The Effect of Simian Immunodeficiency Virus Infectionin Vitroandin Vivoon the Cytokine Production of Isolated Microglia and Peripheral Macrophages from Rhesus Monkey

Abstract

Microglia are the major target for human immunodeficiency virus (HIV) infection within the central nervous system. Because only a few cells are productively infected, it has been suggested that an aberrant cytokine production by this cell population may be an indirect mechanism leading to the development of neurological disorders in HIV-infected patients. Therefore we decided to study the secretion pattern of several interleukins (IL) by microglial cells and peripheral blood macrophages isolated from uninfected and simian immunodeficiency virus (SIV)-infected Rhesus monkeys. We found that uninfected, unstimulated primate microglia produce more IL-6 and less TNF alpha than peripheral blood macrophages, but generate comparable levels of IL-1 beta and IL-8. After infection with SIV in vitro, synthesis of all cytokines tested is increased compared to uninfected cultures and to peripheral blood macrophages. Microglia isolated from infected animals produce more IL-8 and TNF alpha than the uninfected cultures and display a strongly increased capacity to secrete TNF alpha upon stimulation with lipopolysaccharide. In addition, production of IL-6 by in vivo-infected microglia increases with time in culture to very high levels despite the fact that only a few cells contained replicating virus. These findings clearly show that the cytokine production of microglia is impaired after SIV infection both in vitro and in vivo and that a low level of viral replication is sufficient for these alterations to occur. In conclusion, the results of this study further support a possible role of cytokines in the pathogenesis of neuro-AIDS.

Phenotypic characterisation and infection of ovine microglial cells with Maedi-Visna Virus

“…This is consistent with a previous study in which TNFa immunoreactivity in MVV-infected brain tissues was demonstrated to associate with brain macrophages (Craig et al, 1997). Intrathecal expression of TNFa has also been demonstrated in primate lentivirus infections (Nuovo and Al®eri, 1996;Sopper et al, 1996). Increased transcription of IL-6 mRNA has also been reported in caprine microglial cultures infected with CAEV (Baszler et al, 1994) and in the brains of SIV-infected macaques (Sopper et al, 1996).…”

“…Intrathecal expression of TNFa has also been demonstrated in primate lentivirus infections (Nuovo and Al®eri, 1996;Sopper et al, 1996). Increased transcription of IL-6 mRNA has also been reported in caprine microglial cultures infected with CAEV (Baszler et al, 1994) and in the brains of SIV-infected macaques (Sopper et al, 1996). Over-expression of IL-6 in the murine CNS has been shown to result in reactive astrocytosis and an increase in rami®ed microglial cells (Fattori et al, 1995).…”

“…Cytokine production has been closely linked with lentiviral infections of cells of the monocyte/ macrophage lineage and has been suggested to contribute to the CNS pathology (Baszler et al, 1994;Nuovo and Al®eri, 1996;Sopper et al, 1996;Craig et al, 1997). The pro®le of cytokines produced in MVV-infected primary ovine microglial cells A Figure 7 Effect of MVV infection on mRNA expression of microglial-derived cytokines.…”

“…It has been suggested that microglial released cytokines are major contributors to the neuropathology in retroviral neuropathies (Baszler et al, 1994;Nuovo and Al®eri, 1996;Sopper et al, 1996;Craig et al, 1997). To investigate this, changes in cytokine gene expression in infected ovine microglial cells were investigated.…”

Chemokines and chemokine receptors in CNS pathology

“…This last observation gives new insight into mechanisms underlying amyloid plaque formation in the CNS during Alzheimer disease. Microglial cells infected by SIV in vitro can produce more IL-8 than uninfected cultures (Sopper et al, 1996).…”