title: Phenotypic properties of transmitted founder HIV-1.
abstract: Defining the virus-host interactions responsible for HIV-1 transmission, including the phenotypic requirements of viruses capable of establishing de novo infections, could be important for AIDS vaccine development. Previous analyses have failed to identify phenotypic properties other than chemokine receptor 5 (CCR5) and CD4+ T-cell tropism that are preferentially associated with viral transmission. However, most of these studies were limited to examining envelope (Env) function in the context of pseudoviruses. Here, we generated infectious molecular clones of transmitted founder (TF; n = 27) and chronic control (CC; n = 14) viruses of subtypes B (n = 18) and C (n = 23) and compared their phenotypic properties in assays specifically designed to probe the earliest stages of HIV-1 infection. We found that TF virions were 1.7-fold more infectious (P = 0.049) and contained 1.9-fold more Env per particle (P = 0.048) compared with CC viruses. TF viruses were also captured by monocyte-derived dendritic cells 1.7-fold more efficiently (P = 0.035) and more readily transferred to CD4+ T cells (P = 0.025). In primary CD4+ T cells, TF and CC viruses replicated with comparable kinetics; however, when propagated in the presence of IFN-α, TF viruses replicated to higher titers than CC viruses. This difference was significant for subtype B (P = 0.000013) but not subtype C (P = 0.53) viruses, possibly reflecting demographic differences of the respective patient cohorts. Together, these data indicate that TF viruses are enriched for higher Env content, enhanced cell-free infectivity, improved dendritic cell interaction, and relative IFN-α resistance. These viral properties, which likely act in concert, should be considered in the development and testing of AIDS vaccines.
authors.affiliation: Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Nicholas F
authors.initials: NF
authors.lastname: Parrish
authors.forename: Feng
authors.initials: F
authors.lastname: Gao
authors.forename: Hui
authors.initials: H
authors.lastname: Li
authors.forename: Elena E
authors.initials: EE
authors.lastname: Giorgi
authors.forename: Hannah J
authors.initials: HJ
authors.lastname: Barbian
authors.forename: Erica H
authors.initials: EH
authors.lastname: Parrish
authors.forename: Lara
authors.initials: L
authors.lastname: Zajic
authors.forename: Shilpa S
authors.initials: SS
authors.lastname: Iyer
authors.forename: Julie M
authors.initials: JM
authors.lastname: Decker
authors.forename: Amit
authors.initials: A
authors.lastname: Kumar
authors.forename: Bhavna
authors.initials: B
authors.lastname: Hora
authors.forename: Anna
authors.initials: A
authors.lastname: Berg
authors.forename: Fangping
authors.initials: F
authors.lastname: Cai
authors.forename: Jennifer
authors.initials: J
authors.lastname: Hopper
authors.forename: Thomas N
authors.initials: TN
authors.lastname: Denny
authors.forename: Haitao
authors.initials: H
authors.lastname: Ding
authors.forename: Christina
authors.initials: C
authors.lastname: Ochsenbauer
authors.forename: John C
authors.initials: JC
authors.lastname: Kappes
authors.forename: Rachel P
authors.initials: RP
authors.lastname: Galimidi
authors.forename: Anthony P
authors.initials: AP
authors.lastname: West
authors.forename: Pamela J
authors.initials: PJ
authors.lastname: Bjorkman
authors.forename: Craig B
authors.initials: CB
authors.lastname: Wilen
authors.forename: Robert W
authors.initials: RW
authors.lastname: Doms
authors.forename: Meagan
authors.initials: M
authors.lastname: O'Brien
authors.forename: Nina
authors.initials: N
authors.lastname: Bhardwaj
authors.forename: Persephone
authors.initials: P
authors.lastname: Borrow
authors.forename: Barton F
authors.initials: BF
authors.lastname: Haynes
authors.forename: Mark
authors.initials: M
