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KSHV targets multiple leukocyte lineages during long-term productive infection in NOD/SCID mice
Christopher H. Parsons, … , David Camerini, Dean H. Kedes
Christopher H. Parsons, … , David Camerini, Dean H. Kedes
Published July 3, 2006
Citation Information: J Clin Invest. 2006;116(7):1963-1973. https://doi.org/10.1172/JCI27249.
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Research Article Virology

KSHV targets multiple leukocyte lineages during long-term productive infection in NOD/SCID mice

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Abstract

To develop an animal model of Kaposi sarcoma–associated herpesvirus (KSHV) infection uniquely suited to evaluate longitudinal patterns of viral gene expression, cell tropism, and immune responses, we injected NOD/SCID mice intravenously with purified virus and measured latent and lytic viral transcripts in distal organs over the subsequent 4 months. We observed sequential escalation of first latent and then lytic KSHV gene expression coupled with electron micrographic evidence of virion production within the murine spleen. Using novel technology that integrates flow cytometry with immunofluorescence microscopy, we found that the virus establishes infection in murine B cells, macrophages, NK cells, and, to a lesser extent, dendritic cells. To investigate the potential for human KSHV–specific immune responses within this immunocompromised host, we implanted NOD/SCID mice with functional human hematopoietic tissue grafts (NOD/SCID-hu mice) and observed that a subset of animals produced human KSHV–specific antibodies. Furthermore, treatment of these chimeric mice with ganciclovir at the time of inoculation led to prolonged but reversible suppression of KSHV DNA and RNA levels, suggesting that KSHV can establish latent infection in vivo despite ongoing suppression of lytic replication.

Authors

Christopher H. Parsons, Laura A. Adang, Jon Overdevest, Christine M. O’Connor, J. Robert Taylor, David Camerini, Dean H. Kedes

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Figure 1

Sequential increases in KSHV genomic DNA, latent (ORF73) and lytic (ORF50 and ORF65) transcripts within the spleens of KSHV-injected NOD/SCID mice.

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Sequential increases in KSHV genomic DNA, latent (ORF73) and lytic (ORF5...
Mice were administered 3 weekly doses of KSHV (squares, solid lines) or UV-KSHV (triangles, dashed lines) intravenously and euthanized 1 day (DNA only) and 1, 2, and 4 months following the third injection. (A) Genomic KSHV DNA values were determined using qPCR to calculate the ΔCt, representing KSHV Ct normalized to mouse GAPDH Ct (mean of triplicate determinations for each) for each sample. (B–D) Total splenic RNA was subjected to qRT-PCR using primers specific for ORFs 73 (B), 50 (C), and 65 (D) as well as mouse GAPDH. ΔδCt = (ΔCt(G)) – (ΔCt(K)), where ΔCt(K) and ΔCt(G) are the differences between the Ct of each sample (mean of duplicate determinations) without and with reverse transcriptase (RT) for KSHV (K) and GAPDH (G), respectively. Each symbol represents the mean and SE of ΔCt (A) or ΔδCt (B–D). Numbers of mice are indicated in parentheses. Graph-wide dotted lines mark the lower limit of sensitivity of each assay. Of note, UV-KSHV did not establish infection within either primary dermal microvascular endothelial cells (pDMVECs) or HeLa cells in vitro (not shown).
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