title: Heterogeneity in neutralization sensitivities of viruses comprising the simian immunodeficiency virus SIVsmE660 isolate and vaccine challenge stock.
abstract: The sooty mangabey-derived simian immunodeficiency virus (SIV) strain E660 (SIVsmE660) is a genetically heterogeneous, pathogenic isolate that is commonly used as a vaccine challenge strain in the nonhuman primate (NHP) model of human immunodeficiency virus type 1 (HIV-1) infection. Though it is often employed to assess antibody-based vaccine strategies, its sensitivity to antibody-mediated neutralization has not been well characterized. Here, we utilize single-genome sequencing and infectivity assays to analyze the neutralization sensitivity of the uncloned SIVsmE660 isolate, individual viruses comprising the isolate, and transmitted/founder (T/F) viruses arising from low-dose mucosal inoculation of macaques with the isolate. We found that the SIVsmE660 isolate overall was highly sensitive to neutralization by SIV-infected macaque plasma samples (50% inhibitory concentration [IC50] < 10(-5)) and monoclonal antibodies targeting V3 (IC50 < 0.01 μg/ml), CD4-induced (IC50 < 0.1 μg/ml), CD4 binding site (IC50 ~ 1 μg/ml), and V4 (IC50, ~5 μg/ml) epitopes. In comparison, SIVmac251 and SIVmac239 were highly resistant to neutralization by these same antibodies. Differences in neutralization sensitivity between SIVsmE660 and SIVmac251/239 were not dependent on the cell type in which virus was produced or tested. These findings indicate that in comparison to SIVmac251/239 and primary HIV-1 viruses, SIVsmE660 generally exhibits substantially less masking of antigenically conserved Env epitopes. Interestingly, we identified a minor population of viruses (~10%) in both the SIVsmE660 isolate and T/F viruses arising from it that were substantially more resistant (>1,000-fold) to antibody neutralization and another fraction (~20%) that was intermediate in neutralization resistance. These findings may explain the variable natural history and variable protection afforded by heterologous Env-based vaccines in rhesus macaques challenged by high-dose versus low-dose SIVsmE660 inoculation regimens.
authors.affiliation: University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Lopker
authors.forename: Juliet
authors.initials: J
authors.lastname: Easlick
authors.forename: Sarah
authors.initials: S
authors.lastname: Sterrett
authors.forename: Julie M
authors.initials: JM
authors.lastname: Decker
authors.forename: Hannah
authors.initials: H
authors.lastname: Barbian
authors.forename: Gerald
authors.initials: G
authors.lastname: Learn
authors.forename: Brandon F
authors.initials: BF
authors.lastname: Keele
authors.forename: James E
authors.initials: JE
authors.lastname: Robinson
authors.forename: Hui
authors.initials: H
authors.lastname: Li
authors.forename: Beatrice H
authors.initials: BH
authors.lastname: Hahn
authors.forename: George M
authors.initials: GM
authors.lastname: Shaw
authors.forename: Katharine J
authors.initials: KJ
authors.lastname: Bar
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000276:immunology*; D000914:Antibodies, Viral / Q000276:immunology*; D016665:Cercocebus atys; D004195:Disease Models, Animal; D014644:Genetic Variation; D016679:Genome, Viral; D020128:Inhibitory Concentration 50; D008253:Macaca mulatta; D008969:Molecular Sequence Data; D009500:Neutralization Tests; D017422:Sequence Analysis, DNA; D016097:Simian Acquired Immunodeficiency Syndrome / Q000276:immunology* / Q000517:prevention & control* / Q000821:virology; D015302:Simian Immunodeficiency Virus / Q000145:classification / Q000235:genetics* / Q000276:immunology* / Q000302:isolation & purification
chemical_list: D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral