Induction of neutralizing antibodies in rhesus macaques using V3 mimotope peptides.
RV144 vaccinees with low HIV-1 Envelope-specific IgA antibodies (Abs) also had Abs directed to the hypervariable region 3 (V3) that inversely correlated with infection risk. Thus, anti-V3 HIV-1 Abs may contribute to protection from HIV-1 infection. The V3 region contains two dominant clusters of epitopes; one is preferentially recognized by mAbs encoded by VH5-51 and VL lambda genes, while the second one is recognized by mAbs encoded by other VH genes. We designed a study in rhesus macaques to induce anti-V3 Abs specific to each of these two dominant clusters of V3 epitopes to test whether the usage of the VH5-51 gene results in different characteristics of antibodies. The two C4-V3 immunogens used for immunization were each comprised of a fusion of the C4 peptide containing the T cell epitope and a V3 mimotope peptide mimicking the V3 epitope. The C4-447 peptide was designed to target B cells with several VH1-VH4 genes, the C4-VH5-51 peptide was designed to specifically target B cells with the VH5-51 gene. Six animals in two groups were immunized five times with these two immunogens, and screening of 10 sequential plasma samples post immunization demonstrated that C4-447 induced higher titers of plasma anti-V3 Abs and significantly more potent neutralizing activities against tier 1 and some tier 2 pseudoviruses than C4-VH5-51. Levels of anti-V3 Abs in buccal secretions were significantly higher in sequential samples derived from C4-447- than from C4-VH5-51-immunized animals. The titers of anti-V3 Abs in plasma strongly correlated with their levels in mucosal secretions. The results show that high titers of vaccine-induced anti-V3 Abs in plasma determine the potency and breadth of neutralization, as well as the rate of transduction of Abs to mucosal tissues, where they can play a role in preventing HIV-1 infection.
Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR, USA.
Ann J
AJ
Hessell
Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR, USA.
Sean
S
McBurney
Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR, USA.
Shilpi
S
Pandey
Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR, USA.
William
W
Sutton
Department of Pathology, New York University School of Medicine, New York, NY, USA.
Lily
L
Liu
Department of Pathology, New York University School of Medicine, New York, NY, USA.
Liuzhe
L
Li
Molsoft, La Jolla, CA, USA.
Maxim
M
Totrov
Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Susan
S
Zolla-Pazner
Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR, USA.
Nancy L
NL
Haigwood
Department of Pathology, New York University School of Medicine, New York, NY, USA. Electronic address: mirek.gorny@nyumc.org.
Miroslaw K
MK
Gorny
D016915:AIDS Vaccines / Q000276:immunology*; D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D057134:Antibodies, Neutralizing / Q000097:blood*; D000917:Antibody Formation; D000918:Antibody Specificity; D001402:B-Lymphocytes / Q000276:immunology; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D005260:Female; D015483:HIV Antibodies / Q000097:blood*; D015497:HIV-1; D008253:Macaca mulatta; D008297:Male; D009500:Neutralization Tests; D010455:Peptides / Q000276:immunology
D016915:AIDS Vaccines; D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D018984:Epitopes, T-Lymphocyte; D015483:HIV Antibodies; D010455:Peptides
HIV vaccine; HIV-1; HIV-1 neutralizing antibodies; Non-human primates immunization; Rhesus macaque immunoglobulin genes; V3 immunogens