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. 1999 Dec;73(12):10320-8.

Experimental Infection of Rhesus and Pig-Tailed Macaques With Macaque Rhadinoviruses

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Free PMC article

Experimental Infection of Rhesus and Pig-Tailed Macaques With Macaque Rhadinoviruses

K G Mansfield et al. J Virol. .
Free PMC article

Abstract

The recognition of naturally occurring rhadinoviruses in macaque monkeys has spurred interest in their use as models for human infection with Kaposi sarcoma-associated herpesvirus (human herpesvirus 8). Rhesus macaques (Macaca mulatta) and pig-tailed macaques (Macaca nemestrina) were inoculated intravenously with rhadinovirus isolates derived from these species (rhesus rhadinovirus [RRV] and pig-tailed rhadinovirus [PRV]). Nine rhadinovirus antibody-negative and two rhadinovirus antibody-positive monkeys were used for these experimental inoculations. Antibody-negative animals clearly became infected following virus inoculation since they developed persisting antibody responses to virus and virus was isolated from peripheral blood on repeated occasions following inoculation. Viral sequences were also detected by PCR in lymph node, oral mucosa, skin, and peripheral blood mononuclear cells following inoculation. Experimentally infected animals developed peripheral lymphadenopathy which resolved by 12 weeks following inoculation, and these animals have subsequently remained free of disease. No increased pathogenicity was apparent from cross-species infection, i.e., inoculation of rhesus macaques with PRV or of pig-tailed macaques with RRV, whether the animals were antibody positive or negative at the time of virus inoculation. Coinoculation of additional rhesus monkeys with simian immunodeficiency virus (SIV) isolate SIVmac251 and macaque-derived rhadinovirus resulted in an attenuated antibody response to both agents and shorter mean survival compared to SIVmac251-inoculated controls (155.5 days versus 560.1 days; P < 0.019). Coinfected and immunodeficient macaques died of a variety of opportunistic infections characteristic of simian AIDS. PCR analysis of sorted peripheral blood mononuclear cells indicated a preferential tropism of RRV for CD20(+) B lymphocytes. Our results demonstrate persistent infection of macaque monkeys with RRV and PRV following experimental inoculation, but no specific disease was readily apparent from these infections even in the context of concurrent SIV infection.

Figures

FIG. 1
FIG. 1
Antibody responses following experimental inoculation with RRV or PRV. (A) Antibody response to RRV by ELISA in macaque monkeys inoculated with RRV. Mm, M. mulatta; Mn, M. nemestrina. (B) Antibody response to PRV by ELISA in macaque monkeys inoculated with PRV. (C) Antibody response to PRV by ELISA in rhesus monkeys 190-96 and 195-96 inoculated with PRV. Tests in panels A and B were performed with a 1:20 dilution of plasma and 1:100 conjugate, and tests in panel C were performed with a 1:200 dilution of plasma and 1:100 conjugates.
FIG. 2
FIG. 2
Semiquantitative recovery of RRV from PBMC of inoculated monkeys. The numbers of infectious cells in PBMC were quantitated as described in Materials and Methods. Code for PBMC load: 0, virus was not recovered even when 106 PBMC were used; 1, virus was recovered with an average of 106 but not fewer PBMC; 2, 333,333 PBMC; 3, 111,111 PBMC; 4, 37,037 PBMC; 5, 12,345 PBMC. Mm, M. mulatta; Mn, M. nemestrina.
FIG. 3
FIG. 3
Morphologic features associated with experimental inoculation with RRV. (A) Marked paracortical lymphocytic hyperplasia 2 weeks following RRV inoculation in an immunocompetent rhesus macaque. Hematoxylin-and-eosin (H&E) stain; magnification, ×53. (B) Paracortical expansion accompanied by an abundance of small arborizing vessels lined by hypertrophied and hyperplastic endothelium in an immunocompetent rhesus macaque. H&E stain; magnification, ×106. (C) Increased numbers of immunoblasts and mitotic figures 2 weeks after RRV inoculation in an immunocompetent rhesus macaque. H&E stain; magnification, ×315. (D) Marked follicular hyperplasia effacing normal lymph node architecture 4 weeks after RRV inoculation in an immunocompetent rhesus macaque. H&E stain; magnification, ×53. (E) Germinal center surrounded by loosely concentric layers of lymphocytes 12 weeks after RRV inoculation in an immunocompetent rhesus macaque. H&E stain; magnification, ×106. (F) Hyalinized germinal center 12 weeks after RRV inoculation in an immunocompetent rhesus macaque. (G) Proliferative vasculitis 4 weeks after RRV inoculation of an SIV-infected immunodeficient rhesus macaque. H&E stain; magnification, ×315.
FIG. 4
FIG. 4
Antibody responses to PRV following PRV inoculation into SIV-infected M. mulatta (Mm) monkeys.
FIG. 5
FIG. 5
Antibody responses to RRV or PRV in M. mulatta (Mm) monkeys coinoculated with SIV and RRV or SIV and PRV.
FIG. 6
FIG. 6
Anti-SIV antibody responses in M. mulatta (Mm) monkeys inoculated with SIV and RRV, SIV and PRV, or SIV alone. conj, conjugate.
FIG. 6
FIG. 6
Anti-SIV antibody responses in M. mulatta (Mm) monkeys inoculated with SIV and RRV, SIV and PRV, or SIV alone. conj, conjugate.
FIG. 7
FIG. 7
SIV RNA loads in plasma in monkeys inoculated with SIV alone, or SIV and RRV, or SIV and PRV. Numbers in parentheses refer to numbers of animals used for determining the average for each data point.
FIG. 8
FIG. 8
RRV DNA in sorted cells. Products of PCR for RRV DNA in sorted cells were visualized by ethidium bromide staining following agarose gel electrophoresis. MW, molecular weight; FACS, fluorescence-activated cell sorting.

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