authors.lastname: Muldoon
authors.forename: James P
authors.initials: JP
authors.lastname: Theiler
authors.forename: Bette
authors.initials: B
authors.lastname: Korber
authors.forename: George M
authors.initials: GM
authors.lastname: Shaw
authors.forename: Beatrice H
authors.initials: BH
authors.lastname: Hahn
mesh_terms: D001483:Base Sequence; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D003001:Cloning, Molecular; D003713:Dendritic Cells / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D015658:HIV Infections / Q000276:immunology / Q000635:transmission; D015497:HIV-1 / Q000235:genetics* / Q000276:immunology; D006801:Humans; D016014:Linear Models; D008969:Molecular Sequence Data; D010641:Phenotype; D017422:Sequence Analysis, DNA; D014759:Viral Envelope Proteins / Q000378:metabolism*; D014771:Virion / Q000472:pathogenicity*
chemical_list: D014759:Viral Envelope Proteins
references.citation: J Virol. 2005 May;79(10):6528-31
references.pmid: 15858037
references.citation: PLoS Pathog. 2008 Feb 29;4(2):e1000007
references.pmid: 18389079
references.citation: PLoS Pathog. 2010 May 13;6(5):e1000890
references.pmid: 20485520
references.citation: AIDS Res Hum Retroviruses. 1990 Dec;6(12):1433-6
references.pmid: 2078421
references.citation: J Exp Med. 1996 Dec 1;184(6):2433-8
references.pmid: 8976200
references.citation: Nature. 2011 Apr 28;472(7344):481-5
references.pmid: 21478870
references.citation: Immunity. 2007 Feb;26(2):257-70
references.pmid: 17306567
references.citation: J Virol Methods. 2009 Apr;157(1):98-101
references.pmid: 19100289
references.citation: Nature. 2002 Aug 8;418(6898):646-50
references.pmid: 12167863
references.citation: FASEB J. 2009 Oct;23(10):3609-18
references.pmid: 19487309
references.citation: Virology. 2010 May 10;400(2):164-74
references.pmid: 20096914
references.citation: J Virol. 2002 Jun;76(11):5315-25
references.pmid: 11991960
references.citation: J Virol. 2010 Apr;84(8):4100-4
references.pmid: 20147398
references.citation: PLoS Pathog. 2012;8(5):e1002686
references.pmid: 22693444
references.citation: Science. 2004 Mar 26;303(5666):2019-22
references.pmid: 15044802
references.citation: J Virol. 2009 Oct;83(20):10527-37
references.pmid: 19706714
references.citation: PLoS Pathog. 2010 May 27;6(5):e1000908
references.pmid: 20523901
references.citation: J Virol. 1998 Dec;72(12):10286-91
references.pmid: 9811777
references.citation: J Infect Dis. 2013 Apr 15;207(8):1206-15
references.pmid: 23315326
references.citation: PLoS Pathog. 2010 Dec 16;6(12):e1001228
references.pmid: 21187897
references.citation: J Virol. 2005 Oct;79(19):12132-47
references.pmid: 16160141
references.citation: J Virol. 2007 Jul;81(13):6858-68
references.pmid: 17442711
references.citation: Nat Med. 2009 Aug;15(8):955-9
references.pmid: 19597505
references.citation: Science. 1999 Nov 12;286(5443):1353-7
references.pmid: 10558989
references.citation: J Virol. 2008 Apr;82(8):3952-70
references.pmid: 18256145
references.citation: J Infect Dis. 2001 Feb 15;183(4):555-62
references.pmid: 11170980
references.citation: J Infect Dis. 2010 Nov 1;202 Suppl 3:S339-44
references.pmid: 20887221
references.citation: Cold Spring Harb Perspect Med. 2012 Nov 01;2(11):
references.pmid: 23043157
references.citation: J Virol. 2000 Apr;74(8):3740-51
references.pmid: 10729149
references.citation: J Biol Chem. 2012 Dec 28;287(53):44714-35
references.pmid: 23132857
references.citation: J Virol. 2009 Apr;83(7):3288-97
references.pmid: 19129448
references.citation: Science. 1999 Jun 11;284(5421):1835-7
references.pmid: 10364556
references.citation: J Virol. 2006 Jun;80(11):5211-8
references.pmid: 16699001
references.citation: J Virol. 1992 Dec;66(12):7543-8
references.pmid: 1279206
references.citation: J Virol. 2010 Mar;84(6):3106-10
references.pmid: 20042508
references.citation: AIDS. 2007 May 31;21(9):1091-101
