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Induction of B cell hyperplasia in simian immunodeficiency virus-infected rhesus macaques with the simian homologue of Kaposi's sarcoma-associated herpesvirus.

Wong SW, Bergquam EP, Swanson RM, Lee FW, Shiigi SM, Avery NA, Fanton JW, Axthelm MK - J. Exp. Med. (1999)

Bottom Line: Hypergammaglobulinemia was associated with severe immune-mediated hemolytic anemia in one RRV/SIV-infected macaque.Infectious RRV and RRV DNA were present in hyperplastic lymphoid tissues of the RRV/SIV-infected macaques, suggesting that lymphoid hyperplasia is associated with the high levels of replication.Thus, experimental RRV 17577 infection of SIV-infected rhesus macaques induces some of the hyperplastic B cell LPDs manifested in AIDS patients coinfected with KSHV.

View Article: PubMed Central - PubMed

Affiliation: Division of Pathobiology, Oregon Regional Primate Research Center, Beaverton, Oregon 97006, USA. wongs@ohsu.edu

ABSTRACT
A simian homologue of Kaposi's sarcoma-associated herpesvirus (KSHV), the eighth human herpesvirus (HHV8), was isolated from a simian immunodeficiency virus (SIV)-infected rhesus macaque (Macaca mulatta) that developed a multicentric lymphoproliferative disorder (LPD). This simian rhadinovirus is genetically similar to a recently described rhesus rhadinovirus (RRV) (Desrosiers, R.C., V.G. Sasseville, S.C. Czajak, X. Zhang, K.G. Mansfield, A. Kaur, R.P. Johnson, A.A. Lackner, and J.U. Jung. 1997. J. Virol. 71:9764-9769) and is designated RRV 17577. RRV 17577 was experimentally inoculated into rhesus macaques with and without SIV(mac239) infection to determine if RRV played a role in development of the LPD observed in the index case. In contrast to control animals inoculated with SIV(mac239) or RRV alone, two animals coinfected with SIV(mac239) and RRV 17577 developed hyperplastic LPD resembling the multicentric plasma cell variant of Castleman's disease, characterized by persistent angiofollicular lymphadenopathy, hepatomegaly, splenomegaly, and hypergammaglobulinemia. Hypergammaglobulinemia was associated with severe immune-mediated hemolytic anemia in one RRV/SIV-infected macaque. Both RRV/SIV-infected macaques exhibited persistent RRV viremia with little or no RRV-specific antibody response. The macaques inoculated with RRV alone displayed transient viremia followed by a vigorous anti-RRV antibody response and lacked evidence of LPD in peripheral blood and lymph nodes. Infectious RRV and RRV DNA were present in hyperplastic lymphoid tissues of the RRV/SIV-infected macaques, suggesting that lymphoid hyperplasia is associated with the high levels of replication. Thus, experimental RRV 17577 infection of SIV-infected rhesus macaques induces some of the hyperplastic B cell LPDs manifested in AIDS patients coinfected with KSHV.

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PCR amplification and hybridization for RRV in BM from an animal (17577) with LPD. (a) Semiquantitative PCR of BM-derived DNA from the SIV-infected animal with LPD for RRV MIP. Lane 1, BM-derived DNA; lane 2, 100 pg of DNA from uninfected cells; lane 3, 100 pg of DNA from uninfected cells plus 100 fg of vDNA; lane 4, 100 pg of DNA from uninfected cells plus 1 pg of vDNA; lane 5, 100 pg of DNA from uninfected cells plus 10 pg of vDNA; lane 6, 100 pg of DNA from uninfected cells plus 100 pg of vDNA. (b) PCR and Southern blot analysis of DNA amplified from BM for RRV MIP or rhesus β-globin gene. The source for each BM sample is indicated above each lane. The negative (−) control is DNA isolated from uninfected rhesus fibroblasts. (c) Southern blot analysis of DNA PCR amplified with oligonucleotide primers specific for the rhesus (Rh)EBV LMP-1 gene or rhesus β-globin gene. The source for each sample is indicated above each lane. The negative (−) control is DNA isolated from uninfected rhesus fibroblasts, and the positive (+) control is DNA from RhEBV-infected cells.
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Figure 3: PCR amplification and hybridization for RRV in BM from an animal (17577) with LPD. (a) Semiquantitative PCR of BM-derived DNA from the SIV-infected animal with LPD for RRV MIP. Lane 1, BM-derived DNA; lane 2, 100 pg of DNA from uninfected cells; lane 3, 100 pg of DNA from uninfected cells plus 100 fg of vDNA; lane 4, 100 pg of DNA from uninfected cells plus 1 pg of vDNA; lane 5, 100 pg of DNA from uninfected cells plus 10 pg of vDNA; lane 6, 100 pg of DNA from uninfected cells plus 100 pg of vDNA. (b) PCR and Southern blot analysis of DNA amplified from BM for RRV MIP or rhesus β-globin gene. The source for each BM sample is indicated above each lane. The negative (−) control is DNA isolated from uninfected rhesus fibroblasts. (c) Southern blot analysis of DNA PCR amplified with oligonucleotide primers specific for the rhesus (Rh)EBV LMP-1 gene or rhesus β-globin gene. The source for each sample is indicated above each lane. The negative (−) control is DNA isolated from uninfected rhesus fibroblasts, and the positive (+) control is DNA from RhEBV-infected cells.

