Increased Monocyte Turnover from Bone Marrow Correlates with Severity of SIV Encephalitis and CD163 Levels in Plasma

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Abstract
Cells of the myeloid lineage are significant targets for human immunodeficiency virus (HIV) in humans and simian immunodeficiency virus (SIV) in monkeys. Monocytes play critical roles in innate and adaptive immunity during inflammation. We hypothesize that specific subsets of monocytes expand with AIDS and drive central nervous system (CNS) disease. Additionally, there may be expansion of cells from the bone marrow through blood with subsequent macrophage accumulation in tissues driving pathogenesis. To identify monocytes that recently emigrated from bone marrow, we used 5-bromo-2′-deoxyuridine (BrdU) labeling in a longitudinal study of SIV-infected CD8+ T lymphocyte depleted macaques. Monocyte expansion and kinetics in blood was assessed and newly migrated monocyte/macrophages were identified within the CNS. Five animals developed rapid AIDS with differing severity of SIVE. The percentages of BrdU+ monocytes in these animals increased dramatically, early after infection, peaking at necropsy where the percentage of BrdU+ monocytes correlated with the severity of SIVE. Early analysis revealed changes in the percentages of BrdU+ monocytes between slow and rapid progressors as early as 8 days and consistently by 27 days post infection. Soluble CD163 (sCD163) in plasma correlated with the percentage of BrdU+ monocytes in blood, demonstrating a relationship between monocyte activation and expansion with disease. BrdU+ monocytes/macrophages were found within perivascular spaces and SIVE lesions. The majority (80–90%) of the BrdU+ cells were Mac387+ that were not productively infected. There was a minor population of CD68+BrdU+ cells (<10%), very few of which were infected (<1% of total BrdU+ cells). Our results suggest that an increased rate of monocyte recruitment from bone marrow into the blood correlates with rapid progression to AIDS, and the magnitude of BrdU+ monocytes correlates with the severity of SIVE. Human immunodeficiency virus (HIV) and the closely related simian immunodeficiency virus (SIV) can infect monocyte/macrophages, which enter and accumulate in the brain leading to neuronal dysfunction. Monocyte/macrophages exit the bone marrow, transit through the blood and enter the central nervous system (CNS). What triggers these cells to traffic is undefined, but it occurs in normal non-infected conditions at a rate that is accelerated with viral infection. Here, we used 5-bromo-2′-deoxyuridine (BrdU) injection and incorporation into the DNA of monocytes prior to their departure from the bone marrow. We found that the percentage of BrdU+ monocytes leaving the bone marrow 24 hours after injection increased in animals that rapidly succumbed to AIDS and correlated with the severity of SIV encephalitis (SIVE). Differences in BrdU labeled monocytes in slow and rapid progressors were revealed as early as 8 days and were consistent by 27 days post infection. Soluble CD163, shed by activated monocyte/macrophages, directly correlated with BrdU+ monocyte expansion. Our study provides new insights into the development of HIV-related CNS disease and underscores the importance of monocyte/macrophage recruitment from the bone marrow as an AIDS defining event.