title: Neutralization properties of simian immunodeficiency viruses infecting chimpanzees and gorillas.
abstract: Broadly cross-reactive neutralizing antibodies (bNabs) represent powerful tools to combat human immunodeficiency virus type 1 (HIV-1) infection. Here, we examined whether HIV-1-specific bNabs are capable of cross-neutralizing distantly related simian immunodeficiency viruses (SIVs) infecting central (Pan troglodytes troglodytes) (SIVcpzPtt) and eastern (Pan troglodytes schweinfurthii) (SIVcpzPts) chimpanzees (n = 11) as well as western gorillas (Gorilla gorilla gorilla) (SIVgor) (n = 1). We found that bNabs directed against the CD4 binding site (n = 10), peptidoglycans at the base of variable loop 3 (V3) (n = 5), and epitopes at the interface of surface (gp120) and membrane-bound (gp41) envelope glycoproteins (n = 5) failed to neutralize SIVcpz and SIVgor strains. In addition, apex V2-directed bNabs (n = 3) as well as llama-derived (heavy chain only) antibodies (n = 6) recognizing both the CD4 binding site and gp41 epitopes were either completely inactive or neutralized only a fraction of SIVcpzPtt strains. In contrast, one antibody targeting the membrane-proximal external region (MPER) of gp41 (10E8), functional CD4 and CCR5 receptor mimetics (eCD4-Ig, eCD4-Ig(mim2), CD4-218.3-E51, and CD4-218.3-E51-mim2), as well as mono- and bispecific anti-human CD4 (iMab and LM52) and CCR5 (PRO140, PRO140-10E8) receptor antibodies neutralized >90% of SIVcpz and SIVgor strains with low-nanomolar (0.13 to 8.4 nM) potency. Importantly, the latter antibodies blocked virus entry not only in TZM-bl cells but also in Cf2Th cells expressing chimpanzee CD4 and CCR5 and neutralized SIVcpz in chimpanzee CD4(+) T cells, with 50% inhibitory concentrations (IC50s) ranging from 3.6 to 40.5 nM. These findings provide new insight into the protective capacity of anti-HIV-1 bNabs and identify candidates for further development to combat SIVcpz infection.
  
  
  OBJECTIVE
  SIVcpz is widespread in wild-living chimpanzees and can cause AIDS-like immunopathology and clinical disease. HIV-1 infection of humans can be controlled by antiretroviral therapy; however, treatment of wild-living African apes with current drug regimens is not feasible. Nonetheless, it may be possible to curb the spread of SIVcpz in select ape communities using vectored immunoprophylaxis and/or therapy. Here, we show that antibodies and antibody-like inhibitors developed to combat HIV-1 infection in humans are capable of neutralizing genetically diverse SIVcpz and SIVgor strains with considerable breadth and potency, including in primary chimpanzee CD4(+) T cells. These reagents provide an important first step toward translating intervention strategies currently developed to treat and prevent AIDS in humans to SIV-infected apes.
authors.affiliation: Departments of Medicine and Microbiology, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Hannah J
authors.initials: HJ
authors.lastname: Barbian
authors.affiliation: Department of Microbiology, The University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors.forename: Julie M
authors.initials: JM
authors.lastname: Decker
authors.affiliation: Departments of Medicine and Microbiology, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Frederic
authors.initials: F
authors.lastname: Bibollet-Ruche
authors.affiliation: Division of Biology and Biological Engineering and Howard Hughes Medical Institute, California Institute of Technology, Pasadena, California, USA.
authors.forename: Rachel P
authors.initials: RP
authors.lastname: Galimidi
authors.affiliation: Division of Biology and Biological Engineering and Howard Hughes Medical Institute, California Institute of Technology, Pasadena, California, USA.
authors.forename: Anthony P
authors.initials: AP
authors.lastname: West
authors.affiliation: Departments of Medicine and Microbiology, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Gerald H
authors.initials: GH
authors.lastname: Learn
authors.affiliation: Departments of Medicine and Microbiology, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Nicholas F
authors.initials: NF
authors.lastname: Parrish
authors.affiliation: Departments of Medicine and Microbiology, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Shilpa S
authors.initials: SS
authors.lastname: Iyer
authors.affiliation: Departments of Medicine and Microbiology, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Yingying
authors.initials: Y
authors.lastname: Li
authors.affiliation: Gilead Sciences, Foster City, California, USA.
