Marrow accessory cell infection and alterations in hematopoiesis accompany severe neutropenia during experimental acute infection with feline immunodeficiency virus

TY - JOUR

T1 - Marrow accessory cell infection and alterations in hematopoiesis accompany severe neutropenia during experimental acute infection with feline immunodeficiency virus

AU - Linenberger, M. L.

AU - Beebe, A. M.

AU - Pedersen, Niels C

AU - Abkowitz, J. L.

AU - Dandekar, Satya

PY - 1995

Y1 - 1995

N2 - Severe neutropenia and bone marrow (BM) morphologic abnormalities occur during experimentally induced primary infection with feline immunodeficiency virus (FIV), a lentivirus biologically similar to human immunodeficiency virus (HIV). To further characterize the mechanisms involved in this acute infection model of lentivirus-induced BM suppression, peripheral blood counts, histologic BM studies, and BM culture assays were performed on 12 cats that underwent necropsy at regular intervals postinoculation (PI) with FIV Petaluma. Plasma viremia developed at week 3 PI and neutropenia was initially detected at week 6 PI. Low neutrophil counts, but normal hematocrits and platelet counts, persisted through week 12 PI. Infected BM mononuclear cells and megakaryocytes were identified by in situ hybridization assays for FIV nucleic acids in BM sections of cats that underwent necropsy at weeks 4 to 12 PI, correlating with detection of soluble FIV p24 antigen and identification of infected mononuclear and macrophage cells in BM buffy- coat cell cultures from these cats. At weeks 1.5 to 4 PI, the mean frequencies (number per 105 BM mononuclear cells) of erythroid progenitors (erythroid colony-forming units [CFU-E] and erythroid burst-forming units [BFU-E]) and granulocyte/macrophage progenitors (CFU-granulocyte/macrophage [CFU-GM]) were increased to 508 ± 74, 143 ± 24, and 110 ± 17, respectively (n = 5 cats) as compared with controls (172 ± 24, 86 ± 26, and 44 ± 10; n = 3 cats; P < .02), and the percentages of progenitors in the DNA-synthetic phase of the cell cycle were equivalent to controls. In contrast, the progenitor frequencies at weeks 6 to 12 PI were significantly decreased (72 ± 16, 43 ± 6, and 19 ± 4, respectively; n = 7 cats; P < .01), and these progenitors were more frequently in S-phase. Autologous serum significantly inhibited (P < .05) the growth of CFU-GM in 6 of 9 cats and failed to support the maximal growth of BFU-E in 4 of 9 cats studied at weeks 4 to 12 PI, whereas no such abnormalities were observed in colony assays containing autologous sera from control cats (n = 3) or cats studied at weeks 1.5 or 3 PI (n = 3). In comparison, sera from FIV-infected cats did not inhibit the growth of normal, allogeneic progenitors. However, FIV serum frequently failed to support maximal in vitro growth of normal CFU-GM as compared with uninfected allogeneic sera, further suggesting a lack of progenitor growth- promoting substances in infected cat sera. Together, these studies show that neutropenia induced by experimental acute FIV infection is associated with plasma viremia, with the appearance of viral-infected BM accessory cells, and with alterations in progenitor frequencies, cell cycle kinetics, and in vitro growth in autologous sera. Because these virologic, hematologic, and hematopoietic abnormalities resemble those associated with late-stage HIV infection, acute FIV infection may provide an excellent model to characterize the lentiviral and host cell factors relevant to mechanisms of BM suppression in the acquired immunodeficiency syndrome.

AB - Severe neutropenia and bone marrow (BM) morphologic abnormalities occur during experimentally induced primary infection with feline immunodeficiency virus (FIV), a lentivirus biologically similar to human immunodeficiency virus (HIV). To further characterize the mechanisms involved in this acute infection model of lentivirus-induced BM suppression, peripheral blood counts, histologic BM studies, and BM culture assays were performed on 12 cats that underwent necropsy at regular intervals postinoculation (PI) with FIV Petaluma. Plasma viremia developed at week 3 PI and neutropenia was initially detected at week 6 PI. Low neutrophil counts, but normal hematocrits and platelet counts, persisted through week 12 PI. Infected BM mononuclear cells and megakaryocytes were identified by in situ hybridization assays for FIV nucleic acids in BM sections of cats that underwent necropsy at weeks 4 to 12 PI, correlating with detection of soluble FIV p24 antigen and identification of infected mononuclear and macrophage cells in BM buffy- coat cell cultures from these cats. At weeks 1.5 to 4 PI, the mean frequencies (number per 105 BM mononuclear cells) of erythroid progenitors (erythroid colony-forming units [CFU-E] and erythroid burst-forming units [BFU-E]) and granulocyte/macrophage progenitors (CFU-granulocyte/macrophage [CFU-GM]) were increased to 508 ± 74, 143 ± 24, and 110 ± 17, respectively (n = 5 cats) as compared with controls (172 ± 24, 86 ± 26, and 44 ± 10; n = 3 cats; P < .02), and the percentages of progenitors in the DNA-synthetic phase of the cell cycle were equivalent to controls. In contrast, the progenitor frequencies at weeks 6 to 12 PI were significantly decreased (72 ± 16, 43 ± 6, and 19 ± 4, respectively; n = 7 cats; P < .01), and these progenitors were more frequently in S-phase. Autologous serum significantly inhibited (P < .05) the growth of CFU-GM in 6 of 9 cats and failed to support the maximal growth of BFU-E in 4 of 9 cats studied at weeks 4 to 12 PI, whereas no such abnormalities were observed in colony assays containing autologous sera from control cats (n = 3) or cats studied at weeks 1.5 or 3 PI (n = 3). In comparison, sera from FIV-infected cats did not inhibit the growth of normal, allogeneic progenitors. However, FIV serum frequently failed to support maximal in vitro growth of normal CFU-GM as compared with uninfected allogeneic sera, further suggesting a lack of progenitor growth- promoting substances in infected cat sera. Together, these studies show that neutropenia induced by experimental acute FIV infection is associated with plasma viremia, with the appearance of viral-infected BM accessory cells, and with alterations in progenitor frequencies, cell cycle kinetics, and in vitro growth in autologous sera. Because these virologic, hematologic, and hematopoietic abnormalities resemble those associated with late-stage HIV infection, acute FIV infection may provide an excellent model to characterize the lentiviral and host cell factors relevant to mechanisms of BM suppression in the acquired immunodeficiency syndrome.

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M3 - Article

C2 - 7849316

AN - SCOPUS:0028906411

VL - 85

SP - 941

EP - 951

JO - Blood

JF - Blood

SN - 0006-4971

IS - 4

ER -