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, Philippe Benaroch -philippe.benaroch@curie.fr Keywords: macrophages, vol.932
, It is still unclear whether the specific host immune response contributes to the low viral loads observed in HIV-2 infections. One of the important specific features of HIV-2 particles is that they contain Vpx, an accessory protein that is absent from HIV-1, which efficiently counteracts the restriction factor SAMHD1 by promoting its rapid degradation, SAMHD1 is a cytosolic enzyme, active in resting T cells and dendritic cells (DCs), that depletes the stock of cytosolic dNTPs via its deoxynucleoside triphosphate triphosphohydrolase activity, thus blocking reverse transcription (RT) of lentiviruses, 2000.
, Duvall et Gag is almost absent from the cytosol, but concentrated in VCCs in HIV-2 infected macrophages Gag staining in HIV-2-infected MDMs appeared to be almost exclusively concentrated in punctate structures and absent from the cytosol (Fig 3A). This was true for both WT R5 and WT X4 HIV-2 (Fig 3A). We confirmed this observation by quantifying cytosolic Gag in infected MDMs on confocal sections, Monocyte-derived DCs (MDDCs) are a widely-used model of in vitro derived DCs often claimed to correspond to inflammatory DCs, 2007.
, Analysis of the Gag signal distribution, shown in pseudocolors to visualize very low levels, confirmed that Gag was mostly absent from the cytosol in HIV-2-infected macrophages and concentrated in VCCs (Fig 4A, bottom row). This conclusion was further supported by quantification of the Gag signal performed on 3D reconstitutions of the HIV-infected MDMs (Fig 4B), We infected MDMs with HIV strains internally tagged with GFP to rule out that the differential distribution of HIV-1 and HIV-2 Gag was due to differential affinity of the H183-H12-5C mAb used for the cytosolic Gag forms, 2011.
, , 2011.
, Altogether, these data suggest that HIV-2 Gag was more efficiently recruited to VCCs after synthesis in the cytosol
, Ultrastructural analysis of VCCs from HIV-2-infected macrophages We analyzed epon sections of HIV-2-infected macrophages by electron microscopy to further characterize their VCCs (Fig 5), VCCs from MDMs infected with HIV-1 R5 or HIV
, X4 or R5 exhibited highly similar morphologies. In all cases, we observed viral budding profiles at the VCC limiting membranes (see arrowheads), revealing the production of new virions
, The presence of mature (with the electron dense capsid visible inside) and immature (with the electron dense Gag precursor at the periphery and an electron lucent zone at the center) particles revealed that they were able to mature. Quantification of the viral density in the lumen of the BST-2 regulation in HIV-infected macrophages The low amounts and low infectivity of HIV-2 particles produced by MDMs may result from partial down-regulation of the restriction factor BST-2/Tetherin. BST-2 is an IFNstimulated gene (ISG) and localizes to the VCCs in infected MDMs, Moreover, the VCCs contained mature and immature viral particles in their lumen, 2007.
, or HIV-2DEnv X4GFP-G, as a negative control (Fig 8B). Infection by HIV-2DEnv
, induced the highest level of BST-2 expression relative to non-infected cells, showing that HIV-2 was detected by MDMs, probably as for HIV-1, contrast, total BST-2 levels were down-regulated in MDMs infected with Env-encoding HIV-2 (Fig 8B), 2017.
, Thus, expression of Env from HIV-2 reduced total BST-2 levels in MDMs as previously shown for surface BST-2 levels in HeLa cells, 2010.
, We addressed the role of BST-2 more directly by providing VLP encoding Vpu from HIV-1 fused with mCherry to MDMs together with HIV-2. Vpu decreased BST-2 levels for both HIV-2 (Fig 9A and B)
, HIV-2 X4GFP-G-infected MDM transmission to MT4C5 cells increased upon addition of
, There was no transmission between HIV-2 R5GFP-G-infected MDMs and MT4C5 cells, independently of Vpu, confirming the lower infectious capacity of HIV-2R5 relative to that of the HIV-2X4 strain (Fig 9D). The addition of Vpu had no effect on the infectious capacity of the virions produced nor on their release (not shown). Overall, the low amounts and low infectivity of the HIV-2 produced by, Vpu, but remained lower than that of HIV-1 (Fig 9D)
, Differential CD4+ T-cell susceptibility to HIV-1 and HIV-2
, where all donors signed informed consent allowing the use of their blood for research purposes. Peripheral blood mononuclear cells (PBMC) were separated using Ficoll-Paque (GE Healthcare). Monocytes were isolated by CD14+ positive selection using magnetic microbeads (Miltenyi) and differentiated into macrophages for 7 days in RPMI (Gibco, Life Technologies) supplemented with 5% fetal calf serum (FCS; BioWest), 5% human serum AB (Sigma), The poor infectivity of HIV-2 produced by MDMs could be due to the intrinsic features of HIV-2, reducing their infectious capacity, as well as differing susceptibility of the T cells to HIV-1 and HIV-2
, CD4+ T cells were isolated from PBMC by CD4+ were cultured in RPMI 1640 medium, GlutaMAX complemented with FBS 10%
, On day 2 of culture, cells were washed and additionally cultured with IL-2. HEK293T cells were cultured in DMEM medium, GlutaMAX (Thermo Fisher 61965-026) complemented with FBS 10% (Thermo Fisher 10270-106) and Penicillin/Streptomycin. GHOSTX4R5 and TZM-bl cells were cultured in DMEM medium, GlutaMAX complemented with FBS 10% and Penicillin/Streptomycin. MT4C5 cells were cultured in RPMI medium, GlutaMAX complemented with FBS 10% and Penicillin/Streptomycin, Streptomycin at 106 cells/mL in the presence of 5µg/mL PHA
, Institut Pasteur, pp.4-7
, AD8 (Freed and Martin, 1995) derived from of NL4-3 with BaL env, HIV-2 ROD9 and HIV-2
, The GFP viruses all harbor GFP instead of Nef, JK( both gift from N. Manel), pp.1-4
, HIV-1iGFP (Hübner et al., 2007) and HIV-2 ROD9GagiGFP was generated from HIV-2 ROD9GagiGFP?Env (N. Manel) with EGFP sequence between CA and MA and Gag from this plasmid was, X4GFP (N. Manel), HIV-2 ROD9GFP and HIV-2 ROD9?EnvGFP (both kindly provided by O.T. Keppler), 2017.
