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Title: Boosting of HIV envelope CD4 binding site antibodies with long variable heavy third complementarity determining region in the randomized double blind RV305 HIV-1 vaccine trial

Authors:
ORCiD logo; ORCiD logo; ORCiD logo; ORCiD logo; ; ORCiD logo; ; ; ; ; ORCiD logo; ; ; ORCiD logo; ORCiD logo; ; ; ; ; more »; ; ORCiD logo; ; ORCiD logo; ; ; ; ; ; ORCiD logo; ; ; « less
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
OTHER
OSTI Identifier:
1430312
Resource Type:
Journal Article
Resource Relation:
Journal Name: PLoS Pathogens; Journal Volume: 13; Journal Issue: 2
Country of Publication:
United States
Language:
ENGLISH

Citation Formats

Easterhoff, David, Moody, M. Anthony, Fera, Daniela, Cheng, Hao, Ackerman, Margaret, Wiehe, Kevin, Saunders, Kevin O., Pollara, Justin, Vandergrift, Nathan, Parks, Rob, Kim, Jerome, Michael, Nelson L., O’Connell, Robert J., Excler, Jean-Louis, Robb, Merlin L., Vasan, Sandhya, Rerks-Ngarm, Supachai, Kaewkungwal, Jaranit, Pitisuttithum, Punnee, Nitayaphan, Sorachai, Sinangil, Faruk, Tartaglia, James, Phogat, Sanjay, Kepler, Thomas B., Alam, S. Munir, Liao, Hua-Xin, Ferrari, Guido, Seaman, Michael S., Montefiori, David C., Tomaras, Georgia D., Harrison, Stephen C., Haynes, Barton F., and Douek, Daniel C. Boosting of HIV envelope CD4 binding site antibodies with long variable heavy third complementarity determining region in the randomized double blind RV305 HIV-1 vaccine trial. United States: N. p., 2017. Web. doi:10.1371/journal.ppat.1006182.
Easterhoff, David, Moody, M. Anthony, Fera, Daniela, Cheng, Hao, Ackerman, Margaret, Wiehe, Kevin, Saunders, Kevin O., Pollara, Justin, Vandergrift, Nathan, Parks, Rob, Kim, Jerome, Michael, Nelson L., O’Connell, Robert J., Excler, Jean-Louis, Robb, Merlin L., Vasan, Sandhya, Rerks-Ngarm, Supachai, Kaewkungwal, Jaranit, Pitisuttithum, Punnee, Nitayaphan, Sorachai, Sinangil, Faruk, Tartaglia, James, Phogat, Sanjay, Kepler, Thomas B., Alam, S. Munir, Liao, Hua-Xin, Ferrari, Guido, Seaman, Michael S., Montefiori, David C., Tomaras, Georgia D., Harrison, Stephen C., Haynes, Barton F., & Douek, Daniel C. Boosting of HIV envelope CD4 binding site antibodies with long variable heavy third complementarity determining region in the randomized double blind RV305 HIV-1 vaccine trial. United States. doi:10.1371/journal.ppat.1006182.
Easterhoff, David, Moody, M. Anthony, Fera, Daniela, Cheng, Hao, Ackerman, Margaret, Wiehe, Kevin, Saunders, Kevin O., Pollara, Justin, Vandergrift, Nathan, Parks, Rob, Kim, Jerome, Michael, Nelson L., O’Connell, Robert J., Excler, Jean-Louis, Robb, Merlin L., Vasan, Sandhya, Rerks-Ngarm, Supachai, Kaewkungwal, Jaranit, Pitisuttithum, Punnee, Nitayaphan, Sorachai, Sinangil, Faruk, Tartaglia, James, Phogat, Sanjay, Kepler, Thomas B., Alam, S. Munir, Liao, Hua-Xin, Ferrari, Guido, Seaman, Michael S., Montefiori, David C., Tomaras, Georgia D., Harrison, Stephen C., Haynes, Barton F., and Douek, Daniel C. Fri . "Boosting of HIV envelope CD4 binding site antibodies with long variable heavy third complementarity determining region in the randomized double blind RV305 HIV-1 vaccine trial". United States. doi:10.1371/journal.ppat.1006182.
@article{osti_1430312,
title = {Boosting of HIV envelope CD4 binding site antibodies with long variable heavy third complementarity determining region in the randomized double blind RV305 HIV-1 vaccine trial},
author = {Easterhoff, David and Moody, M. Anthony and Fera, Daniela and Cheng, Hao and Ackerman, Margaret and Wiehe, Kevin and Saunders, Kevin O. and Pollara, Justin and Vandergrift, Nathan and Parks, Rob and Kim, Jerome and Michael, Nelson L. and O’Connell, Robert J. and Excler, Jean-Louis and Robb, Merlin L. and Vasan, Sandhya and Rerks-Ngarm, Supachai and Kaewkungwal, Jaranit and Pitisuttithum, Punnee and Nitayaphan, Sorachai and Sinangil, Faruk and Tartaglia, James and Phogat, Sanjay and Kepler, Thomas B. and Alam, S. Munir and Liao, Hua-Xin and Ferrari, Guido and Seaman, Michael S. and Montefiori, David C. and Tomaras, Georgia D. and Harrison, Stephen C. and Haynes, Barton F. and Douek, Daniel C.},
