@article{7314241b7919480fb207ef86fdfeceb6,
title = "Elicitation of cluster a and co-receptor binding site antibodies are required to eliminate HIV-1 infected cells",
abstract = "HIV-1-infected individuals raise a polyclonal antibody response targeting multiple envelope glycoprotein (Env) epitopes. Interestingly, two classes of non-neutralizing CD4-induced (CD4i) antibodies, present in the majority of HIV-1-infected individuals have been described to mediate antibody-dependent cellular cytotoxicity (ADCC) in the presence of small CD4 mimetic compounds (CD4mc). These antibodies recognize the coreceptor binding site (CoRBS) and the constant region one and two (C1C2 or inner domain cluster A) of the gp120. In combination with CD4mc they have been shown to stabilize an antibody-vulnerable Env conformation, known as State 2A. Here we evaluated the importance of these two families of Abs in ADCC responses by immunizing guinea pigs with gp120 immunogens that have been modified to elicit or not these types of antibodies. Underlying the importance of anti-CoRBS and anti-cluster A Abs in stabilizing State 2A, ADCC responses were only observed in the presence of these two types of CD4i antibodies. Altogether, our results suggest that these two families of CD4i antibodies must be taken into account when considering future strategies relying on the use of CD4mc to eliminate HIV-1-infected cells in vivo.",
keywords = "ADCC, Cluster A, Coreceptor binding site, Guinea pigs, HIV-1, Small CD4 mimetics",
author = "Guillaume Beaudoin-Bussi{\`e}res and J{\'e}r{\'e}mie Pr{\'e}vost and Gabrielle Gendron-Lepage and Bruno Melillo and Junhua Chen and Smith, {Amos B.} and Marzena Pazgier and Andr{\'e}s Finzi",
note = "Funding Information: This work was supported by a CIHR foundation grant #352417 and by NIH R01 AI150322 to A.F. This study was also supported by R01 AI129769 to M.P. and A.F., by P01-GM56550/AI150741 to A.B.S. and A.F. and by NIAID R01 AI116274 to M.P. A.F. is the recipient of a Canada Research Chair on Retroviral Entry # RCHS0235 950-232424. G.B.B is the recipient of an Excellence Scholarship from Universit{\'e} de Montr{\'e}al. J.P. is a recipient of a CIHR doctoral award. The funders had no role in study design, data collection, and analysis, decision to publish, or preparation of the manuscript. Funding Information: In conclusion, gp120core as immunogens fail to induce specific CD4i responses to both clusters A and CoRBS in guinea pig at the levels that in combination with CD4mc could induce effective killing of HIV-infected cells by ADCC. While gp120core immunizations afford induction of cluster A antibodies In conclusion, gp120core as immunogens fail to induce specific CD4i responses to both clusters A at the functional ADCC titer, the CoRBS specific response is low and insufficient to act synergistically and CoRBS in guinea pig at the levels that in combination with CD4mc could induce effective killing with cluster A antibodies and CD4mc to mediate ADCC. Augmentation of sera with extra doses of of HIV-infected cells by ADCC. While gp120core immunizations afford induction of cluster A CoRBS-specific antibody 17b is required, in the presence of CD4mc, to induce effective recognition antibodies at the functional ADCC titer, the CoRBS specific response is low and insufficient to act and killing of HIV-infected by cluster A antibodies present in immunized sera. Altogether, our data synergistically with cluster A antibodies and CD4mc to mediate ADCC. Augmentation of sera with indicate that strategies aimed at eliminating HIV-1-infected cells in the presence of CD4mc must take extra doses of CoRBS-specific antibody 17b is required, in the presence of CD4mc, to induce effective into account the presence/elicitation of these two families of CD4i antibodies. recognition and killing of HIV-infected by cluster A antibodies present in immunized sera. Altogether, our data indicate that strategies aimed at eliminating HIV-1-infected cells in the presence of CD4mc must take into account the presence/elicitation of these two families of CD4i antibodies. supplied novel reagents. G.B.-B, J.P. and A.F. wrote the paper. All authors have read, edited, and approved the Afinuatlhmora nCuosncrtripibt.uAtiollnasu:thoJ.rPs.haanvde rAea.dF.ancodnacgeirveedttohtehestpuudbyl.ishGe.Bd.vBe.,rsJi.oPn.,oafntdheAm.Fan.udsecsriigpnt.ed experimental approaches. G.B.B., J.P., G.G.L. and A.F. performed, analyzed, and interpreted the experiments. B.M., J.C., A.B.S. aTnhdis Mstu.Pd.yswupaspalilesdo snuopvpeolrrteedagbeyntRs0.1GA.BI1.B2,97J.6P9.taonMd .PA. .aFn.dwAro.Ft.e, btyheP0p1a-GpeMr.5 A65l5l0a/uAtIh1o5r0s7 4h1atvoeA r.eBa.Sd.,aendditAed.F,. and by NIAID R01 AI116274 to M.P. A.F. is the recipient of a Canada Research Chair on Retroviral Entry # RCHS0235 approved the final manuscript. 950-232424. G.B.B is the recipient of an Excellence Scholarship from Universit{\'e} de Montr{\'e}al. J.P. is a recipient of FauCnIHdiRngd:o Tchtoisra wl aowrkarwda. sT shuepfpuonrdteerdsbhya da nCoIHroRle foinusntduadtyiodne gsirgann,td #a3t5a2c4o1l7le acntido nb,ya nNdIHan Ra0ly1sAis,I1d5e0c3is2i2o ntot oAp.Fu.bTlihsihs, study was also supported by R01 AI129769 to M.P. and A.F., by P01-GM56550/AI150741 to A.B.S. and A.F. and Abyc kNnIoAwIDleRd0g1m AenI1t1s6: 2T74heto aMu.tPh.oArs.Ft.hisa nthke trheecipCiRenCtHofUaM CaFnlaodwa RCeysteoamrceht rCyhaanird onB RioestarfoevtyiraLl eEvnetlry3#LRaCbHorSa0t2o3ry5 9P5la0t-f2o3r2m42s4, .MGa.rBi.oBLise gthaeulrtefcoipriceonht oorftacno oErxdcienlaletinocne aSnchdocllairnsihcaipl sfarommplUesn,iavnedrsiCt{\'e}ocdaeliMcooBnitor{\'e}loagl.icJ.aPl.siIsn ac .refocirpgieunint eoaf a CIHR doctoral award. The funders had no role in study design, data collection, and analysis, decision to pCuobnlfilsihct,soorfpIrneptearreastti:oTn hoefrtehaer me nanoucsocnrifplitc.ts of interest to declare. The views expressed in this presentation are those of the authors and do not reflect the official policy or position of the Uniformed Services University, US Army, Acknowledgments: The authors thank the CRCHUM Flow Cytometry and Biosafety Level 3 Laboratory Platforms, Mario Legault for cohort coordination and clinical samples, and Cocalico Biologicals Inc. for guinea pig immunization. Publisher Copyright: {\textcopyright} 2020 by the authors. Licensee MDPI, Basel, Switzerland.",
year = "2020",
month = may,
doi = "10.3390/microorganisms8050710",
language = "English",
volume = "8",
journal = "Microorganisms",
issn = "2076-2607",
number = "5",
}