Immunogenicity of constrained monoclonal antibody A32-human immunodeficiency virus (HIV) Env gp120 complexes compared to that of recombinant HIV type 1 gp120 envelope glycoproteins.
One strategy for the generation of broadly reactive neutralizing antibodies (NA) against human immunodeficiency virus type 1 (HIV-1) primary isolates is to use immunogens that have constrained HIV-1 envelope gp120 conformations reflective of triggered envelope on the surface of virions. A major change in gp120 following binding to CD4 is the enhanced exposure of the CCR5 binding site. One inducer of CCR5 binding site epitopes on gp120 is the human anti-gp120 monoclonal antibody, A32. We have made cross-linked A32-rgp120(89.6) and A32-rgp120(BaL) complexes and have compared their immunogenicities to those of uncomplexed recombinant gp120(BaL) (rgp120(BaL)) and rgp120(89.6). A32-rgp120(89.6) and A32-rgp120(BaL) complexes had stable induced CCR5 binding site expression compared to that of uncomplexed rgp120s. However, the A32-rgp120 complexes had similar capacities in guinea pigs for induction of NA against HIV-1 primary isolates versus that of rgp120 alone. A32-rgp120(89.6) induced antibodies that neutralized 6 out of 11 HIV-1 isolates, while rgp120(89.6) alone induced antibodies that neutralized 4 out of 11 HIV-1 isolates. A32-rgp120(BaL) complexes induced antibodies that neutralized 4 out of 14 HIV-1 isolates while, surprisingly, non-cross-linked rgp120(BaL) induced antibodies that neutralized 9 out of 14 (64%) HIV-1 isolates. Thus, stable enhanced expression of the coreceptor binding site on constrained gp120 is not sufficient for inducing broadly neutralizing anti-HIV-1 NA. Moreover, the ability of HIV-1 rgp120(BaL) to induce antibodies that neutralized approximately 60% of subtype B HIV-1 isolates warrants consideration of using HIV-1 BaL as a starting point for immunogen design for subtype B HIV-1 experimental immunogens.
Liao
Hua-Xin
HX
Duke Human Vaccine Institute and Department of Medicine, Duke University School of Medicine, Durham, NC 27710, USA. liao0001@mc.duke.edu
Alam
S Munir
SM
Mascola
John R
JR
Robinson
James
J
Ma
Benjiang
B
Montefiori
David C
DC
Rhein
Maria
M
Sutherland
Laura L
LL
Scearce
Richard
R
Haynes
Barton F
BF
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology*; D000939:Epitopes; D006168:Guinea Pigs; D015699:HIV Envelope Protein gp120 / Q000737:chemistry / Q000276:immunology*; D015497:HIV-1 / Q000276:immunology*; D007106:Immune Sera / Q000276:immunology; D009500:Neutralization Tests; D011994:Recombinant Proteins / Q000276:immunology
D000911:Antibodies, Monoclonal; D000939:Epitopes; D015699:HIV Envelope Protein gp120; D007106:Immune Sera; D011994:Recombinant Proteins