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, To detect transgene expression, 1 10 6 separated by 12% SDS-PAGE, transferred onto a PVDF membrane (Millipore), and detected by mouse anti-hemagglutinin (anti-HA) tag antibody (Sigma) and mouse anti-GAPDH antibody (Sigma) as a control. FACS analysis. To measure green fluorescent protein (GFP) expression, 1 10 5 mock-, rhTRIM5/GFP-, or GPI-VHH E4-or JM4-2A-BD LSRII flow cytometer (BD Biosciences), Number 23 Journal of Virology duced CEMss-CCR5 cells, or mock-and GPI-VHH E4-or JM4, vol.90, 2016.

, To analyze the capping of the CXCR4 coreceptor, mock-and GPI-VHH-JM4-or E4-transduced CEMss-poly-L-lysine (0.002%, wt/vol; Sigma) in H 2 O 2 for 2 min and stained with anti-CXCR4 antibody (R&D Systems; MAB172 at 10 g/ml) for 30 min and Alexa 488-conjugated anti-mouse IgG Fc antibody (Invitrogen) for 30 min. Cells were then permeabilized in PBS containing 1% BSA and 0.15% Triton X-100 and stained with Alexa 647-conjugated phalloidin (Invitrogen), Intracellular HIV-1 Gag p24 was stained as described before (15). analyzed by FACS Fortessa (BD Biosciences) using FlowJo and GraphPad Prism software. Immunofluorescence staining and confocal analysis. Mock-and GPI-VHH E4-, JM2-, or JM4-transduced TZM.bl cells were seeded, pp.92-975

A. Yu2, J. , P. Thro, and C. Rejo, one of molecular clones of HIV-1 transmitted founder viruses WITO

, In a single-cycle assay, 1 10 4 TZM.bl cells mock transduced or transduced with pRRL-VHH E4, JM2, or JM4/ hinge/his-tag/DAF-, and pRRL-VHH E4, vol.2, p.4

. Bru-3, . Bru-yu2, J. Ad8, and P. , HIV-1 transmitted founder viruses WITO, CH040, THRO, REJO, CH077, and CH106, and SIV strain the manufacturer's instructions (Promega)

, To test the effect of GPI-VHH JM4 on cell-free HIV-1 infection, 1 10 6 GPI-VHH JM4-or E4-transduced CEMss-CCR5 cells were infected with HIV-1 strains Bru-3, Bru-Yu2, Cell-free HIV-1 infection and p24 assay, vol.8, p.4

, HIV-1 Inhibition by GPI-Anchored VHH JM4

, For the comparison, JRCSF-infected donor cells and uninfected CEMss-CCR5-rhTRIM5/GFP cells or CEMss-CCR5

, which JRCSF-infected donor cells added to the Transwell insert and uninfected CEMss-CCR5

V. Targeting and . Jm2, To generate GPI-anchored and secreted VHH, the sequences encoding VHH from the heavy chain-only antibodies E4, JM2, and JM4 were genetically linked inserted into a third-generation lentiviral vector, pRRLsin-18.PPT.hPGK.Wpre (Fig. 1A). The recombinant viruses were then generated and used to transduce TZM.bl, CEMss-CCR5, JM4, and E4 to the lipid rafts of the plasma membrane through a GPI anchor

, To localize GPI-VHH, mock-and GPI-VHH E4-, JM2-, or JM4-transduced TZM.bl cells were seeded onto a glass slide and costained with (i) anti-his tag antibody followed by Alexa 488-conjugated anti-mouse IgG antibody, (ii) Alexa 555-conjugated cholera toxin subunit B (CtxB), and (iii) DAPI. CtxB interacts with GM1 (a lipid raft marker). Figure 1D shows that GPI-VHH E4, JM2, or JM4 is colocalized with GM1 on cell surface, indicating that it is located in the lipid rafts of the plasma membrane, GPI-VHH JM4 in transduced TZM.bl cells exhibits a remarkable degree of breadth and potency against HIV-1. Next, we compared CD4, CCR5, and CXCR4 expression in Sec-VHH-and GPI-VHH E4-, JM2-, or JM4-transduced TZMneutralization activity of Sec-VHH and GPI-VHH E4, JM2, and JM4 against cell-free HIV-1A (Q168 and Q461ENVe2), subtype B (Yu2, AD8, JRFL, SF162, HxBc2, consensus B, PVO.4, and QH0692.42), subtype B= (CNE11), subtype C (consensus C and 92BR025.9

