TY - JOUR
T1 - Interferon-γ and tumor necrosis factor-α specifically induce formation of cytomegalovirus-permissive monocyte-derived macrophages that are refractory to the antiviral activity of these cytokines
AU - Söderberg-Nauclér, Cecilia
AU - Fish, Kenneth N.
AU - Nelson, Jay A.
PY - 1997/12/15
Y1 - 1997/12/15
N2 - Monocytes/macrophages are key cells in the pathogenesis of human cytomegalovirus (HCMV). Although HCMV infection in monocytes is restricted to early events of gene expression, productive infection has been demonstrated in differentiated macrophages in vitro. We examined the cellular and cytokine components that are essential for HCMV replication in Concanavalin A- stimulated monocyte-derived macrophages (MDM). By negative selection, depletion of CD8+ T lymphocytes, but not CD4+ T lymphocytes, CD19+ B cells, or CD56+ NK cells, resulted in a 60-70% reduction in the number of HCMV- infected MDM, and a 4 log decrease in virus production. Neutralization of IFN-γ and TNF-α, but not IL-1, IL-2, or TGF-β, decreased production of virus by 4 logs and 2 logs, respectively. Subsequently, addition of recombinant IFN-γ or TNF-α to purified monocyte cultures was sufficient to produce HCMV-permissive MDM. While IFN-γ and TNF-α possess antiviral properties, addition of these cytokines to permissive MDM cultures did not affect production of HCMV. Thus, rather than inhibiting replication of HCMV, IFN-γ and TNF-α specifically induce differentiation of monocytes into HCMV- permissive MDM, which are resistant to the antiviral effects of these cytokines.
AB - Monocytes/macrophages are key cells in the pathogenesis of human cytomegalovirus (HCMV). Although HCMV infection in monocytes is restricted to early events of gene expression, productive infection has been demonstrated in differentiated macrophages in vitro. We examined the cellular and cytokine components that are essential for HCMV replication in Concanavalin A- stimulated monocyte-derived macrophages (MDM). By negative selection, depletion of CD8+ T lymphocytes, but not CD4+ T lymphocytes, CD19+ B cells, or CD56+ NK cells, resulted in a 60-70% reduction in the number of HCMV- infected MDM, and a 4 log decrease in virus production. Neutralization of IFN-γ and TNF-α, but not IL-1, IL-2, or TGF-β, decreased production of virus by 4 logs and 2 logs, respectively. Subsequently, addition of recombinant IFN-γ or TNF-α to purified monocyte cultures was sufficient to produce HCMV-permissive MDM. While IFN-γ and TNF-α possess antiviral properties, addition of these cytokines to permissive MDM cultures did not affect production of HCMV. Thus, rather than inhibiting replication of HCMV, IFN-γ and TNF-α specifically induce differentiation of monocytes into HCMV- permissive MDM, which are resistant to the antiviral effects of these cytokines.
KW - Cytomegalovirus
KW - Differentiation
KW - Interferon
KW - Macrophages
KW - Tumour necrosis factor
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U2 - 10.1172/JCI119871
DO - 10.1172/JCI119871
M3 - Article
C2 - 9399963
AN - SCOPUS:0242504922
SN - 0021-9738
VL - 100
SP - 3154
EP - 3163
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 12
ER -