references.pmid: 17502719
references.citation: J Virol. 2003 Jan;77(2):989-98
references.pmid: 12502815
references.citation: AIDS. 2008 Jul 31;22(12):1493-501
references.pmid: 18614873
references.citation: J Infect Dis. 1991 Sep;164(3):588-91
references.pmid: 1869844
references.citation: Mucosal Immunol. 2010 Jul;3(4):410-8
references.pmid: 20410876
references.citation: J Virol. 2013 Mar;87(5):2401-11
references.pmid: 23269796
references.citation: Cell. 2000 Mar 3;100(5):587-97
references.pmid: 10721995
references.citation: J Acquir Immune Defic Syndr (1988). 1990;3(11):1046-51
references.pmid: 2213506
references.citation: J Virol. 2011 Sep;85(17):8514-27
references.pmid: 21715507
references.citation: Nat Immunol. 2002 Oct;3(10):975-83
references.pmid: 12352970
references.citation: J Acquir Immune Defic Syndr. 2006 Oct 1;43(2):137-43
references.pmid: 16940859
references.citation: Cell. 1996 Aug 9;86(3):367-77
references.pmid: 8756719
references.citation: Nature. 2008 Jan 24;451(7177):425-30
references.pmid: 18200009
references.citation: PLoS Pathog. 2011 Feb;7(2):e1001301
references.pmid: 21383973
references.citation: J Gen Virol. 2001 Aug;82(Pt 8):1893-1897
references.pmid: 11457995
references.citation: Science. 1990 Mar 9;247(4947):1216-9
references.pmid: 2180064
references.citation: J Virol. 2010 Jan;84(1):261-9
references.pmid: 19864392
references.citation: J Virol. 2011 Dec;85(24):13443-7
references.pmid: 21976645
references.citation: J Virol. 2009 Apr;83(8):3719-33
references.pmid: 19176632
references.citation: AIDS Res Hum Retroviruses. 1990 May;6(5):659-72
references.pmid: 1694453
references.citation: Proc Natl Acad Sci U S A. 2011 Nov 15;108(46):E1156-63
references.pmid: 22065783
references.citation: Virology. 2005 Feb 5;332(1):418-29
references.pmid: 15661172
references.citation: J Virol. 2011 Sep;85(18):9637-40
references.pmid: 21734037
references.citation: Nature. 2009 Apr 23;458(7241):1034-8
references.pmid: 19262509
references.citation: J Exp Med. 1996 Jan 1;183(1):215-25
references.pmid: 8551225
references.citation: J Virol. 2003 Dec;77(23):12865-74
references.pmid: 14610207
references.citation: AIDS. 1993 Jan;7(1):95-102
references.pmid: 8442924
references.citation: Lancet. 2001 Apr 14;357(9263):1149-53
references.pmid: 11323041
references.citation: Proc Natl Acad Sci U S A. 2008 May 27;105(21):7552-7
references.pmid: 18490657
references.citation: J Virol. 2001 May;75(10):4664-72
references.pmid: 11312337
references.citation: Proc Natl Acad Sci U S A. 2012 May 8;109(19):7475-80
references.pmid: 22529395
references.citation: J Virol. 2011 Oct;85(19):10389-98
references.pmid: 21775457
references.citation: J Virol. 2007 Jul;81(14):7559-70
references.pmid: 17475656
references.citation: J Virol. 2011 Oct;85(20):10669-81
references.pmid: 21835785
references.citation: Nat Med. 2009 Aug;15(8):886-92
references.pmid: 19648930
references.citation: J Virol. 2005 Nov;79(22):14355-70
references.pmid: 16254370
references.citation: J Virol. 2009 Aug;83(16):8208-20
references.pmid: 19515785
references.citation: Science. 1992 Jul 17;257(5068):383-7
references.pmid: 1352913
references.citation: J Exp Med. 2009 Jun 8;206(6):1273-89
references.pmid: 19487424
references.citation: J Virol. 2012 Mar;86(5):2715-28
references.pmid: 22190722
references.citation: Proc Natl Acad Sci U S A. 1998 Dec 22;95(26):15623-8
references.pmid: 9861020
references.citation: Nat Rev Immunol. 2008 Jun;8(6):447-57
references.pmid: 18469831
references.citation: PLoS Pathog. 2011 Sep;7(9):e1002209
references.pmid: 21980282
references.citation: PLoS Pathog. 2012;8(8):e1002880
references.pmid: 22927816
references.citation: Virology. 2008 May 10;374(2):229-33
references.pmid: 18314154
references.citation: PLoS One. 2011;6(8):e23673
references.pmid: 21876761
references.citation: J Exp Med. 2004 Sep 20;200(6):761-70
references.pmid: 15365095