Structure-guided design and immunological characterization of immunogens presenting the HIV-1 gp120 V3 loop on a CTB scaffold.
V3 loop is a major neutralizing determinant of the HIV-1 gp120. Using 3D structures of cholera toxin B subunit (CTB), complete V3 in the gp120 context, and V3 bound to a monoclonal antibody (mAb), we designed two V3-scaffold immunogen constructs (V3-CTB). The full-length V3-CTB presenting the complete V3 in a structural context mimicking gp120 was recognized by the large majority of our panel of 24 mAbs. The short V3-CTB presenting a V3 fragment in the conformation observed in the complex with the 447-52D Fab, exhibited high-affinity binding to this mAb. The immunogens were evaluated in rabbits using DNA-prime/protein-boost protocol. Boosting with the full-length V3-CTB induced high anti-V3 titers in sera that potently neutralize multiple HIV virus strains. The short V3-CTB was ineffective. The results suggest that very narrow antigenic profile of an immunogen is associated with poor Ab response. An immunogen with broader antigenic activity elicits robust Ab response.
Totrov
Maxim
M
Molsoft LLC, 3366 N Torrey Pines Ct., La Jolla, CA 92037, USA. max@molsoft.com
Jiang
Xunqing
X
Kong
Xiang-Peng
XP
Cohen
Sandra
S
Krachmarov
Chavdar
C
Salomon
Aidy
A
Williams
Constance
C
Seaman
Michael S
MS
Abagyan
Ruben
R
Cardozo
Timothy
T
Gorny
Miroslaw K
MK
Wang
Shixia
S
Lu
Shan
S
Pinter
Abraham
A
Zolla-Pazner
Susan
S
D016915:AIDS Vaccines; D000818:Animals; D000911:Antibodies, Monoclonal / Q000097:blood* / Q000276:immunology; D057134:Antibodies, Neutralizing / Q000276:immunology; D002772:Cholera Toxin / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015195:Drug Design; D015483:HIV Antibodies / Q000097:blood* / Q000276:immunology; D015699:HIV Envelope Protein gp120 / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D015497:HIV-1 / Q000276:immunology; D007114:Immunization; D010446:Peptide Fragments / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D011817:Rabbits
D016915:AIDS Vaccines; D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D015483:HIV Antibodies; D015699:HIV Envelope Protein gp120; C059762:HIV envelope protein gp120 (305-321); D010446:Peptide Fragments; D002772:Cholera Toxin