abstractNote = {},
doi = {10.1371/journal.ppat.1006182},
journal = {PLoS Pathogens},
number = 2,
volume = 13,
place = {United States},
year = {Fri Feb 24 00:00:00 EST 2017},
month = {Fri Feb 24 00:00:00 EST 2017}
}
  • Highlights: Black-Right-Pointing-Pointer Some recombinant HIV-1 gp120s do not preserve their conformations on gp140s. Black-Right-Pointing-Pointer We hypothesize that CD4i antibodies could induce conformational changes in gp120. Black-Right-Pointing-Pointer CD4i antibodies enhance binding of CD4 and CD4bs antibodies to gp120. Black-Right-Pointing-Pointer CD4i antibody-gp120 fusion proteins could have potential as vaccine immunogens. -- Abstract: Development of successful AIDS vaccine immunogens continues to be a major challenge. One of the mechanisms by which HIV-1 evades antibody-mediated neutralizing responses is the remarkable conformational flexibility of its envelope glycoprotein (Env) gp120. Some recombinant gp120s do not preserve their conformations on gp140s and functional viral spikes, and exhibitmore » decreased recognition by CD4 and neutralizing antibodies. CD4 binding induces conformational changes in gp120 leading to exposure of the coreceptor-binding site (CoRbs). In this study, we test our hypothesis that CD4-induced (CD4i) antibodies, which target the CoRbs, could also induce conformational changes in gp120 leading to better exposed conserved neutralizing antibody epitopes including the CD4-binding site (CD4bs). We found that a mixture of CD4i antibodies with gp120 only weakly enhanced CD4 binding. However, such interactions in single-chain fusion proteins resulted in gp120 conformations which bound to CD4 and CD4bs antibodies better than the original or mutagenically stabilized gp120s. Moreover, the two molecules in the fusion proteins synergized with each other in neutralizing HIV-1. Therefore, fusion proteins of gp120 with CD4i antibodies could have potential as components of HIV-1 vaccines and inhibitors of HIV-1 entry, and could be used as reagents to explore the conformational flexibility of gp120 and mechanisms of entry and immune evasion.« less
  • The HIV-1 envelope glycoprotein (Env) undergoes conformational transitions consequent to CD4 binding and coreceptor engagement during viral entry. The physical steps in this process are becoming defined, but less is known about their significance as targets of antibodies potentially protective against HIV-1 infection. Here we probe the functional significance of transitional epitope exposure by characterizing 41 human mAbs specific for epitopes exposed on trimeric Env after CD4 engagement. These mAbs recognize three epitope clusters: cluster A, the gp120 face occluded by gp41 in trimeric Env; cluster B, a region proximal to the coreceptor-binding site (CoRBS) and involving the V1/V2 domain;more » and cluster C, the coreceptor-binding site. The mAbs were evaluated functionally by antibody-dependent, cell-mediated cytotoxicity (ADCC) and for neutralization of Tiers 1 and 2 pseudoviruses. All three clusters included mAbs mediating ADCC. However, there was a strong potency bias for cluster A, which harbors at least three potent ADCC epitopes whose cognate mAbs have electropositive paratopes. Cluster A epitopes are functional ADCC targets during viral entry in an assay format using virion-sensitized target cells. In contrast, only cluster C contained epitopes that were recognized by neutralizing mAbs. There was significant diversity in breadth and potency that correlated with epitope fine specificity. In contrast, ADCC potency had no relationship with neutralization potency or breadth for any epitope cluster. In conclusion, Fc-mediated effector function and neutralization coselect with specificity in anti-Env antibody responses, but the nature of selection is distinct for these two antiviral activities.« less