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In vivo characterization of macrophage-tropic simian immunodeficiency virus molecular clones in rhesus macaques

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Abstract

Macrophages are a major target of HIV/SIV infection and play an important role in pathogenesis by serving as viral reservoirs in the central nervous system. Previously, a unique early SIVmac251 envelope (Env) variant, deSIV147 was cloned from blood of a rhesus macaque with rapid disease progression and SIV-associated encephalitis. Here, we show that infectious molecular clone deSIV147 caused systemic infection in rhesus macaques following intravenous or intrarectal exposure. Next, we inoculated deSIV147 into macaques depleted of CD4+ T cells and found that animals were SIV-positive, with high plasma and CSF viral loads. These macaques also showed SIVp17-positive macrophages in brain, lymph nodes, colon, lung, and liver. Furthermore, accumulation of perivascular macrophages, multinucleated giant cells, and microgliosis was detected. These findings suggest that the neurotropic deSIV147 clone will be useful to study macrophage infection in HIV/SIV-associated neurocognitive disorders, gain insights into myeloid cell reservoirs in brain and other anatomical sites, as well as test strategies for eradication.

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Acknowledgements

We thank Ms. Stephanie Ehnert and the veterinary/support staff of the Yerkes National Primate Research center for their help in conducting macaque studies.

Funding

This study was supported in part by NIH R01AI113883 & R21AI114415 to SNB. DG was supported by NIH R01 MH 97659. Several antibodies and TZm-bl cells were obtained from NIH AIDS Reagent Reference Program.

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Authors and Affiliations

  1. Division of Pathology, Yerkes National Primate Research Center, Emory University, Atlanta, 30329, GA, Georgia

    Sanjeev Gumber

  2. New Iberia Research Center, University of Louisiana at Lafayette, New Iberia, LA, 70560, USA

    Praveen Kumar Amancha & Francois Villinger

  3. Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA

    Po-Jen Yen & Dana Gabuzda

  4. Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, 68198, USA

    Siddappa N. Byrareddy

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  1. Sanjeev Gumber
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  2. Praveen Kumar Amancha
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  3. Po-Jen Yen
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  6. Siddappa N. Byrareddy
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Correspondence to Siddappa N. Byrareddy.

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Electronic supplementary material

Supplementary Fig.S1

Frequencies of classical monocytes (CD14+16-), intermediate monocytes (CD14+CD16+), and mDCs (CD3-CD8-CD20-CD14-CD16-HLADR+CD11c+) from CD4+ T cells depleted (top panel) and non-depleted (bottom panel) animals are shown. (TIFF 661 kb) (GIF 47 kb)

High resolution image (TIFF 661 kb)

Supplementary Fig.S2:

Area under curve data for the CD14+16- (classical monocytes) is calculated from the longitudinal data shown in supplementary Fig S1A. A) is the data on individual animal and B) is the Mean and SD of both the groups. The sample size is too small to perform statistical analysis for the observed difference between the two groups. (TIFF 103 kb) (GIF 18 kb)

high resolution image (TIFF 103 kb)

Supplementary Fig.S3:

IHC staining from representative tissue sections from CD4+ T cells depleted SIVmac251desiv147#C4 infected rhesus macaques (RDn15 & RCb15). Cervical lymph node (A), lung (B), small intestine (C), and mesenteric lymph node (D) showing SIVmac251 p17 (green) and CD68 (Fuchsin-red) labeled cells along with SIV/CD68 colocalization. (TIFF 661 kb) (TIFF 15577 kb) (GIF 362 kb)

High resolution image (TIFF 15577 kb)

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Gumber, S., Amancha, P.K., Yen, PJ. et al. In vivo characterization of macrophage-tropic simian immunodeficiency virus molecular clones in rhesus macaques. J. Neurovirol. 24, 411–419 (2018). https://doi.org/10.1007/s13365-018-0628-2

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  • DOI: https://doi.org/10.1007/s13365-018-0628-2

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