title: Indirect detection of an epitope-specific response to HIV-1 gp120 immunization in human subjects.
abstract: A specific response of human serum neutralizing antibodies (nAb) to a conformational epitope as a result of vaccination of human subjects with the surface envelope glycoprotein (gp120) of HIV-1 has not previously been documented. Here, we used computational analysis to assess the epitope-specific responses of human subjects, which were immunized with recombinant gp120 immunogens in the VAX003 and VAX004 clinical trials. Our computational methodology--a variation of sieve analysis--compares the occurrence of specific nAb targeted conformational 3D epitopes on viruses from infected individuals who received vaccination to the occurrence of matched epitopes in the viruses infecting placebo subjects. We specifically studied seven crystallographically defined nAb targeted conformational epitopes in the V3 loop, an immunogenic region of gp120. Of the six epitopes present in the immunogens and targeted by known monoclonal neutralizing antibodies, only the one targeted by the anti-V3 nAb 2219 exhibited a significant reduction in occurrence in vaccinated subjects compared to the placebo group. This difference occurred only in the VAX003 Thailand cohort. No difference was seen between vaccinated and placebo groups for the occurrence of an epitope that was not present in the immunogen. Thus, it can be theorized that a specific 2219-like human neutralizing antibody immune response to AIDSVAX immunization occurred in the VAX003 cohort, and that this response protected subjects from a narrow subset of HIV-1 viruses circulating in Thailand in the 1990s and bearing the conformational epitope targeted by the neutralizing antibody 2219.
authors.affiliation: Department of Pharmacology, New York University School of Medicine (NYUSoM), New York, New York, United States of America.
authors.forename: Evgeny
authors.initials: E
authors.lastname: Shmelkov
authors.forename: Arthur
authors.initials: A
authors.lastname: Nadas
authors.forename: James
authors.initials: J
authors.lastname: Swetnam
authors.forename: Susan
authors.initials: S
authors.lastname: Zolla-Pazner
authors.forename: Timothy
authors.initials: T
authors.lastname: Cardozo
mesh_terms: D016915:AIDS Vaccines / Q000276:immunology* / Q000627:therapeutic use; D000595:Amino Acid Sequence; D000911:Antibodies, Monoclonal / Q000276:immunology; D057134:Antibodies, Neutralizing / Q000276:immunology*; D000939:Epitopes / Q000276:immunology*; D015483:HIV Antibodies / Q000276:immunology*; D015699:HIV Envelope Protein gp120 / Q000276:immunology*; D015658:HIV Infections / Q000097:blood / Q000276:immunology* / Q000517:prevention & control; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D008969:Molecular Sequence Data; D009500:Neutralization Tests; D011994:Recombinant Proteins / Q000276:immunology; D017386:Sequence Homology, Amino Acid; D013785:Thailand; D014611:Vaccination
chemical_list: D016915:AIDS Vaccines; C112734:AIDSVAX; D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D000939:Epitopes; D015483:HIV Antibodies; D015699:HIV Envelope Protein gp120; D011994:Recombinant Proteins
references.citation: AIDS. 2006 Oct 24;20(16):W13-23
references.pmid: 17053344
references.citation: PLoS One. 2010 Dec 29;5(12):e15994
references.pmid: 21209919
references.citation: Structure. 2009 Nov 11;17(11):1538-46
references.pmid: 19913488
references.citation: AIDS Res Hum Retroviruses. 2009 Apr;25(4):441-50
references.pmid: 19320565
references.citation: Proc Natl Acad Sci U S A. 1991 Apr 15;88(8):3238-42
references.pmid: 2014246
references.citation: J Acquir Immune Defic Syndr. 2002 Feb 1;29(2):184-90
references.pmid: 11832690
references.citation: AIDS Clin Care. 2003 Apr;15(4):42
references.pmid: 12712958
references.citation: Proc Natl Acad Sci U S A. 1989 Sep;86(17):6768-72
references.pmid: 2771954
references.citation: J Infect Dis. 2006 Dec 15;194(12):1661-71
references.pmid: 17109337
references.citation: AIDS. 2003 Jan 24;17(2):147-56
references.pmid: 12545073
references.citation: N Engl J Med. 2009 Dec 3;361(23):2209-20
references.pmid: 19843557
references.citation: J Infect Dis. 2005 Mar 1;191(5):654-65
references.pmid: 15688278
references.citation: AIDS Res Hum Retroviruses. 1998 Mar 1;14(4):319-27
references.pmid: 9519893
references.citation: Science. 1990 Aug 24;249(4971):932-5
references.pmid: 2392685
references.citation: Nat Rev Immunol. 2004 Mar;4(3):199-210
references.pmid: 15039757
references.citation: J Clin Epidemiol. 2001 Jan;54(1):68-85
references.pmid: 11165470
references.citation: Structure. 2004 Feb;12(2):193-204
references.pmid: 14962380
references.citation: Vaccine. 2011 Sep 9;29(39):6736-41
references.pmid: 21216319
references.citation: J Infect Dis. 2005 Mar 1;191(5):666-77
references.pmid: 15688279
references.citation: J Virol. 2006 Jul;80(14):7127-35
references.pmid: 16809318
references.citation: J Virol. 2006 Jun;80(12):6093-105
references.pmid: 16731948
references.citation: Nat Med. 2011 Mar;17(3):366-71
references.pmid: 21358627
references.citation: AIDS Res Hum Retroviruses. 1992 Aug;8(8):1471-2
references.pmid: 1466984