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Vpx is required for dissemination and pathogenesis of SIVSM PBj: Evidence of macrophage-dependent viral amplification

Nature Medicine volume 4, pages 1401–1408 (1998)Cite this article

Abstract

The viral accessory protein Vpx is required for productive in vitro infection of macrophages by simian immunodeficiency virus from sooty mangabey monkeys (SIV SM ). To evaluate the roles of Vpx and macrophage infection in vivo , we inoculated pigtailed macaques intravenously or intrarectally with the molecularly cloned, macrophage tropic, acutely pathogenic virus SIV SM PBj 6.6, or accessory gene deletion mutants (ΔVpr or ΔVpx) of this virus. Both wild-type and SIV SM PBj ΔVpx viruses were readily transmitted across the rectal mucosa. A subsequent 'stepwise' process of local amplification of infection and dissemination was observed for wild-type virus, but not for SIV SM PBj ΔVpx, which also showed considerable impairment of the overall kinetics and extent of its replication. In animals co-inoculated with equivalent amounts of wild-type and SIV SM Pbj ΔVpx intravenously or intrarectally, the ΔVpx mutant was at a strong competitive disadvantage. Vpx-dependent viral amplification at local sites of initial infection, perhaps through a macrophage-dependent mechanism, may be a prerequisite for efficient dissemination of infection and pathogenic consequences after exposure through either mucosal or intravenous routes.

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Figure 1: Kinetics of plasma viremia and lymphopenia in macaques inoculated intrarectally with ΔVpr (left graphs: □, 541; ○, 547) or ΔVpx mutants (right graphs: □, 607; ○, 608) or with WT SIVSM PBj (▪, 526; •, 539).
Figure 2: Kinetics of plasma viremia and lymphopenia in macaques inoculated intravenously with ΔVpr (left graphs: □, 437; ○, 453) or ΔVpx mutants (right graphs: □, 537; ○, 549) or with WT SIVSM PBj (▪, 123; •, 389).
Figure 3: Representative SIV-specific in situ hybridization and immunohistochemistry for Ham-56 (macrophage marker) in tissues of macaques inoculated intrarectally with either WT SIVSM PBj (a,d–g) or the ΔVpx mutant virus (b and c).
Figure 4: Double labeling for SIV expression and cell surface expression of CD3 or Ham56 (macrophage) in rectal sections collected at peak viremia, demonstrating both SIV-infected T lymphocytes (top row, a–c) and macrophages (middle row, d–f).
Figure 5: Replication and proportional representation of SIVSM PBj WT, ΔVpr and ΔVpx mutant viruses after intravenous or intrarectal co-inoculation.

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Acknowledgements

The authors thank S. Mc Pherson (UAB CFAR Protein Expression Core) for construction of the PBj 6.6 X2 and R2 clones, and T. Wiltrout and G. Vasquez for technical assistance with viral load analyses. This research was supported in part by grants AI37475, HL57880 and RR11589 (MS) and AI34748 and U01 AI 35282 (BHH) and with federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. NO1-CO-56000.

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Authors and Affiliations

  1. Laboratory of Molecular Microbiology, NIAID Twinbrook Facility, Rockville, 20852, Maryland, USA

    V.M. Hirsch, C.R. Brown & S. Goldstein

  2. University of Massachusetts Medical Center, Program in Molecular Medicine, Worcester, 01605, Massachusetts, USA

    M.E. Sharkey, B. Brichacek & M. Stevenson

  3. University of Alabama at Birmingham, Birmingham, 38294, Alabama, USA

    J. Wakefield & B.H. Hahn

  4. Bioqual Inc., Rockville, 20850, Maryland, USA

    R. Byrum

  5. Laboratory of Infectious Diseases, NIAID Twinbrook Facility, Rockville, 20852, Maryland, USA

    W.R. Elkins

  6. Laboratory of Retroviral Pathogenesis, AIDS Vaccine Program, NCI-Frederick Cancer Research and Development Center, Frederick, 21702, Maryland, USA

    J.D. Lifson

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Hirsch, V., Sharkey, M., Brown, C. et al. Vpx is required for dissemination and pathogenesis of SIVSM PBj: Evidence of macrophage-dependent viral amplification. Nat Med 4, 1401–1408 (1998). https://doi.org/10.1038/3992

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