, and Q461ENV2e pseudotypes, respectively, over 99% neutralization activity was detected against all other 19 HIV-1 pseudotypes. For the comparison, none of the transduced TZM

, Schematic diagram of the lentiviral vectors pRRL-VHH/hinge/his-tag and pRRL-VHH/ hinge/his-tag/DAF. VHHs were derived from llama heavy chain-only antibodies E4, JM2, and JM4. Hinge, a human IgG3 hinge region, FIG 1 Expression of GPI-VHH and Sec-VHH in transduced TZM.bl cells. (A)

, GPI-VHH, GPI-anchored VHH; Sec-VHH, secreted VHH; anti-his, anti-his tag antibody; SN, supernatants; CL, cell lysates. (C) FACS analysis of cell surface expression of GPI-VHH E4, JM2, and JM4 in mock-or VHH/hinge/his-tag/DAF-transduced TZM.bl cells with or without PI-PLC treatment. Red, mock-transduced cells stained with anti-his tag antibody; blue, VHH E4, JM2, or JM4/hinge/his-tag/DAF-transduced cells without PI-PLC treatment stained with anti-his tag antibody; yellow, VHH E4, JM2, or JM4/hinge/his-tag/DAF-transduced cells with PI-PLC treatment stained with anti-his tag antibody. (D) Confocal analysis of mock or pRRL-VHH/hinge/his-tag/DAF-transduced TZM.bl cells. CtxB, cells were stained with Alexa 555-conjugated cholera toxin B subunit; anti-his, cells were stained with mouse anti-his tag antibody followed by Alexa 488, DAF, the C-terminal 34 amino acid residues of decay-accelerating factor. (B) Western blot analysis of VHH E4, JM2, and JM4 in TZM.bl cells transduced with VHH/hinge/his-tag and VHH/hinge/his-tag/DAF

, Summary of mean and median fluorescence intensities of CD4, CCR5, and CXCR4 expression in mock-transduced and GPI-VHH and Sec-VHH E4-, JM2-, and JM4-transduced TZM.bl cells. (B) Neutralization by GPI-VHH and Sec-VHH E4, JM2, and JM4 against HIV-1 and VSV-G pseudotypes. The numbers represent the percent inhibition, which was calculated as follows: (RLA in virus alone to a given transduced cell RLA in no virus to the same transduced cell)/(RLA in virus alone to parental cells RLA in no virus to parental cell). (C and D) Purified soluble CD4 (sCD4) and soluble VHH (sVHH) JM4 (lane 2) and E4 (lane 3) revealed by SDS-PAGE followed by Coomassie blue staining (C) or Western blotting (D). (E) Determination of the highest concentrations of sCD4 that did not have an inhibitory effect by itself on a given HIV-1 strain (highlighted in red). These sCD4 concentrations were used in the coculture assay with sVHH JM4 and E4. (F) The neutralization activity of various indicated concentrations of sVHH JM2 and JM4 in the presence or absence of sCD4 on infectivity of HIV-1 and VSV-G pseudotypes. The numbers represent the percent inhibition, based on the calculation described above, Number 23 jvi.asm.org 10647 Journal of Virology FIG 2 Neutralization by GPI-VHH and Sec-VHH JM2 and JM4 in transduced TZM.bl cells against HIV-1 or VSV-G pseudotypes using a single-cycle infectivity assay. (A), vol.90, 2016.

S. Gpi-vhh-and, A. , J. , P. Wito, . Ch040 et al., HKU004, and HKU1447 along with an SIV control, SIVMne027 (40), in a single-round infecof 99%. In contrast, TZM.bl cells transduced with GPI-VHH E4 or Sec-VHH E4 had no significant neutralization activity. Interestingly, TZM.bl cells transduced with GPI-VHH JM2 or Sec-VHH JM2 and JM4 exhibited moderate neutralization (ranging from 51 to 81% inhibition) against a few HIV-1 strains (Bru-3, Mj4, THRO, CH040, and CH077). Thus, taken together, these results clearly show that TZM.bl cells transduced with GPI-VHH JM4 exhibit remarkable desdAb JM4. GPI-VHH JM4-transduced CEMss-CCR5 cells completely vectors expressing GPI-VHH E4 or JM4. Importantly, both GPI-VHH E4 and JM4 are expressed at high levels on transduced CEMss-CCR5 cells (Fig. 3A and B), and no significant difference in CD4, CCR5, and CXCR4 expression was observed in GPI-VHH E4-and JM4-transduced CEMss-CCR5 cells compared to that in mock-transduced CEMss-CCR5 cells (Fig. 3C). Importantly, when stimulated with 100 ng/ml of SDF1, mock-and GPI-VHH E4-and JM4-transduced CEMss-CCR5 cells exhibited comparable levels of migration (chemotaxis) (Fig. 3D) as well as capping activities (Fig. 3E), indicating that the functions of CXCR4 coreceptor are not impaired due to the lipid raft expression of GPI-VHHs. Mock-and GPI-VHH E4-and JM4-transduced CEMss-CCR5 cells were then, sCD4. To test if GPI-VHH JM4-transduced TZM.bl cells are resistant to replication competent HIV-1 infection

