title: Selection of a rare neutralization-resistant variant following passive transfer of convalescent immune plasma in equine infectious anemia virus-challenged SCID horses.
abstract: Vaccines preventing HIV-1 infection will likely elicit antibodies that neutralize diverse strains. However, the capacity for lentiviruses to escape broadly neutralizing antibodies (NAbs) is not completely understood, nor is it known whether NAbs alone can control heterologous infection. Here, we determined that convalescent immune plasma from a horse persistently infected with equine infectious anemia virus (EIAV) neutralized homologous virus and several envelope variants containing heterologous principal neutralizing domains (PND). Plasma was infused into young horses (foals) affected with severe combined immunodeficiency (SCID), followed by challenge with a homologous EIAV stock. Treated SCID foals were protected against clinical disease, with complete prevention of infection occurring in one foal. In three SCID foals, a novel neutralization-resistant variant arose that was found to preexist at a low frequency in the challenge inoculum. In contrast, SCID foals infused with nonimmune plasma developed acute disease associated with high levels of the predominant challenge virus. Following transfer to an immunocompetent horse, the neutralization-resistant variant induced a single febrile episode and was subsequently controlled in the absence of type-specific NAb. Long-term control was associated with the presence of cytotoxic T lymphocytes (CTL). Our results demonstrate that immune plasma with neutralizing activity against heterologous PND variants can prevent lentivirus infection and clinical disease in the complete absence of T cells. Importantly, however, rare neutralization-resistant envelope variants can replicate in vivo under relatively broad selection pressure, highlighting the need for protective lentivirus vaccines to elicit NAb responses with increased breadth and potency and/or CTL that target conserved epitopes.
authors.affiliation: Department of Veterinary Microbiology and Pathology, Washington State University, Pullman, WA 99164-7040, USA.
authors.forename: Sandra D
authors.initials: SD
authors.lastname: Taylor
authors.forename: Steven R
authors.initials: SR
authors.lastname: Leib
authors.forename: Susan
authors.initials: S
authors.lastname: Carpenter
authors.forename: Robert H
authors.initials: RH
authors.lastname: Mealey
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000276:immunology*; D000914:Antibodies, Viral / Q000276:immunology*; D004859:Equine Infectious Anemia / Q000276:immunology*; D006736:Horses; D007106:Immune Sera / Q000276:immunology*; D004860:Infectious Anemia Virus, Equine / Q000235:genetics / Q000276:immunology*; D016511:Severe Combined Immunodeficiency / Q000150:complications; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology
chemical_list: D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; D007106:Immune Sera
references.citation: J Am Vet Med Assoc. 1980 Jun 1;176(11):1250-1
references.pmid: 7429919
references.citation: Proc Natl Acad Sci U S A. 1995 Dec 5;92(25):11485-9
references.pmid: 8524788
references.citation: Nature. 2007 Sep 6;449(7158):29-30
references.pmid: 17805280
references.citation: Virology. 2007 Jun 20;363(1):156-65
references.pmid: 17328936
references.citation: Vaccine. 2009 Apr 21;27(18):2453-68
references.pmid: 19368787
references.citation: Nature. 2003 Mar 20;422(6929):307-12
references.pmid: 12646921
references.citation: J Infect Dis. 2004 Jun 15;189(12):2167-73
references.pmid: 15181562
references.citation: Virology. 2005 Nov 25;342(2):228-39
references.pmid: 16139857
references.citation: J Gen Virol. 2000 Nov;81(Pt 11):2735-2739
references.pmid: 11038386
references.citation: J Virol. 1999 May;73(5):4009-18
references.pmid: 10196297
references.citation: Clin Immunol. 2001 Nov;101(2):237-47
references.pmid: 11683583
references.citation: J Virol. 1987 Dec;61(12):3783-9
references.pmid: 2446008
references.citation: J Virol. 1997 Dec;71(12):9627-39
