Vaccination with peptide mimetics of the gp41 prehairpin fusion intermediate yields neutralizing antisera against HIV-1 isolates.
Eliciting a broadly neutralizing polyclonal antibody response against HIV-1 remains a major challenge. One approach to vaccine development is prevention of HIV-1 entry into cells by blocking the fusion of viral and cell membranes. More specifically, our goal is to elicit neutralizing antibodies that target a transient viral entry intermediate (the prehairpin intermediate) formed by the HIV-1 gp41 protein. Because this intermediate is transient, a stable mimetic is required to elicit an immune response. Previously, a series of engineered peptides was used to select a mAb (denoted D5) that binds to the surface of the gp41 prehairpin intermediate, as demonstrated by x-ray crystallographic studies. D5 inhibits the replication of HIV-1 clinical isolates, providing proof-of-principle for this vaccine approach. Here, we describe a series of peptide mimetics of the gp41 prehairpin intermediate designed to permit a systematic analysis of the immune response generated in animals. To improve the chances of detecting weak neutralizing polyclonal responses, two strategies were employed in the initial screening: use of a neutralization-hypersensitive virus and concentration of the IgG fraction from immunized animal sera. This allowed incremental improvements through iterative cycles of design, which led to vaccine candidates capable of generating a polyclonal antibody response, detectable in unfractionated sera, that neutralize tier 1 HIV-1 and simian HIV primary isolates in vitro. Our findings serve as a starting point for the design of more potent immunogens to elicit a broadly neutralizing response against the gp41 prehairpin intermediate.
Bianchi
Elisabetta
E
Department of Peptide Chemistry, Merck Research Laboratories, Pomezia, 00040 Rome, Italy.
Joyce
Joseph G
JG
Miller
Michael D
MD
Finnefrock
Adam C
AC
Liang
Xiaoping
X
Finotto
Marco
M
Ingallinella
Paolo
P
McKenna
Philip
P
Citron
Michael
M
Ottinger
Elizabeth
E
Hepler
Robert W
RW
Hrin
Renee
R
Nahas
Deborah
D
Wu
Chengwei
C
Montefiori
David
D
Shiver
John W
JW
Pessi
Antonello
A
Kim
Peter S
PS
D000595:Amino Acid Sequence; D000818:Animals; D057134:Antibodies, Neutralizing / Q000276:immunology*; D040761:Biomimetic Materials; D006168:Guinea Pigs; D015483:HIV Antibodies / Q000276:immunology*; D015700:HIV Envelope Protein gp41 / Q000737:chemistry / Q000276:immunology*; D015497:HIV-1 / Q000737:chemistry / Q000276:immunology* / Q000302:isolation & purification; D007106:Immune Sera / Q000276:immunology*; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry / Q000276:immunology; D011817:Rabbits; D014611:Vaccination
D057134:Antibodies, Neutralizing; D015483:HIV Antibodies; D015700:HIV Envelope Protein gp41; D007106:Immune Sera; D010455:Peptides