, CCR5, and CXCR4 expression (Fig. 4C), it significantly blocks cell-free HIV-1 (Fig. 4D) but not cell-cell transmission of HIV-1

, To test if GPI-VHH JM4 blocks T cell-T cell transmission of HIV-1

, Neutralization activity of GPI-VHH JM4 in transduced CEMss-CCR5 cells to replication-competent HIV-1. (A) Western blot analysis of mock-and GPI-VHH E4 or JM4-transduced CEMss-CCR5 cells. Anti-his tag, anti-his tag antibody

. Sn and . Cl, Summary of mean and median fluorescence intensities of CD4, CCR5, and CXCR4 expression in mock-and GPI-VHH E4-and JM4-transduced CEMss-CCR5 cells. (D) Chemotaxis of mock-and GPI-VHH E4-or JM4-transduced CEMss-CCR5 cells to SDF1. Cells were loaded onto the upper chamber of a 5-m Transwell filter, whereas medium containing SDF1 was added in the lower chamber, Expression of GPI-VHH E4 and JM4 on the surface of transduced CEMss-CCR5 cells. (Left) Mock-and GPI-VHH E4-transduced CEMss-CCR5 cells; (right) mock-and GPI-VHH JM4-transduced CEMss-CCR5 cells. (C)

G. Gpi-vhh-e4 and . E4,

. Liu, As expected, no cell-cell HIV-1 transmission was observed in coculture between mock-, GFP-GPI-VHH E4-, or JM4-transduced CEMss-CCR5-rhTRIM5/GFP and HIV-1 JRCSF-infected cells in a Transwell plate (Fig. 5B). A similar pattern of cell-cell HIV-1 transmission was observed at 12 days postcoculture (Fig. 5C). For comparison, we also did intracellular Gag staining in coculture between CEMss-CCR5-rhTRIM5/GFP cells and JRCSFsoluble VHH JM4, HIV-1 transmission was moderately reduced, to 28.7% and 14.2%, respectively, in coculture between JRCSF-infected CEMss-CCR5 donor cells and CEMss-CCR5-rhTRIM5/GFP cells (rightmost and middle right images). The experiment was repeated three times, with similar results. Thus, taken together, these results indicate of rhesus TRIM5 on cell-free and cell-cell transmission of HIV-1. (A) Schematic diagram of the lentiviral vector MND-rhTRIM5-IRES-GFP. In this vector the rhTRIM5-IRES-GFP was driven by an internal MND promoter. (B) Western blot analysis of mock-and rhTRIM5-IRES-GFP-transduced CEMss-CCR5 cells (lanes 1 and 2) as well as GPI-VHH E4 or JM4-transduced CEMss-CCR5-rhTRIM5-IRES-GFP cells (lanes 3 and 4), No significant difference in CD4, CCR5, and CXCR4 expression was observed in CEMss-CCR5-rhTRIM5/GFP-GPI-VHH E4 and JM4 cells compared to CEMss-CCR5-rhTRIM5/ GFP cells (Fig. 4C). GPI-VHH E4-or JM4-transduced CEMss--or GFP-GPI-VHH E4-transduced CEMss-CCR5-rhTRIM5/GFP cells and HIV-1 JRCSF-infected cells (middle left and middle right images), vol.90, 2016.

