Inducing cross-clade neutralizing antibodies against HIV-1 by immunofocusing.
BACKGROUND
Although vaccines are important in preventing viral infections by inducing neutralizing antibodies (nAbs), HIV-1 has proven to be a difficult target and escapes humoral immunity through various mechanisms. We sought to test whether HIV-1 Env mimics may serve as immunogens.


RESULTS
Using random peptide phage display libraries, we identified the epitopes recognized by polyclonal antibodies of a rhesus monkey that had developed high-titer, broadly reactive nAbs after infection with a simian-human immunodeficiency virus (SHIV) encoding env of a recently transmitted HIV-1 clade C (HIV-C). Phage peptide inserts were analyzed for conformational and linear homology using computational analysis; some peptides mimicked various domains of the original HIV-C Env, such as conformational V3 loop epitopes and the conserved linear region of the gp120 C-terminus. Next, we devised a novel prime/boost strategy to test the immunogenicity of such phage-displayed peptides and primed mice only once with HIV-C gp160 DNA followed by boosting with mixtures of recombinant phages.


CONCLUSIONS
This strategy, which was designed to focus the immune system on a few Env epitopes (immunofocusing), not only induced HIV-C gp160 binding antibodies and cross-clade nAbs, but also linked a conserved HIV Env region for the first time to the induction of nAbs: the C-terminus of gp120. The identification of conserved antigen mimics may lead to novel immunogens capable of inducing broadly reactive nAbs.
Humbert
Michael
M
Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America.
Rasmussen
Robert A
RA
Ong
Helena
H
Kaiser
Fabian M P
FM
Hu
Shiu-Lok
SL
Ruprecht
Ruth M
RM
D000595:Amino Acid Sequence; D000818:Animals; D001800:Blood Specimen Collection; D015153:Blotting, Western; D003429:Cross Reactions / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D000939:Epitopes / Q000737:chemistry / Q000276:immunology; D005260:Female; D015483:HIV Antibodies / Q000276:immunology* / Q000302:isolation & purification; D015497:HIV-1 / Q000145:classification* / Q000276:immunology*; D007106:Immune Sera; D020128:Inhibitory Concentration 50; D051379:Mice; D008807:Mice, Inbred BALB C; D008958:Models, Molecular; D018716:Molecular Mimicry; D008969:Molecular Sequence Data; D009500:Neutralization Tests / Q000379:methods*; D019151:Peptide Library; D011487:Protein Conformation; D011993:Recombinant Fusion Proteins / Q000276:immunology; D013045:Species Specificity; D014611:Vaccination; D054299:env Gene Products, Human Immunodeficiency Virus / Q000737:chemistry / Q000276:immunology
D000939:Epitopes; D015483:HIV Antibodies; D007106:Immune Sera; D019151:Peptide Library; D011993:Recombinant Fusion Proteins; D054299:env Gene Products, Human Immunodeficiency Virus