Neutralization Properties of Simian Immunodeficiency Viruses Infecting Chimpanzees and Gorillas

Hannah Barbian (1) , Julie Decker (2) , Frederic Bibollet-Ruche (1) , Rachel Galimidi (3) , Anthony West (3) , Gerald H Learn (1) , Nicholas F Parrish (1) , Shilpa Iyer (1) , Yingying Li (1) , Craig Pace (4) , Ruijiang Song (5) , Yaoxing Huang (5) , Thomas Denny (6) , Hugo Mouquet (7, 8) , Loïc M Martin (9) , Priyamvada Acharya (10) , Baoshan Zhang (10) , Peter D. Kwong (10) , John R. Mascola (10) , C. Theo Verrips (11) , Nika Strokappe (12) , Lucy Rutten (12) , Laura Mccoy (13) , Robin Weiss (13) , Corrine Brown (14) , Raven Jackson (14) , Guido Silvestri (15) , Mark Connors (16) , Dennis Burton (17) , George Shaw (1) , Michel C. Nussenzweig (18) , Pamela Bjorkman (3) , David Ho (5) , Michael Farzan (17) , Beatrice H Hahn (1)

1 University of Pennsylvania
2 UAB - University of Alabama at Birmingham [ Birmingham]
3 CALTECH - California Institute of Technology
4 Gilead Sciences, Inc. [Foster City, CA, USA]
5 Aaron Diamond AIDS Research Center [New York]
6 Duke Human Vaccine Institute [Durham, North Carolina, USA]
7 Immunologie humorale - Humoral Immunology
8 HHMI - Howard Hughes Medical Institute [New York]
9 SIMoS - Service d'Ingénierie Moléculaire pour la Santé (ex SIMOPRO)
10 VRC - Vaccine Research Center
11 QVQ Holding B.V.
12 Universiteit Utrecht / Utrecht University [Utrecht]
13 Division of Infection and Immunity [London, UK]
14 Chimp Haven [Keithville]
15 Yerkes Regional Primate Research Center [Atlanta]
16 Laboratory of Immunoregulation [Bethesda, MD, USA]
17 Department of Immunology and Microbial Sciences [La Jolla]
18 Laboratory of Molecular Immunology [Rockfeller university, NY]

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-Igmim2, 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. IMPORTANCE 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.

Domaines: Immunothérapie; Vaccinologie; Médecine vétérinaire et santé animale

Hannah Barbian, Julie Decker, Frederic Bibollet-Ruche, Rachel Galimidi, Anthony West, et al.. Neutralization Properties of Simian Immunodeficiency Viruses Infecting Chimpanzees and Gorillas. mBio, 2015, 6 (2), ⟨10.1128/mBio.00296-15⟩. ⟨cea-02530869⟩