, JRCSF-infected donor cells was significantly lower, similar to the case with HIV-1 JRCSF-infected donor cells alone (Fig. 5E)

, significant HIV-1 envelope-mediated cell-cell fusion (on average, there were 40 and 41 syncytia per picture, respectively) was observed in cocultures between CEMss-CCR5-rhTRIM5/GFP or CEMss-CCR5-rhTRIM5/GFP-GPI-VHH E4 cells and HIV-1 JRCSF-infected cells (Fig. 6A and D, middle left and middle right images). In contrast, no HIV-1 envelopemediated cell-cell fusion was observed in cocultures between GPI-VHH JM4-transduced CEMss-CCR5-rhTRIM5/GFP cells and HIV-1 JRCSF-infected donor cells (Fig. 6A and D, rightmost image). As expected, no cell-cell fusion was observed in coculture between CEMss-CCR5-rhTRIM5/GFP cells and HIV-1 JRCSFinfected cells in a Transwell plate (Fig. 6B). For comparison, we also recorded cell-cell fusion, GPI-VHH JM4 completely blocks HIV-1 envelope-mediated and uninfected donor cells (Fig. 6A, leftmost image), vol.10, p.40

, In contrast, coculture between JRCSF-infected CEMss-CCR5 donor cells and CEMss-CCR5-rhTRIM5/ be efficiently transduced with GPI-VHH JM4 or E4 and, if so, whether GPI-VHH JM4-transduced human primary CD4 T cells could efficiently resist cell-free and T cell-T cell transmission of HIV-1. To facilitate monitoring of transduced human primary CD4 T cells, we inserted genes encoding GPI-VHH JM4 or E4 into the pRRLsin-18.PPT.EF10.2A.GFP.Wpre (31). The resulting pRRL-GPI-VHH JM4 or E4-2A-GFP transfer vectors (Fig. 7A) were used to produce recombinant lentiviruses. The latter were used to transduce human primary CD4 T cells. Figure 7B shows that after a single round of transduction, over 80% of human primary CD4 T cells became transgene positive as measured by GFP and GPI-VHH JM4, g/ml of sVHH E4 and JM4 (Fig. 6C and D). Coculture between JRCSF-infected CEMss-CCR5 donor cells and CEMss-44, respectively) (Fig. 6C and D, leftmost and middle left images)

, Same coculture as in panel A but using Transwell plates. (C) Same coculture as in panel A but with day 12 coculture samples. (D) GFP Gag cells in coculture between HIV-1 JRCSF-infected CEMss-CCR5 and rhTRIM5/GFP-transduced CEMss-CCR5 cells in the presence of 40 and 10 g/ml of sVHH E4 (far left and middle left) and GFP Gag cells, GFP Gag cells in coculture between HIV-1 JRCSF-infected CEMss-CCR5 and GPI-VHH E4-transduced CEMss-CCR5-rhTRIM5/GFP cells (middle right), and GFP Gag cells in coculture between HIV-1 JRCSF-infected CEMss-CCR5 and GPI-VHH JM4-transduced CEMss-CCR5-rhTRIM5/GFP cells (far right). (B), vol.40, p.10

, g/ml of soluble JM4 (middle right and far right). (E) HIV-1 replication measured by Gag p24 in coculture supernatants between HIV-1 JRCSF-infected CEMss-CCR5 and rhTRIM5/GFP-transduced CEMss-CCR5 cells and between HIV-1 JRCSF-infected CEMss-CCR5 and GPI-VHH E4-or JM4-transduced CEMss-CCR5-rhTRIM5/GFP cells, along with HIV-1 JRCSF

