Department of Biological Sciences, University of Warwick, Coventry CV4 7AL, UK
Correspondence
Nigel J. Dimmock
ndimmock{at}bio.warwick.ac.uk
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ABSTRACT |
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INTRODUCTION |
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The gp41 subunit of HIV-1 and simian immunodeficiency viruses comprises the ectodomain, the tm domain, and a long C-terminal tail of approximately 150 aa residues (Gallaher et al., 1992). There is structural information on the ectodomain (Caffrey et al., 1998
; Chan et al., 1997
; Malashkevitch et al., 1998
; Tan et al., 1997
; Weissenhorn et al., 1997
), but not on the C-terminal tail. The limits of the tm domain are not known exactly (West et al., 2001
). Conventionally the tail is regarded as being located entirely inside the virion or the infected cell, but it has been proposed that about 40 residues of the tail region are looped out to the external surface of the virion (Cleveland et al., 2003
; McLain et al., 2001
). The main evidence for this relates to the neutralization of infectivity by certain tail epitope-specific antibodies (Buratti et al., 1998
; Chanh et al., 1986
; Cheung, 2002
; Cheung et al., 2005
; Cleveland et al., 2000a
, b
, 2003
; Dalgleish et al., 1988
; Durrani et al., 1998
; Evans et al., 1989
; Ho et al., 1987
; Kennedy et al., 1986
; McLain et al., 1995
, 1996a
, b
, 2001
; Newton et al., 1995
), and since particles of infectious virus are by definition intact, and IgG does not cross lipid bilayers, it follows that the epitope is expressed on the outside of the virion. The neutralization epitope (centred on the sequence ERDRD) is constitutively exposed on the surface of virions (Cleveland et al., 2003
), and two other non-neutralizing epitopes are sited close by. Interaction with mAbs to all these epitopes is abrogated by digestion with trypsin or thermolysin, and is consistent with their external location (Cleveland et al., 2003
). To explain the external location of the epitope-bearing loop, we have hypothesized that the conventional tm region has a
-turn at its centre that takes the tail back across the viral membrane to the exterior surface of the virion (Cleveland et al., 2003
). Furthermore, we suggest that the loop is completed by a third potential tm region then takes the tail back inside the virion. All three proposed tm regions comprise approximately 10 residues and are theoretically compatible with predictions for
-sheet structures (M. J. Hollier & N. J. Dimmock, unpublished data). Although short in length, there is a precedent for such tm regions in bacterial porins (Schirmer, 1998
; Schirmer & Cowan, 1993
). The approximately 40 aa residue external loop is thus defined by tm2 and 3. The gp41 tail C-terminal to tm3 comprises approximately 100 residues, is inside the virion, and can interact with internal components of the virion (e.g. Freed, 1998
).
The gp41 external tail loop includes the 22-residue Kennedy sequence, 731PRGPDRPEGIEEEGGERDRDRS752 (Chanh et al., 1986; numbering system of Ratner et al., 1985
). This is a hydrophilic, antigenically complex region with no apparent structural organization. Confusingly both neutralizing and non-neutralizing antibodies recognize the Kennedy sequence, and 746ERDRD750 that forms the minimum epitope for a number of antibodies, appears to adopt a number of different conformations. These are recognized by a neutralizing epitope-purified, ERDRD-specific (EPES) polyclonal antibody (Buratti et al., 1998
; Cleveland et al., 2000a
, b
, 2003
; McLain et al., 2001
), by mAbs 1577 and 1583, which neutralize only in the presence of complement (Cleveland et al., 2003
; Vella et al., 1993
), and by mAb SAR1, which neutralizes free virions poorly or not at all, but is active in post-attachment neutralization (PAN) (Reading et al., 2003
). mAb C8 recognizes 734PDRPEG739 on the surface of infected cells (Abacioglu et al., 1994
), but not virions and is thus non-neutralizing. Lastly the non-neutralizing mAb 1575 recognizes residues 740IEEE743. This is an immunodominant, non-conformational epitope that is present on virions and the surface of infected cells (Cleveland et al., 2000b
; McLain et al., 2001
; Vella et al., 1993
).
