MARROW ACCESSORY CELL INFECTION AND ALTERATIONS IN HEMATOPOIESIS ACCOMPANY SEVERE NEUTROPENIA DURING EXPERIMENTAL ACUTE INFECTION WITH FELINE IMMUNODEFICIENCY VIRUS
Ml. Linenberger et al., MARROW ACCESSORY CELL INFECTION AND ALTERATIONS IN HEMATOPOIESIS ACCOMPANY SEVERE NEUTROPENIA DURING EXPERIMENTAL ACUTE INFECTION WITH FELINE IMMUNODEFICIENCY VIRUS, Blood, 85(4), 1995, pp. 941-951
Severe neutropenia and bone marrow (BM) morphologic abnormalities occu
r during experimentally induced primary infection with feline immunode
ficiency virus (FIV), a lentivirus biologically similar to human immun
odeficiency virus (HIV). To further characterize the mechanisms involv
ed 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 interval
s postinoculation (PI) with FIV Petaluma. Plasma viremia developed at
week 3 PI and neutropenia was initially detected at week 6 PI. Low neu
trophil counts, but normal hematocrits and platelet counts, persisted
through week 12 PI. Infected BM mononuclear cells and megakaryocytes w
ere identified by in situ hybridization assays for FIV nucleic acids i
n BM sections of cats that underwent necropsy at weeks 4 to 12 PI, cor
relating with detection of soluble FIV p24 antigen and identification
of infected mononuclear and macrophage cells in BM buffy-coat cell cul
tures from these cats. At weeks 1.5 to 4 PI, the mean frequencies (num
ber per 10(5) BM mononuclear cells) of erythroid progenitors (erythroi
d 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, r
espectively (n = 5 cats) as compared with controls (172 +/- 24, 86 +/-
26, and 44 +/- 10; n = 3 cats; P < .02), and the percentages of proge
nitors 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, resp
ectively; n = 7 cats; P < .01), and these progenitors were more freque
ntly in S-phase. Autologous serum significantly inhibited (P < .05) th
e growth of CFU-GM in 6 of 9 cats and failed to support the maximal gr
owth of BFU-E in 4 of 9 cats studied at weeks 4 to 12 PI, whereas no s
uch 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 frequent
ly failed to support maximal in vitro growth of normal CFU-GM as compa
red with uninfected allogeneic sera, further suggesting a lack of prog
enitor growth-promoting substances in infected cat sera. Together, the
se studies show that neutropenia induced by experimental acute FIV inf
ection is associated with plasma viremia, with the appearance of viral
-infected BM accessory cells, and with alterations in progenitor frequ
encies, cell cycle kinetics, and in vitro growth in autologous sera. B
ecause these virologic, hematologic, and hematopoietic abnormalities r
esemble those associated with late-stage HIV infection, acute FIV infe
ction may provide an excellent model to characterize the lentiviral an
d host cell factors relevant to mechanisms of BM suppression in the ac
quired immunodeficiency syndrome. (C) 1995 by The American Society of
Hematology.