, HIV-1 Inhibition by GPI-Anchored VHH JM4

, dramatic cell-cell fusion in coculture between HIV-1 JRCSF-infected CEMss-CCR5 and GPI-VHH E4-transduced CEMss-CCR5-rhTRIM5/GFP cells (middle right), and absence of cell-cell fusion in coculture between HIV-1 JRCSF-infected CEMss-CCR5 and GPI-VHH JM4-transduced CEMss-CCR5-rhTRIM5/GFP cells (far right). (B) Same fusion assay as in panel A but using Transwell plates. (C) Dramatic cell-cell fusion in coculture between HIV-1 JRCSF-infected CEMss-CCR5 and rhTRIM5/GFP-transduced CEMss-CCR5 cells in the presence of 40 and 10 g/ml of sVHH E4 (far left and middle left) and moderate reduction in cell-cell fusion in coculture between HIV-1 JRCSF-infected CEMss-CCR5 and rhTRIM5/GFP-transduced CEMss-CCR5 cells in the presence of 40 and 10 g/ml of soluble JM4 (middle right and far right). (D) Mean and standard deviation (SD) of the number of syncytia in coculture between HIV-1 JRCSF-infected CEMss-CCR5 and mock-transduced CEMss-CCR5-rhTRIM5/GFP cells (red bar), between HIV-1 JRCSF-infected CEMss-CCR5 and GPI-VHH E4-transduced CEMss-CCR5-rhTRIM5/GFP cells (brown bar); between HIV-1 JRCSF-infected CEMss-CCR5 and GPI-VHH JM4-transduced CEMss-CCR5-rhTRIM5/GFP cells (gray bar), between HIV-1 JRCSF-infected CEMss-CCR5 and rhTRIM5/GFP-transduced CEMss-CCR5 cells in the presence of 40 g/ml of sVHH E4 (yellow bar), Number 23 jvi.asm.org 10653 Journal of Virology FIG 6 GPI-VHH JM4-transduced CEMss-CCR5-rhTRIM/GFP are resistant to HIV-1 envelope-mediated cell-cell fusion. (A) Absence of cell-cell fusion in coculture between uninfected CEMss-CCR5 and rhTRIM5/GFP-transduced CEMss-CCR5 cells (far left), dramatic cell-cell fusion in coculture between HIV-1 JRCSF-infected CEMss-CCR5 and rhTRIM5/GFP-transduced CEMss-CCR5 cells (middle left), vol.90, 2016.

. Liu, Sewald et al. showed that in secondary lymph tissues, HIV-1 and murine leukemia virus (MLV) are captured by sinus-lining macrophages via CD169. MLV-captured by macrophages can then trans-infect B-1 cells. Infected B-1 cells then migrate into the lymph node to spread the infection through virological synapses (44). HIV-1 transmission from infected T cells to uninfected T cells occurs via virological synapses (4). The formation of such structures allows the coordination of viral assembly with viral entry at sites of cell-cell contacts, Number 23 Journal of Virology systemic HIV-1 infection, vol.90, 2016.

, As a result, T cell-T cell transmission of HIV-1 is much more efficient for spreading virus and is much less susceptible to neutralizing antibodies and entry inhibitors than cell-free HIV-1, vol.8, pp.10-14

, Schematic diagram of transducing human CD4 T cells with lentiviral vectors expressing GPI-VHH E4 or JM4, establishing HIV-1 AD8-or Bru-3-infected Jurkat cells; coculture between infected or uninfected Jurkat cells, and GPI-VHH JM4-or E4-transduced human primary CD4 T cells. (B) Representative gating of Gag GFP cells in human primary CD4 T cells transduced with GPI-VHH JM4 (right) or E4 (middle) cocultured with HIV-1 Bru-3-infected Jurkat cells at 6 days postcoculture along with uninfected mock-transduced control cells (left). (C) Summary of percentages of Gag GFP cells at 3, 6, and 9 days postinfection of coculture between GPI-VHH E4-or JM4, FIG 8 GPI-VHH JM4-transduced human primary CD4 T cells are resistant to cell-cell transmission of HIV-1. (A)

M. Bru-3,-ad8, ;. Yu2, . Wito, . Ch040, and R. Thro, R-E-transfer vector, and DNA plasmids encoding Q168, Q461ENVe2, Yu2, AD8, JRFL, SF162, HxBc2, PVO.4, QH0692.42, 92BR025.9, 93TH966.8, and 92UG975.10 envelope proteins were obtained through the AIDS Research and Reference Reagent Program, Division of AIDS, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Germantown, MD. The relevant reagents were originally developed and contributed by, pp.4-7

B. H. Shaw and . Hahn, This work was supported by research grants from the Chinese National Natural Science Foundation (number 31170871) and the National Science and Technology Major Project (number 2014ZX10001-001) to P.Z.; by research grants from the National Institutes of Health (R56 AI108467 to, J.T.K.) and the Baylor-UTHouston CFAR, issue.P30AI036211

, National Natural Science Foundation-National Institutes of Health joint grant (number 81361120406-R01 AI106574) to P.Z. and J.T.K.; by a Chinese National Natural Science Foundation-Hong Kong RGC joint grant (number 81161160569-N_HKU709/11) to P.Z. and Z.C.; and by research grants from the French National Agency for AIDS Research to, obtained a Visiting Professorship from the Chinese Academy of Sciences (number 2012T1S0024 and number, 2016062.

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