mAb SAR1 is a novel IgG that was raised recently by immunizing mice with a plant virus chimera expressing the gp41 tail sequence 745GERDRDR751 (Reading et al., 2003). SAR1 recognizes gp41 expressed on the surface of infected cells, and binds to some, but not all, preparations of purified virions, suggesting that it may recognize non-infectious virions or degraded/immature forms of the envelope protein. In general, three types of neutralization activity can be distinguished: (i) standard neutralization (STAN), which takes place when virus and antibody are incubated together before they are added to target cells; (ii) PAN, which occurs when mAb is added to virions after they have attached to cells this can be measured by inhibition of syncytium formation or p24 production; and (iii) neutralization of infectious progeny (NIP), which is the reduction in the amount of infectivity produced by the infected culture. SAR1 gives poor or no STAN, significant PAN and good NIP (Reading et al., 2003
). Location of the SAR1 epitope was confirmed by failure of antibody to neutralize a mutant virus lacking the 144 C-terminal gp41 residues, and by competition with a mAb that recognizes an adjacent epitope (740IEEE743) (Reading et al., 2003
). Here, we have further investigated the unusual pattern of SAR1 neutralization. We found that temperature requirements suggest that SAR1 effects PAN by inhibition of virioncell fusion, and SAR1 was shown to be directly inhibitory in a virus-mediated cellcell fusion assay. This is the first time that a region of the gp41 C-terminal tail has been implicated in fusion. Together these data support the view that part of the gp41 C-terminal tail lies outside the virion and the infected cell.
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METHODS |
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Antibodies.
mAb SAR1, a murine IgG2a, , was produced by immunization with the plant cowpea mosaic virus chimera, CPMV-HIV/29 that expresses 745GERDRDR751 on its surface from the C-terminal tail of gp41 (Cleveland et al., 2000a
; Reading et al., 2003
). We also used the gp41 C-terminal tail mAbs: C8 to 734PDRPEG739 (Abacioglu et al., 1994
), 1575 to 740IEEE743, 1577 and 1583 to 746ERDRD750 (Vella et al., 1993
), and gp120 mAbs: ICR41.1i to a conformational epitope in the V3 loop (Cordell et al., 1991
) and mAb b12 to the gp120 CD4-binding site (Barbas et al., 1992
; Bender et al., 1993
). IgG concentrations were determined by ELISA after capture of serial dilutions of purified IgG with immobilized goat anti-species IgG. IgG concentration was interpolated from a standard curve of IgG.
Assay for PAN.
Virus infectivity was assayed by the production of syncytia in C8166 cell monolayers. There is a linear relationship between the number of syncytia and the amount of inoculum, meaning that each syncytium is the product of a single infectious unit (McLain & Dimmock, 1994). The assay thus reflects a single cycle of replication. Plates (96-well, Gibco-BRL) were treated with 50 µg poly-L-lysine (Sigma) ml1 to anchor cells, and seeded with 5x104 C8166 cells per well (McLain & Dimmock, 1994
). Cells were inoculated with approximately 50 syncytium forming units (s.f.u.) per well usually for 1 h at 20 °C, but this was varied according to protocols described later. After removing virus and rinsing cells, medium, or medium containing mAb SAR1 (200 µl per well in five replicates) was added. Antibody was incubated with infected cells according to protocols presented later. When required, antibody was removed and replaced with fresh medium. It takes 3 days at 37 °C for primary syncytia to develop fully; secondary syncytia do not appear until after this time. Syncytia contain three or more nuclei, and their identity has been confirmed by cytostaining. However, they are readily recognized under low-power microscopy. The same virus titre is obtained when culture fluid p24 is assayed by ELISA (data not shown). PAN was calculated as the percentage reduction in syncytium formation in cultures treated with antibody compared to syncytium formation in the virus control without antibody (approx. 50 s.f.u. per well counted). Values were corrected for the very few syncytia (mean <1 per well) that occurred in cell controls.
Fusion of HIV-1-infected cells with non-infected cells.
This method was essentially as previously described (Armstrong et al., 1996). C8166 cells (1x107 cells in 10 ml) were infected with HIV-1 (5x104 s.f.u.) for 2 days at 37 °C. The medium was changed and cells incubated for a further day. Washed cells (6x104 in 100 µl) were mixed with an equal volume of medium or medium containing antibody for 1 h at 37 °C. A 10-fold excess of non-infected C8166 cells (6x105 in 50 µl) was then added and fusion allowed to proceed for 3·5 h at 37 °C. Infected and non-infected cells without mAb, were incubated in parallel at 4 °C to control the level of spontaneous cellcell fusion. All cells were then washed with PBS and stained with chilled 0·2 % Wright's stain in methanol. These were rehydrated, pelleted and stained further with 0·05 % Giemsa in distilled water. After washing, at least 1000 cells from each sample were counted by low-power microscopy. Syncytia are defined as cells containing three or more nuclei. The baseline number of syncytia was subtracted from all samples and the percentage inhibition of cellcell fusion calculated.
