TY - JOUR
T1 - Vaccine Induction of Antibodies against a Structurally Heterogeneous Site of Immune Pressure within HIV-1 Envelope Protein Variable Regions 1 and 2
AU - Liao, Hua Xin
AU - Bonsignori, Mattia
AU - Alam, S. Munir
AU - McLellan, Jason S.
AU - Tomaras, Georgia D.
AU - Moody, M. Anthony
AU - Kozink, Daniel M.
AU - Hwang, Kwan Ki
AU - Chen, Xi
AU - Tsao, Chun Yen
AU - Liu, Pinghuang
AU - Lu, Xiaozhi
AU - Parks, Robert J.
AU - Montefiori, David C.
AU - Ferrari, Guido
AU - Pollara, Justin
AU - Rao, Mangala
AU - Peachman, Kristina K.
AU - Santra, Sampa
AU - Letvin, Norman L.
AU - Karasavvas, Nicos
AU - Yang, Zhi Yong
AU - Dai, Kaifan
AU - Pancera, Marie
AU - Gorman, Jason
AU - Wiehe, Kevin
AU - Nicely, Nathan I.
AU - Rerks-Ngarm, Supachai
AU - Nitayaphan, Sorachai
AU - Kaewkungwal, Jaranit
AU - Pitisuttithum, Punnee
AU - Tartaglia, James
AU - Sinangil, Faruk
AU - Kim, Jerome H.
AU - Michael, Nelson L.
AU - Kepler, Thomas B.
AU - Kwong, Peter D.
AU - Mascola, John R.
AU - Nabel, Gary J.
AU - Pinter, Abraham
AU - Zolla-Pazner, Susan
AU - Haynes, Barton F.
N1 - Funding Information:
This study was supported by Collaboration for AIDS Vaccine Discovery grants from Bill & Melinda Gates Foundation, by grants from NIH/NIAID (AI067854, the Center for HIV/AIDS Vaccine Immunology, and AI100645, the Center for HIV/AIDS Vaccine Immunology-Immunogen Discovery), by research funds from the Department of Veterans Affairs, by an Interagency Agreement Y1-AI-2642-12 between U.S. Army Medical Research and Material Command (USAMRMC), by a cooperative agreement (W81XWH-07-2-0067) between the Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc. and the U.S. Department of Defense (DOD), and by intramural NIH support for the NIAID Vaccine Research Center. The authors thank A. Foulger, H. Chen, M. Cooper, S. Crawford, J. Holland, R. De, R. Scearce, L. Jeffries, Jr., A. Hogan, J. Pritchett, D. Pause, E. Solomon, L. Sutherland, J. Blinn, and K. Lloyd for expert technical assistance in antibody and HIV-1 Env protein production; D. Marshall and J. Whitesides for expert technical assistance in flow cytometry; and K. Soderberg, J. Kircherr, and C. Andrews for project management. Flow cytometry supported by NIH grants S10RR019145, UC6 AI058607, AI64518, and P30 AI051445. The opinions herein are those of the authors and should not be construed as official or representing the views of the U.S. Department of Health and Human Services, National Institute for Allergy and Infectious Diseases, the Department of Defense, the Department of the Army, or the Department of Veteran Affairs. Materials from the RV144 clinical trial were provided by the Ministry of Public Health, Thailand, the Thai AIDS Vaccine Evaluation Group, and the USMHRP through the Henry M. Jackson Foundation for the Advancement of Military Medicine. H.-X.L., M.B., S.M.A., J.H.K., N.L.M., T.B.K., S.Z.-P., and B.F.H. have filed partent applications on the RV144 V2 mAbs and related antigens used in this study.
PY - 2013/1/24
Y1 - 2013/1/24
N2 - The RV144 HIV-1 trial of the canary pox vector (ALVAC-HIV) plus the gp120 AIDSVAX B/E vaccine demonstrated an estimated efficacy of 31%, which correlated directly with antibodies to HIV-1 envelope variable regions 1 and 2 (V1-V2). Genetic analysis of trial viruses revealed increased vaccine efficacy against viruses matching the vaccine strain at V2 residue 169. Here, we isolated four V2 monoclonal antibodies from RV144 vaccinees that recognize residue 169, neutralize laboratory-adapted HIV-1, and mediate killing of field-isolate HIV-1-infected CD4+ T cells. Crystal structures of two of the V2 antibodies demonstrated that residue 169 can exist within divergent helical and loop conformations, which contrasted dramatically with the β strand conformation previously observed with a broadly neutralizing antibody PG9. Thus, RV144 vaccine-induced immune pressure appears to target a region that may be both sequence variable and structurally polymorphic. Variation may signal sites of HIV-1 envelope vulnerability, providing vaccine designers with new options.
AB - The RV144 HIV-1 trial of the canary pox vector (ALVAC-HIV) plus the gp120 AIDSVAX B/E vaccine demonstrated an estimated efficacy of 31%, which correlated directly with antibodies to HIV-1 envelope variable regions 1 and 2 (V1-V2). Genetic analysis of trial viruses revealed increased vaccine efficacy against viruses matching the vaccine strain at V2 residue 169. Here, we isolated four V2 monoclonal antibodies from RV144 vaccinees that recognize residue 169, neutralize laboratory-adapted HIV-1, and mediate killing of field-isolate HIV-1-infected CD4+ T cells. Crystal structures of two of the V2 antibodies demonstrated that residue 169 can exist within divergent helical and loop conformations, which contrasted dramatically with the β strand conformation previously observed with a broadly neutralizing antibody PG9. Thus, RV144 vaccine-induced immune pressure appears to target a region that may be both sequence variable and structurally polymorphic. Variation may signal sites of HIV-1 envelope vulnerability, providing vaccine designers with new options.
UR - http://www.scopus.com/inward/record.url?scp=84872809067&partnerID=8YFLogxK
U2 - 10.1016/j.immuni.2012.11.011
DO - 10.1016/j.immuni.2012.11.011
M3 - Article
C2 - 23313589
AN - SCOPUS:84872809067
SN - 1074-7613
VL - 38
SP - 176
EP - 186
JO - Immunity
JF - Immunity
IS - 1
ER -