, Saint Louis Hospital)). The Vpu-Cherry was generated by introducing Cherry in the place of GFP. Vpu-Cherry was cloned to a pDONOR vector and introduced in an adapted to gateway technology version of pCDH-CMV-MCS-EF1-Puro, p.3
, plasmid for Vpx, psPAX2 for lentiviral encapsidation and pDM2G for VSV-G pseudotyping. pSVR?NBDM (Manel) was used to encapsidate HIV-2ROD9iGFP for productive infection
, Mirus Bio) per well. For non-pseudotyped virus 3µg of HIV plasmid were used. For VSV-G pseudotyped virus 0.4µg pDM2G and 2.6µg HIV plasmid were used. For Vpx and Vpu-Cherry lentivectors 0.4µg pDM2G, 1 µg psPAX and 1.6µg Vpx or Vpu-Cherry plasmid were used. For HIV-2*GagiGFP 0.4µg pDM2G, 1 µg pSVR?NBDM and 1.6µg pROD9 iGFP plasmid were used. 16h after transfection, media was removed, and fresh RPMI medium was added. Viral supernatants were harvested 36h later, filtered at 0.45µM, used freshly or aliquoted and frozen at -80°C, HIV-1 and lentiviral production and titration HIV Viral particles were produced by transfection of HEK293T cells in 6-well plates with 3µg DNA and 8µl TransIT-293, 2010.
, Cells were fixed for 20 min in 4% paraformaldehyde (PFA), washed in PBS, and when stained, permeabilized for 30 min in PBS plus 0.2% BSA and 0.05% saponin. Infection was detected by GFP coding viruses and BST2 was detected using a coupled BST2-PE antibody (eBioscience) or IgG1-PE (eBioscience) as a control and analyzed on a FACS Verse (BD). For Vpu-Cherry expressing cells CYTOFLEX cytometer (Beckman Coulter) was used. Recovery of intracellular virus Macrophages in a 24-well plate were washed twice in PBS after supernatant collection and 400µL of media were added and put at -80ºC. After couple of hours the plate was thaw and medium was collected and centrifuged at 15000rpm 1h30 at 4ºC. The pellet was resuspended in 200µL. 100 µL were used for RNA extraction and 100 µL were diluted with 300 µL of PBS for titration into TZM-bl. RNA isolation, reverse transcription, Drugs Azidothymidine (AZT; Sigma) was used at 25µM final concentration and added at time of co-culture with T cells as control or after 24h of co-culture to avoid T-to-T cell transmission
, HIV-2 X4GFP, HIV-2 R5GFP at different MOIs, washed extensively 3 days later, and received 7.5 × 105 CD4+ T lymphocytes/ well in the 96-well plate. The macrophages on 24-well plate were harvested for %of infected cells. The CD4+ T lymphocytes were purified by negative selection (Miltenyi Biotec) from heterologous PBMCs that had been activated 48, For Macrophage-to-T cell transmission, macrophages in 96-well plate and 24-well plate were infected with VSV-G-pseudotyped HIV-1 X4GFP
, 30 U/ml IL2. 25 µM AZT was added at 0 h (as a negative control) or 24 h after the beginning of the co-cultures, p.4
, PFA, permeabilized, stained with PE-Cy7 anti-CD3 (BD), and analyzed on a FACS Verse (BD)
, For Macrophage-to-MT4C5 cell transmission, macrophages were infected 96-well plate and 24-well plate with VSV-G-pseudotyped HIV-1 X4GFP, HIV-2 X4GFP, p.5
, HIV-2?Env X4GFP at MOI 1.5, washed extensively 8 h later and at day 3, when received
, The macrophages on 24-well plate were harvested for % of infected cells, and supernatant was harvested for gRNA and infectivity quantification. 25 µM AZT was added at 24 h after the beginning of the co-cultures, Data were analyzed using FlowJo v10 and Prism v7 for Mac
, Statistics Data were analyzed using using Prism v7 for Mac (GraphPad)
, On Figures 3, 4 and 5 P values were calculated using Kruskal-Wallis multiple comparison non-parametric test
, For experiments for which n was lower than 4 or uneven numbers on conditions statistics were not included due to lack of power. References Andersson, S
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, CD3+GFP+ T cells after co-culture with infected MDM (see in C), n=5 donors from 3 independent experiments with bars representing the mean
, Viral release at 3 dpi in the supernatant of infected MDM evaluated by RT-qPCR. (F) Infectivity of the released viruses was calculated as follows: rate of infection/ HIV RNA copies. (G) Infectivity normalized to HIV-1 for each donor
, EM micrograph of an epon section in the vicinity of HIV-2 X4 VSV-G-infected MDM. Released particles appear tethered. Arrowheads point at visible connections between viral particles. (B) Flow cytometry overlay histograms of BST-2 expression by MDMs infected or not with the indicated HIV. HIV-1 X4GFP-infected MDMs were used as a positive control and HIV-2 ROD9?EnvGFP-infected MDMs as a negative one, Figure 8 BST-2 expression in HIV-infected macrophages. (A)