Binding of soluble recombinant (sr) CD4 to HIV-1.
SrCD4 expressed by CHO cells, was generously provided by W. Meier (Biogen Inc, Cambridge, MA). Purified virus (5x105 s.f.u.) was incubated with 0·5 µg srCD4 in 1 ml for 1 h at 20 °C in 100 mM sodium bicarbonate, pH 8·5. The mix (100 µl per well) was then transferred to a 96-well plate (Immulon 2; Dylan). Other wells contained virus alone, srCD4 alone or buffer. The plate was incubated overnight at 20 °C. Plates were washed with Tris-buffered saline (TBS; 50 mM Tris, 140 mM NaCl, pH 7·6), blocked with 3 % BSA (Sigma) in TBS, and incubated overnight at 20 °C with envelope-specific IgGs in TBS containing 0·05 % Tween 20 (TBS-T) and 1 % BSA. Virus was also incubated with an irrelevant IgG. After washing, the plate was immersed overnight at 4 °C in 3 % paraformaldehyde. Bound IgG was assayed with biotinylated anti-species IgG, and colour developed with streptavidin-linked alkaline phosphatase (Amersham Life Science) and p-nitrophenyl phosphate in diethanolamine buffer (Pierce & Warriner) with MgCl2, pH 9·8. Controls gave a reading of <0·2 OD405 units, when the virus with SAR1 gave approximately 1·0 OD405 units.
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RESULTS |
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DISCUSSION |
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It is interesting how closely our data parallel those in which peptide inhibitors and antibodies to the gp41 main ectodomain were used to probe the temperature requirements for cellcell fusion directed by vaccinia virus-expressed gp160 (Golding et al., 2002). Here, it was found that peptides (including T-20) block the formation of fusion intermediates (coiled-coil and six-helix bundle formation) more effectively if incubated with Env-expressing cells at a subfusion temperature before shifting to 37 °C. Antibodies to the N-heptad region and the six-helix bundle behaved similarly, and inhibited only if they were pre-incubated with Env-expressing cells at the lower temperature. The half-time at 37 °C transition from the six-helix bundle intermediate to fusion was 3·59·5 min, and bearing in mind differences in Env expression systems [vaccinia-expressed Env (Golding et al., 2002
) and HIV-1 virus infection] and cells used, were of the same order as we report above for complete transition to fusion (1030 min). The authors conclude that the coiled-coil and six-helix bundle form prior to fusion, and that the lag time is needed to accumulate sufficient six-helix bundles at the fusion site. Our data are consistent with SAR1 inhibiting an early event in the fusion pathway, and we now need to determine what role the gp41 tail loop has in fusion, and which fusion intermediate is inhibited.
The increase in PAN, discussed above, that arises when virus and cells are incubated at 20 °C reflects greater reactivity of the SAR1 epitope. This recalls the induction of gp120 and gp41 ectodomain epitopes and the co-receptor-binding site on incubation with srCD4 (Allaway et al., 1993; Doranz et al., 1999
; Mbah et al., 2001
; McKeating et al., 1992
; Sattentau & Moore, 1991
; Sattentau et al., 1993
; Sullivan et al., 1998
; Thali et al., 1993
; Xiang et al., 2002
). However, we found no increase in binding of SAR1 to purified virions complexed with srCD4, even though this doubled the binding of a gp120 V3 loop-specific mAb (Fig. 6
; McKeating et al., 1992
). Activation of the SAR1 epitope may require multiple contacts between viral envelope proteins and CD4 molecules inserted in the cell membrane, or binding to other virus receptors.
Work with SAR1 has revealed previously unknown properties of the gp41 C-terminal tail, which adds to the case that part of the C-terminal tail is exposed on both the external surface of the virion (Buratti et al., 1998; Cleveland et al., 2000a
, b
, 2003
; McLain et al., 2001
), and the infected cell (Cheung et al., 2005
; Reading et al., 2003
), rather than being entirely inside the virion. Further study of the structure and function of the gp41 external tail loop is required to elucidate its significance for the virus life-cycle. If antibodies targeted to the gp41 tail loop prove to be of clinical benefit, the well defined, cost-effective plant virus chimeras that stimulate SAR1-like antibodies (Reading et al., 2003
) and standard neutralizing antibodies (Cheung, 2002
; Cheung et al., 2005
; Cleveland et al., 2000a
, b
, 2003
; Durrani et al., 1998
; McLain et al., 1995
, 1996a
, b
, 2001
) could be a useful vaccine component.
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ACKNOWLEDGEMENTS |
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Received 2 July 2004;
accepted 2 February 2005.
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