authors.forename: Craig S
authors.initials: CS
authors.lastname: Pace
authors.affiliation: Aaron Diamond AIDS Research Center, The Rockefeller University, New York, New York, USA.
authors.forename: Ruijiang
authors.initials: R
authors.lastname: Song
authors.affiliation: Aaron Diamond AIDS Research Center, The Rockefeller University, New York, New York, USA.
authors.forename: Yaoxing
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Duke Human Vaccine Institute, Duke University School of Medicine, Durham, North Carolina, USA.
authors.forename: Thomas N
authors.initials: TN
authors.lastname: Denny
authors.forename: Hugo
authors.initials: H
authors.lastname: Mouquet
authors.affiliation: CEA, iBiTecS, Service d'Ingénierie Moléculaire des Protéines, Gif-sur-Yvette, France.
authors.forename: Loic
authors.initials: L
authors.lastname: Martin
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Priyamvada
authors.initials: P
authors.lastname: Acharya
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Baoshan
authors.initials: B
authors.lastname: Zhang
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Peter D
authors.initials: PD
authors.lastname: Kwong
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: John R
authors.initials: JR
authors.lastname: Mascola
authors.affiliation: QVQ BV, Utrecht, the Netherlands.
authors.forename: C Theo
authors.initials: CT
authors.lastname: Verrips
authors.affiliation: Biomolecular Imaging (BMI), Faculty of Science, Utrecht University, Utrecht, the Netherlands.
authors.forename: Nika M
authors.initials: NM
authors.lastname: Strokappe
authors.affiliation: Biomolecular Imaging (BMI), Faculty of Science, Utrecht University, Utrecht, the Netherlands.
authors.forename: Lucy
authors.initials: L
authors.lastname: Rutten
authors.affiliation: Division of Infection and Immunity, University College London, London, United Kingdom.
authors.forename: Laura E
authors.initials: LE
authors.lastname: McCoy
authors.affiliation: Division of Infection and Immunity, University College London, London, United Kingdom.
authors.forename: Robin A
authors.initials: RA
authors.lastname: Weiss
authors.affiliation: Chimp Haven, Inc., Keithville, Louisiana, USA.
authors.forename: Corrine S
authors.initials: CS
authors.lastname: Brown
authors.affiliation: Chimp Haven, Inc., Keithville, Louisiana, USA.
authors.forename: Raven
authors.initials: R
authors.lastname: Jackson
authors.affiliation: Yerkes Regional Primate Research Center, Emory University, Atlanta, Georgia, USA.
authors.forename: Guido
authors.initials: G
authors.lastname: Silvestri
authors.affiliation: Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Connors
authors.affiliation: Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, California, USA.
authors.forename: Dennis R
authors.initials: DR
authors.lastname: Burton
authors.affiliation: Departments of Medicine and Microbiology, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: George M
authors.initials: GM
authors.lastname: Shaw
authors.affiliation: Laboratory of Molecular Immunology and Howard Hughes Medical Institute, The Rockefeller University, New York, New York, USA.
authors.forename: Michel C
authors.initials: MC
authors.lastname: Nussenzweig
authors.affiliation: Division of Biology and Biological Engineering and Howard Hughes Medical Institute, California Institute of Technology, Pasadena, California, USA.
authors.forename: Pamela J
authors.initials: PJ
authors.lastname: Bjorkman
authors.affiliation: Aaron Diamond AIDS Research Center, The Rockefeller University, New York, New York, USA.
authors.forename: David D
authors.initials: DD
authors.lastname: Ho
authors.affiliation: Department of Immunology and Microbial Science, The Scripps Research Institute, Jupiter, Florida, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Farzan
authors.affiliation: Departments of Medicine and Microbiology, University of Pennsylvania, Philadelphia, Pennsylvania, USA bhahn@upenn.edu.
authors.forename: Beatrice H
authors.initials: BH
authors.lastname: Hahn
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000276:immunology*; D003429:Cross Reactions; D006071:Gorilla gorilla; D015483:HIV Antibodies / Q000276:immunology*; D006801:Humans; D020128:Inhibitory Concentration 50; D009500:Neutralization Tests; D002679:Pan troglodytes; D016097:Simian Acquired Immunodeficiency Syndrome / Q000821:virology*; D015302:Simian Immunodeficiency Virus / Q000276:immunology* / Q000302:isolation & purification
chemical_list: D057134:Antibodies, Neutralizing; D015483:HIV Antibodies