references.pmid: 9371627
references.citation: J Immunol. 1997 Apr 15;158(8):3565-9
references.pmid: 9103416
references.citation: Proc Natl Acad Sci U S A. 2003 Apr 1;100(7):4144-9
references.pmid: 12644702
references.citation: J Virol. 2009 Mar;83(6):2743-55
references.pmid: 19116253
references.citation: J Virol. 2006 Jul;80(13):6525-33
references.pmid: 16775339
references.citation: Dev Biol Stand. 1990;72:31-7
references.pmid: 2178127
references.citation: Proc Natl Acad Sci U S A. 2005 Dec 20;102(51):18514-9
references.pmid: 16339909
references.citation: J Virol. 2004 Sep;78(17):9295-305
references.pmid: 15308724
references.citation: Nature. 2009 Apr 2;458(7238):636-40
references.pmid: 19287373
references.citation: Proc Natl Acad Sci U S A. 2007 Sep 18;104(38):15105-10
references.pmid: 17846425
references.citation: Transfusion. 2004 Jun;44(6):886-90
references.pmid: 15157256
references.citation: J Virol. 1988 Aug;62(8):3073-6
references.pmid: 2839723
references.citation: J Virol. 2009 Jan;83(2):662-72
references.pmid: 18987151
references.citation: J Virol. 2008 Apr;82(8):3952-70
references.pmid: 18256145
references.citation: J Gen Virol. 2005 Jan;86(Pt 1):139-149
references.pmid: 15604441
references.citation: Am J Vet Res. 1972 Jan;33(1):11-8
references.pmid: 4333633
references.citation: J Virol. 2001 May;75(10):4570-83
references.pmid: 11312327
references.citation: J Gen Virol. 2002 Jun;83(Pt 6):1353-1359
references.pmid: 12029150
references.citation: J Am Vet Med Assoc. 1974 Jan 1;164(1):70-6
references.pmid: 4358832
references.citation: AIDS Res Hum Retroviruses. 2005 Dec;21(12):1057-9
references.pmid: 16379610
references.citation: J Virol. 1986 Jan;57(1):71-80
references.pmid: 3001367
references.citation: Nature. 1998 Jun 18;393(6686):648-59
references.pmid: 9641677
references.citation: Am J Vet Res. 1978 Jun;39(6):1043-7
references.pmid: 208432
references.citation: J Clin Microbiol. 2005 Jan;43(1):406-13
references.pmid: 15635002
references.citation: Antiviral Res. 2004 Mar;61(3):141-51
references.pmid: 15168794
references.citation: Virology. 2005 Aug 15;339(1):110-26
references.pmid: 15979679
references.citation: Virology. 2007 Feb 5;358(1):69-78
references.pmid: 16996554
references.citation: Vet Immunol Immunopathol. 1989 Nov 30;23(1-2):41-9
references.pmid: 2559537
references.citation: AIDS. 2003 Feb 14;17(3):301-9
references.pmid: 12556683
references.citation: J Virol. 1987 Oct;61(10):2956-61
references.pmid: 2442410
references.citation: Nat Rev Immunol. 2004 Mar;4(3):199-210
references.pmid: 15039757
references.citation: Nat Rev Microbiol. 2008 Feb;6(2):143-55
references.pmid: 18197170
references.citation: Vet Immunol Immunopathol. 2008 Jan 15;121(1-2):8-22
references.pmid: 17727961
references.citation: J Gen Virol. 2008 Aug;89(Pt 8):2011-2019
references.pmid: 18632973
references.citation: J Virol. 2004 Apr;78(7):3561-71
references.pmid: 15016879
references.citation: J Virol. 2002 Nov;76(21):10588-97
references.pmid: 12368301
references.citation: Virology. 2003 Sep 1;313(2):537-52
references.pmid: 12954220
references.citation: AIDS Res Hum Retroviruses. 2003 Oct;19(10):923-4
references.pmid: 14601590
references.citation: Virology. 2004 Sep 15;327(1):144-54
references.pmid: 15327905
references.citation: Proc Natl Acad Sci U S A. 2005 Jul 12;102(28):9918-23
references.pmid: 15985554
references.citation: Virology. 1999 Sep 1;261(2):242-52
references.pmid: 10497109
references.citation: Virology. 2007 Jul 5;363(2):447-53
references.pmid: 17355886
references.citation: J Gen Virol. 1988 Mar;69 ( Pt 3):667-74
references.pmid: 3351480
references.citation: Science. 2009 Nov 20;326(5956):1123-7
references.pmid: 19965434
references.citation: Arch Virol. 1988;98(1-2):91-7
references.pmid: 2829799
references.citation: J Immunol. 1985 Aug;135(2):906-14
references.pmid: 2409158
references.citation: J Virol. 1992 Feb;66(2):732-42
references.pmid: 1370556
references.citation: Nat Med. 1999 Feb;5(2):204-10
references.pmid: 9930869
references.citation: J Virol. 1996 Nov;70(11):7842-50
references.pmid: 8892906