US Department of Defense

 

Authors

S. Munir Alam, Duke University Medical CenterFollow
Hua-Xin Liao, Duke University Medical Center
Georgia D. Tomaras, Duke University Medical Center
Mattia Bonsignori, Duke University Medical Center
Chun-Yen Tsao, Duke University Medical Center
Kwan-Ki Hwang, Duke University Medical Center
Hiayan Chen, Duke University Medical Center
Krissey E. Lloyd, Duke University Medical Center
Cindy Bowman, Duke University Medical Center
Laura Sutherland, Duke University Medical Center
Thomas L. Jeffries Jr., Duke University Medical Center
Daniel M. Kozink, Duke University Medical Center
Shelley Stewart, Duke University Medical Center
Kara Anasti, Duke University Medical Center
Frederick H. Jaeger, Duke University Medical Center
Robert Parks, Duke University Medical Center
Nicole L. Yates, Duke University Medical Center
R. Glenn Overman, Duke University Medical Center
Faruk Sinangil, Global Solutions For Infectious Diseases
Phillip W. Berman, University of California - Santa Cruz
Punnee Pitisuttithum, Duke University Medical Center
Jaranit Kaewkungwal, Mahidol University
Sorachai Nitayaphan, Armed Forces Institute of Medical Sciences
Nicos Karasavva, Armed Forces Institute of Medical Sciences
Supachai Rerks-Ngarm, Ministry of Public Health
Jerome H. Kim, Walter Reed Army Institute of Research
Nelson L. Michael, Walter Reed Army Institute of Research
Susan Zolla-Pazner, New York University School of Medicine
Sampa Santra, Beth Israel Deaconess Medical Center
Norman L. Letvin, Beth Israel Deaconess Medical Center
Stephen C. Harrison, Howard Hughes Medical Institute
Barton F. Haynes, Duke University Medical CenterFollow

Date of this Version

2013

Citation

Published in Journal of Virology (2013) 87(3): 1554-1568. DOI:10.1128/JVI.00718-12

Abstract

An immune correlates analysis of the RV144 HIV-1 vaccine trial revealed that antibody responses to the gp120 V1/V2 region correlated inversely with infection risk. The RV144 protein immunogens (A244-rp120 and MN-rgp120) were modified by an N-terminal 11-amino-acid deletion (Δ11) and addition of a herpes simplex virus (HSV) gD protein-derived tag (gD). We investigated the effects of these modifications on gp120 expression, antigenicity, and immunogenicity by comparing unmodified A244 gp120 with both Δ11 deletion and gD tag and with Δ11 only. Analysis of A244 gp120, with or without Δ11 or gD, demonstrated that the Δ11 deletion, without the addition of gD, was sufficient for enhanced antigenicity to gp120 C1 region, conformational V2, and V1/V2 gp120 conformational epitopes. RV144 vaccinee serum IgGs bound more avidly to A244 gp120 Δ11 than to the unmodified gp120, and their binding was blocked by C1, V2, and V1/V2 antibodies. Rhesus macaques immunized with the three different forms of A244 gp120 proteins gave similar levels of gp120 antibody titers, although higher antibody titers developed earlier in A244 Δ11 gp120-immunized animals. Conformational V1/V2 monoclonal antibodies (MAbs) gave significantly higher levels of blocking of plasma IgG from A244 Δ11 gp120-immunized animals than IgG from animals immunized with unmodified A244 gp120, thus indicating a qualitative difference in the V1/V2 antibodies induced by A244 Δ11 gp120. These results demonstrate that deletion of N-terminal residues in the RV144 A244 gp120 immunogen improves both envelope antigenicity and immunogenicity.

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