Mentions: To determine if the LPD lesions in macaque 17577 harbored RRV, oligonucleotide primers specific to the RRV MIP homologue were designed to detect vDNA by PCR amplification and Southern blot analysis. By semiquantitative PCR analysis, vDNA sequences were found to be present at >590 copies/0.1 μg of BM-derived DNA (Fig. 3 a). As most animals held in captivity are naturally infected with RRV 1836, BM aspirates were obtained from other animals to determine if RRV is a common resident of BM. BM samples were collected from two SIV-infected animals without peripheral lymphadenopathy, and two additional samples were obtained from animals that were killed due to disease unrelated to SIV infection or LPD. Analysis of these samples revealed no detectable signal, suggesting that RRV DNA in the BM-derived DNA from these four animals was either absent or below the limits of detection (Fig. 3 b). Finally, the BM-derived DNA from macaque 17577 was analyzed for rhesus EBV–specific sequences, as rhesus EBV has been shown to be associated with LPD in SIV-infected animals 37. No signal corresponding to rhesus EBV DNA sequences was detected (Fig. 3 c), indicating that rhesus EBV was not present in this lesion.


Induction of B cell hyperplasia in simian immunodeficiency virus-infected rhesus macaques with the simian homologue of Kaposi's sarcoma-associated herpesvirus.

Wong SW, Bergquam EP, Swanson RM, Lee FW, Shiigi SM, Avery NA, Fanton JW, Axthelm MK - J. Exp. Med. (1999)

PCR amplification and hybridization for RRV in BM from an animal (17577) with LPD. (a) Semiquantitative PCR of BM-derived DNA from the SIV-infected animal with LPD for RRV MIP. Lane 1, BM-derived DNA; lane 2, 100 pg of DNA from uninfected cells; lane 3, 100 pg of DNA from uninfected cells plus 100 fg of vDNA; lane 4, 100 pg of DNA from uninfected cells plus 1 pg of vDNA; lane 5, 100 pg of DNA from uninfected cells plus 10 pg of vDNA; lane 6, 100 pg of DNA from uninfected cells plus 100 pg of vDNA. (b) PCR and Southern blot analysis of DNA amplified from BM for RRV MIP or rhesus β-globin gene. The source for each BM sample is indicated above each lane. The negative (−) control is DNA isolated from uninfected rhesus fibroblasts. (c) Southern blot analysis of DNA PCR amplified with oligonucleotide primers specific for the rhesus (Rh)EBV LMP-1 gene or rhesus β-globin gene. The source for each sample is indicated above each lane. The negative (−) control is DNA isolated from uninfected rhesus fibroblasts, and the positive (+) control is DNA from RhEBV-infected cells.
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Related In: Results  -  Collection

