An Investigation of changes in monocyte gene expression and CNS macrophage recruitment associated with the development of SIV encephalitis

Abstract

Factors that impact the development of neuroAIDS include monocyte expansion and activation, viral neuroinvasion and replication, and accumulation of activated and infected macrophages in the CNS. To better understand changes in monocyte/macrophage biology associated with the development of SIV encephalitis (SIVE) and neuroAIDS, we: 1) performed gene expression analyses using high density microarrays to characterize the response of monocyte subsets to SIV infection, 2) serially labeled CNS macrophages with fluorescent dextrans by intracranial injection and labeled myeloid progenitors in the bone marrow with BrdU to determine the timing of SIV neuroinvasion and macrophage recruitment/turnover in the CNS, and 3) performed in vitro studies to determine the role of PCNA expression in macrophages with SIV infection. We found the majority of macrophages in SIVE lesions were present in the CNS early in infection and productively infected macrophages were recruited to the CNS terminally with AIDS. We observed differences in the timing of recruitment, rate of turnover, PCNA expression, and productive infection between CD163+ and MAC387+ macrophages in the CNS. SIV infection was associated with induction of interferon stimulated genes in all monocytes, maturation of the intermediate monocyte subset, and increased rate of monocyte/macrophage recruitment to the CNS. Greater ratios of CD163+ to MAC387+ macrophages in the CNS were associated with SIVE. We also found that PCNA expression decreased macrophage apoptosis with SIV infection. Together, these studies suggest that the development of SIVE is a dynamic process and that continuous recruitment of activated monocyte/macrophage and reintroduction of virus from the periphery is required to drive CNS disease.