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Pathogenesis and Immunity

TRIM5α Restriction Affects Clinical Outcome and Disease Progression in Simian Immunodeficiency Virus-Infected Rhesus Macaques

Fan Wu, Ilnour Ourmanov, Nadeene Riddick, Kenta Matsuda, Sonya Whitted, Ronald J. Plishka, Alicia Buckler-White, Matthew F. Starost, Vanessa M. Hirsch
F. Kirchhoff, Editor
Fan Wu
aLaboratory of Molecular Microbiology, NIAID, NIH, Bethesda, Maryland, USA
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Ilnour Ourmanov
aLaboratory of Molecular Microbiology, NIAID, NIH, Bethesda, Maryland, USA
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Nadeene Riddick
aLaboratory of Molecular Microbiology, NIAID, NIH, Bethesda, Maryland, USA
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Kenta Matsuda
aLaboratory of Molecular Microbiology, NIAID, NIH, Bethesda, Maryland, USA
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Sonya Whitted
aLaboratory of Molecular Microbiology, NIAID, NIH, Bethesda, Maryland, USA
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Ronald J. Plishka
aLaboratory of Molecular Microbiology, NIAID, NIH, Bethesda, Maryland, USA
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Alicia Buckler-White
aLaboratory of Molecular Microbiology, NIAID, NIH, Bethesda, Maryland, USA
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Matthew F. Starost
bDivision of Veterinary Resources, OD, ORS, NIH, Bethesda, Maryland, USA
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Vanessa M. Hirsch
aLaboratory of Molecular Microbiology, NIAID, NIH, Bethesda, Maryland, USA
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F. Kirchhoff
Roles: Editor
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DOI: 10.1128/JVI.02978-14
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  • FIG 1
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    FIG 1

    Replication of SIVsmE543-3 and SIVsmE543-3 S37S98 in macaques with the TRIM5TFP/TFP genotype. Viral loads were quantified and are shown as RNA copies in rhesus macaques infected with SIVsmE543-3 (red) or SIVsmE543-3 S37S98 (blue). vRNA, viral RNA.

  • FIG 2
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    FIG 2

    Survival curves of macaques infected with SIVsmE543-3 or SIVsmE543-3 S37S98. The cumulative survival rates of macaques infected with SIVsmE543-3 (red) or SIVsmE543-3 S37S98 (blue) are shown as Kaplan-Meier curves and were compared by a log rank test (P = 0.0141).

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    FIG 3

    Peripheral CD4+ T cell kinetics. (A to C) Peripheral CD4+ T cells (A), central memory CD4+ T cells (CD28+ CD95+) (B), and naïve CD4+ T cells (CD28+ CD95−) (C) were quantified by FACS and are shown as the absolute numbers per microliter of blood. (D to F) The kinetics of total CD4+ T cells (D), central memory CD4+ T cells (E), and naïve CD4+ T cells (F) at the acute phase of infection for groups infected with SIVsmE543-3 (red line) or SIVsmE543-3 S37S98 (blue line) were compared by two-way ANOVA.

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    FIG 4

    Variance of the SIV capsid sequence at chronic and late stages of infection. The nucleotide sequences encoding the capsid domains of SIV Gag cloned from the plasma of macaques Rh824, Rh825, and Rh831 (SIVsmE543-3 infected) and from the plasma of macaques Rh826, Rh827, Rh832, Rh833, and Rh835 (SIVsmE543-3 S37S98 infected) were aligned to the SIVSmE543-3 capsid sequence. The sequences encoding the capsid N-terminal domains are shown. Codons 37 and 98, which are associated with TRIM5α sensitivity, are highlighted in yellow. w.p.i., weeks postinfection.

Tables

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  • TABLE 1

    Summary of clinical and pathological findings

    Inoculated virusMacaqueMHC genotypeaTime to death (weeks p.i.)Clinical and pathological findingsOpportunistic agent
    SIVsmE543-3Rh824A08, B01105Seizures, interstitial pneumonia, splenomegaly, PMLSV40
    Rh825A02, B01SurvivingN/AbN/A
    Rh828A01, A08, B17SurvivingN/AN/A
    Rh829NegativeSurvivingN/AN/A
    Rh830A08SurvivingN/AN/A
    Rh831B1795Lymphoproliferative disorder (kidney, lymph nodes, spleen), enteritisN/Dc
    SIVsmE543-3 S37S98Rh826B0111Significant weight loss, diarrhea, severe enterocolitisBrachyspira
    Rh827A02, A0863Severe diarrhea, severe enterocolitisCytomegalovirus
    Rh832A01, B0193Diarrhea, lymphoproliferative disorder (kidney, lymph nodes, spleen), enteritisN/D
    Rh833A08, B01, B0854Diarrhea, PML, esophagitis, enterocolitisCandida, SV40
    Rh834B17SurvivingN/AN/A
    Rh835Negative41Severe diarrhea, enterocolitis, focal pyogranulomatous lymphadenitisN/D
    • ↵a Restrictive alleles Mamu-A01, -B08, and -B17 are shown in boldface.

    • ↵b N/A, not available.

    • ↵c N/D, not detected.

  • TABLE 2

    Summary of amino acid substitutions in progressors

    Virus and macaqueTime point (weeks p.i.)aCapsid amino acid at position:
    3798
    SIVsmE543-3PR
        Rh82440SG
    105*ST
        Rh82560SR/I
    106*ST
        Rh83148SR
    95*SR/S
    SIVsmE543-3 S37S98SS
        Rh82611*SS
        Rh82736SS
    63*SS
        Rh83235SS
    93*SS
        Rh83354*SS
        Rh83541*SS
    • ↵a *, necropsy time point.

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TRIM5α Restriction Affects Clinical Outcome and Disease Progression in Simian Immunodeficiency Virus-Infected Rhesus Macaques
Fan Wu, Ilnour Ourmanov, Nadeene Riddick, Kenta Matsuda, Sonya Whitted, Ronald J. Plishka, Alicia Buckler-White, Matthew F. Starost, Vanessa M. Hirsch
Journal of Virology Jan 2015, 89 (4) 2233-2240; DOI: 10.1128/JVI.02978-14

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TRIM5α Restriction Affects Clinical Outcome and Disease Progression in Simian Immunodeficiency Virus-Infected Rhesus Macaques
Fan Wu, Ilnour Ourmanov, Nadeene Riddick, Kenta Matsuda, Sonya Whitted, Ronald J. Plishka, Alicia Buckler-White, Matthew F. Starost, Vanessa M. Hirsch
Journal of Virology Jan 2015, 89 (4) 2233-2240; DOI: 10.1128/JVI.02978-14
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