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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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CD20+ lymphocytes, antibody response, and RRV strain 17577 isolation/detection in SIVmac-infected animals. Total CD20+ cells were measured at the indicated weeks after infection, virus isolations (virus PBMCs) were determined by coculture of PBMCs with primary rhesus fibroblasts, and the presence of vDNA (virus PCR) was determined by PCR analysis on DNA derived from PBLs. Detection of antibodies to RRV strain 17577 were determined by ELISA on plates coated with extracts derived from RRV-infected cells. +, positive for virus culture or vDNA, as defined by PCR and Southern blot analysis; −, negative virus culture or vDNA. Animals 18483 (a) and 18570 (b) were experimentally inoculated with SIVmac239 and RRV strain 17577, animals 18503 (c) and 18540 (d) were experimentally inoculated with SIVmac239 only, and animals 19092 (e) and 19286 (f) were experimentally inoculated with RRV strain 17577.
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Figure 4: CD20+ lymphocytes, antibody response, and RRV strain 17577 isolation/detection in SIVmac-infected animals. Total CD20+ cells were measured at the indicated weeks after infection, virus isolations (virus PBMCs) were determined by coculture of PBMCs with primary rhesus fibroblasts, and the presence of vDNA (virus PCR) was determined by PCR analysis on DNA derived from PBLs. Detection of antibodies to RRV strain 17577 were determined by ELISA on plates coated with extracts derived from RRV-infected cells. +, positive for virus culture or vDNA, as defined by PCR and Southern blot analysis; −, negative virus culture or vDNA. Animals 18483 (a) and 18570 (b) were experimentally inoculated with SIVmac239 and RRV strain 17577, animals 18503 (c) and 18540 (d) were experimentally inoculated with SIVmac239 only, and animals 19092 (e) and 19286 (f) were experimentally inoculated with RRV strain 17577.

Mentions: Sequential FACS™ analysis of PBMCs from the experimental animals revealed limited CD4+ lymphocyte depletion (mean values = 900–1,100/μl) 2 wk after SIV infection in the SIV-infected animals, followed by a rebound and sustained CD4+ lymphocyte counts in the normal range (mean values = 1,500–2,000/μl), whereas CD8+ lymphocyte counts increased slightly compared with the preinoculation time points. Significant differences in the number of CD20+ B lymphocytes were observed among the three groups of animals. As early as 6 wk after RRV infection, the number of CD20+ B lymphocytes increased dramatically in the two RRV/SIV-infected macaques (mean values = 2,900–3,360/μl) and persisted for 34 wk in animal 18483 and 14 wk in animal 18570 (Fig. 4, a and b). In contrast, the SIV-infected control animals exhibited persistently low numbers of CD20+ B lymphocytes (mean values = 200–300/μl) beginning 2 wk after SIV infection (Fig. 4c and Fig. d). The number of circulating CD20+ B lymphocytes increased slightly 2 wk after infection (mean values = 950–1,000/μl) in the RRV-only controls (Fig. 4e and Fig. f). Further FACS™ analysis revealed that the PBMCs from the two RRV/SIV-infected macaques expressed the CD40 activation marker coincident with CD20 but not CD23, which is expressed after rhesus EBV infection (reference 38; data not shown).


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)

CD20+ lymphocytes, antibody response, and RRV strain 17577 isolation/detection in SIVmac-infected animals. Total CD20+ cells were measured at the indicated weeks after infection, virus isolations (virus PBMCs) were determined by coculture of PBMCs with primary rhesus fibroblasts, and the presence of vDNA (virus PCR) was determined by PCR analysis on DNA derived from PBLs. Detection of antibodies to RRV strain 17577 were determined by ELISA on plates coated with extracts derived from RRV-infected cells. +, positive for virus culture or vDNA, as defined by PCR and Southern blot analysis; −, negative virus culture or vDNA. Animals 18483 (a) and 18570 (b) were experimentally inoculated with SIVmac239 and RRV strain 17577, animals 18503 (c) and 18540 (d) were experimentally inoculated with SIVmac239 only, and animals 19092 (e) and 19286 (f) were experimentally inoculated with RRV strain 17577.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2195633&req=5

Figure 4: CD20+ lymphocytes, antibody response, and RRV strain 17577 isolation/detection in SIVmac-infected animals. Total CD20+ cells were measured at the indicated weeks after infection, virus isolations (virus PBMCs) were determined by coculture of PBMCs with primary rhesus fibroblasts, and the presence of vDNA (virus PCR) was determined by PCR analysis on DNA derived from PBLs. Detection of antibodies to RRV strain 17577 were determined by ELISA on plates coated with extracts derived from RRV-infected cells. +, positive for virus culture or vDNA, as defined by PCR and Southern blot analysis; −, negative virus culture or vDNA. Animals 18483 (a) and 18570 (b) were experimentally inoculated with SIVmac239 and RRV strain 17577, animals 18503 (c) and 18540 (d) were experimentally inoculated with SIVmac239 only, and animals 19092 (e) and 19286 (f) were experimentally inoculated with RRV strain 17577.
Mentions: Sequential FACS™ analysis of PBMCs from the experimental animals revealed limited CD4+ lymphocyte depletion (mean values = 900–1,100/μl) 2 wk after SIV infection in the SIV-infected animals, followed by a rebound and sustained CD4+ lymphocyte counts in the normal range (mean values = 1,500–2,000/μl), whereas CD8+ lymphocyte counts increased slightly compared with the preinoculation time points. Significant differences in the number of CD20+ B lymphocytes were observed among the three groups of animals. As early as 6 wk after RRV infection, the number of CD20+ B lymphocytes increased dramatically in the two RRV/SIV-infected macaques (mean values = 2,900–3,360/μl) and persisted for 34 wk in animal 18483 and 14 wk in animal 18570 (Fig. 4, a and b). In contrast, the SIV-infected control animals exhibited persistently low numbers of CD20+ B lymphocytes (mean values = 200–300/μl) beginning 2 wk after SIV infection (Fig. 4c and Fig. d). The number of circulating CD20+ B lymphocytes increased slightly 2 wk after infection (mean values = 950–1,000/μl) in the RRV-only controls (Fig. 4e and Fig. f). Further FACS™ analysis revealed that the PBMCs from the two RRV/SIV-infected macaques expressed the CD40 activation marker coincident with CD20 but not CD23, which is expressed after rhesus EBV infection (reference 38; data not shown).

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