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Figure 3: PCR amplification and hybridization for RRV in BM from an animal (17577) with LPD. (a) Semiquantitative PCR of BM-derived DNA from the SIV-infected animal with LPD for RRV MIP. Lane 1, BM-derived DNA; lane 2, 100 pg of DNA from uninfected cells; lane 3, 100 pg of DNA from uninfected cells plus 100 fg of vDNA; lane 4, 100 pg of DNA from uninfected cells plus 1 pg of vDNA; lane 5, 100 pg of DNA from uninfected cells plus 10 pg of vDNA; lane 6, 100 pg of DNA from uninfected cells plus 100 pg of vDNA. (b) PCR and Southern blot analysis of DNA amplified from BM for RRV MIP or rhesus β-globin gene. The source for each BM sample is indicated above each lane. The negative (−) control is DNA isolated from uninfected rhesus fibroblasts. (c) Southern blot analysis of DNA PCR amplified with oligonucleotide primers specific for the rhesus (Rh)EBV LMP-1 gene or rhesus β-globin gene. The source for each sample is indicated above each lane. The negative (−) control is DNA isolated from uninfected rhesus fibroblasts, and the positive (+) control is DNA from RhEBV-infected cells.
Mentions: To determine if the LPD lesions in macaque 17577 harbored RRV, oligonucleotide primers specific to the RRV MIP homologue were designed to detect vDNA by PCR amplification and Southern blot analysis. By semiquantitative PCR analysis, vDNA sequences were found to be present at >590 copies/0.1 μg of BM-derived DNA (Fig. 3 a). As most animals held in captivity are naturally infected with RRV 1836, BM aspirates were obtained from other animals to determine if RRV is a common resident of BM. BM samples were collected from two SIV-infected animals without peripheral lymphadenopathy, and two additional samples were obtained from animals that were killed due to disease unrelated to SIV infection or LPD. Analysis of these samples revealed no detectable signal, suggesting that RRV DNA in the BM-derived DNA from these four animals was either absent or below the limits of detection (Fig. 3 b). Finally, the BM-derived DNA from macaque 17577 was analyzed for rhesus EBV–specific sequences, as rhesus EBV has been shown to be associated with LPD in SIV-infected animals 37. No signal corresponding to rhesus EBV DNA sequences was detected (Fig. 3 c), indicating that rhesus EBV was not present in this lesion.

Bottom Line: Hypergammaglobulinemia was associated with severe immune-mediated hemolytic anemia in one RRV/SIV-infected macaque.Infectious RRV and RRV DNA were present in hyperplastic lymphoid tissues of the RRV/SIV-infected macaques, suggesting that lymphoid hyperplasia is associated with the high levels of replication.Thus, experimental RRV 17577 infection of SIV-infected rhesus macaques induces some of the hyperplastic B cell LPDs manifested in AIDS patients coinfected with KSHV.

View Article: PubMed Central - PubMed

Affiliation: Division of Pathobiology, Oregon Regional Primate Research Center, Beaverton, Oregon 97006, USA. wongs@ohsu.edu

ABSTRACT
A simian homologue of Kaposi's sarcoma-associated herpesvirus (KSHV), the eighth human herpesvirus (HHV8), was isolated from a simian immunodeficiency virus (SIV)-infected rhesus macaque (Macaca mulatta) that developed a multicentric lymphoproliferative disorder (LPD). This simian rhadinovirus is genetically similar to a recently described rhesus rhadinovirus (RRV) (Desrosiers, R.C., V.G. Sasseville, S.C. Czajak, X. Zhang, K.G. Mansfield, A. Kaur, R.P. Johnson, A.A. Lackner, and J.U. Jung. 1997. J. Virol. 71:9764-9769) and is designated RRV 17577. RRV 17577 was experimentally inoculated into rhesus macaques with and without SIV(mac239) infection to determine if RRV played a role in development of the LPD observed in the index case. In contrast to control animals inoculated with SIV(mac239) or RRV alone, two animals coinfected with SIV(mac239) and RRV 17577 developed hyperplastic LPD resembling the multicentric plasma cell variant of Castleman's disease, characterized by persistent angiofollicular lymphadenopathy, hepatomegaly, splenomegaly, and hypergammaglobulinemia. Hypergammaglobulinemia was associated with severe immune-mediated hemolytic anemia in one RRV/SIV-infected macaque. Both RRV/SIV-infected macaques exhibited persistent RRV viremia with little or no RRV-specific antibody response. The macaques inoculated with RRV alone displayed transient viremia followed by a vigorous anti-RRV antibody response and lacked evidence of LPD in peripheral blood and lymph nodes. Infectious RRV and RRV DNA were present in hyperplastic lymphoid tissues of the RRV/SIV-infected macaques, suggesting that lymphoid hyperplasia is associated with the high levels of replication. Thus, experimental RRV 17577 infection of SIV-infected rhesus macaques induces some of the hyperplastic B cell LPDs manifested in AIDS patients coinfected with KSHV.

Show MeSH
Related in: MedlinePlus