Profiling the specificity of neutralizing antibodies in a large panel of plasmas from patients chronically infected with human immunodeficiency virus type 1 subtypes B and C.
Identifying the viral epitopes targeted by broad neutralizing antibodies (NAbs) that sometimes develop in human immunodeficiency virus type 1 (HIV-1)-infected subjects should assist in the design of vaccines to elicit similar responses. Here, we investigated the activities of a panel of 24 broadly neutralizing plasmas from subtype B- and C-infected donors using a series of complementary mapping methods, focusing mostly on JR-FL as a prototype subtype B primary isolate. Adsorption with gp120 immobilized on beads revealed that an often large but variable fraction of plasma neutralization was directed to gp120 and that in some cases, neutralization was largely mediated by CD4 binding site (CD4bs) Abs. The results of a native polyacrylamide gel electrophoresis assay using JR-FL trimers further suggested that half of the subtype B and a smaller fraction of subtype C plasmas contained a significant proportion of NAbs directed to the CD4bs. Anti-gp41 neutralizing activity was detected in several plasmas of both subtypes, but in all but one case, constituted only a minor fraction of the overall neutralization activity. Assessment of the activities of the subtype B plasmas against chimeric HIV-2 viruses bearing various fragments of the membrane proximal external region (MPER) of HIV-1 gp41 revealed mixed patterns, implying that MPER neutralization was not dominated by any single specificity akin to known MPER-specific monoclonal Abs. V3 and 2G12-like NAbs appeared to make little or no contribution to JR-FL neutralization titers. Overall, we observed significant titers of anti-CD4bs NAbs in several plasmas, but approximately two-thirds of the neutralizing activity remained undefined, suggesting the existence of NAbs with specificities unlike any characterized to date.
Binley
James M
JM
Torrey Pines Institute for Molecular Studies, 3550 General Atomics Court, San Diego, California 92121, USA.
Lybarger
Elizabeth A
EA
Crooks
Emma T
ET
Seaman
Michael S
MS
Gray
Elin
E
Davis
Katie L
KL
Decker
Julie M
JM
Wycuff
Diane
D
Harris
Linda
L
Hawkins
Natalie
N
Wood
Blake
B
Nathe
Cory
C
Richman
Douglas
D
Tomaras
Georgia D
GD
Bibollet-Ruche
Frederic
F
Robinson
James E
JE
Morris
Lynn
L
Shaw
George M
GM
Montefiori
David C
DC
Mascola
John R
JR
D000163:Acquired Immunodeficiency Syndrome / Q000276:immunology*; D000818:Animals; D000918:Antibody Specificity; D015704:CD4 Antigens / Q000502:physiology; D002908:Chronic Disease; D004591:Electrophoresis, Polyacrylamide Gel; D004797:Enzyme-Linked Immunosorbent Assay; D006168:Guinea Pigs; D015483:HIV Antibodies / Q000097:blood*; D015699:HIV Envelope Protein gp120 / Q000276:immunology; D015700:HIV Envelope Protein gp41 / Q000276:immunology; D015497:HIV-1 / Q000145:classification* / Q000276:immunology*; D006801:Humans; D007070:Immunoglobulin A / Q000097:blood; D007074:Immunoglobulin G / Q000097:blood / Q000145:classification; D009500:Neutralization Tests; D010446:Peptide Fragments / Q000276:immunology; D019713:Receptors, CCR5 / Q000502:physiology; D054299:env Gene Products, Human Immunodeficiency Virus / Q000276:immunology
D015704:CD4 Antigens; D015483:HIV Antibodies; D015699:HIV Envelope Protein gp120; D015700:HIV Envelope Protein gp41; C059762:HIV envelope protein gp120 (305-321); D007070:Immunoglobulin A; D007074:Immunoglobulin G; D010446:Peptide Fragments; D019713:Receptors, CCR5; D054299:env Gene Products, Human Immunodeficiency Virus; C514793:gp120 protein, Human immunodeficiency virus 1; C097729:gp140 envelope protein, Human immunodeficiency virus 1; C514787:gp41 protein, Human immunodeficiency virus 1