpu and Vpr have minor influence on the downregulation of HLA-A and HLA-B surface expression. However, in the study of Kerkau et al. (1997)
, it appears that Vpu is crucial for downregulating MHC-I. Major differences in the experimental procedures, such as use of recombinant vaccinia virus (Kerkau et al., 1997
) versus reporter viruses (Cohen et al., 1999
), can explain this apparent discrepancy. Considering that Nef and Vpu can affect the expression of the same host molecule, for example CD4, HLA-A2 (present study), through distinct mechanisms (Vincent et al., 1993
; Buonocore et al., 1994
; Blagoveshchenskaya et al., 2002
), it is possible that both HIV proteins co-operate to downregulate the expression of MHC-I molecules by interfering with different regulatory pathways responsible for proper MHC-I expression (Gromme & Neefjes, 2002
). This would indicate that HIV-1 has evolved several strategies to ultimately downregulate the same molecule and escape immune defences.
As observed here in cells infected with HIV, acute infection with other viruses, such as human cytomegalovirus (HCMV) and herpes simplex virus, was shown to decrease cell surface expression of HLA-G1 (Schust et al., 1999; Tortorella et al., 2000
; Fisher et al., 2000
). Nevertheless, HCMV was also found to increase HLA-G1 expression, either upon viral reactivation (Onno et al., 2000
) or through indirect mechanisms, involving cytokines, in particular HCMV IL10 (Spencer et al., 2002
). Likewise, HLA-G1 is decreased in cells acutely infected with HIV-1 (present study) and might be increased in cells surviving HIV infection, in latently and/or chronically infected cells that constitute a reservoir for HIV (Lozano et al., 2002
). Modulations of HLA-G1 expression during HIV-1 infection may have functional consequences. Thus, recognition of HIV-1-infected cells by CD8+ CTL and/or natural killer cells (Lopez-Botet et al., 2000
) and survival of these cells may, at least in part, depend on HLA-G1 expression levels. Future experiments will determine whether changes in the expression of different isoforms of HLA-G1, including soluble, could limit or favour HIV spreading through the host or the placenta, where HLA-G1 is highly expressed (Le Bouteiller & Blaschitz, 1999
; Solier et al., 2002
; Ishitani et al., 2003
).
In conclusion, our results show that acute HIV-1 infection results in the downregulation of the cell surface expression of membrane-bound HLA-G1. They also indicate that HIV-1 uses distinct mechanisms to alter the surface expression of this non-classical MHC-I molecule and of HLA-A2. Further investigations are required to understand the functional significance of this HLA-G1 downregulation after acute HIV-1 infection.
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ACKNOWLEDGEMENTS |
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Received 2 December 2003;
accepted 23 February 2004.
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