This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Infection of the central nervous system (CNS) by human immunodeficiency virus (HIV) or its simian counterpart, SIV, occurs early during disease likely within trafficking monocyte/macrophages. However, histopathological studies, by their nature, tend to focus on chronic, end stage disease. Work by our group and others underscored that active and continuous monocyte/macrophage traffic occurs throughout infection, increases with to the development of AIDS and is required for HIV/SIV encephalitis. Using a panel of monocyte/macrophage markers and BrdU labeling experiments, we sought to characterize macrophage differentiation/activation in SIVE in acute and chronic infection and HIVE in chronic AIDS patients. We distinguished between recently infiltrated macrophages and macrophages to characterize severity of lesions. HIVE and SIVE lesions were heterogeneously composed of recently infiltrated MAC387+ monocyte/macrophages, CD163+ MAC387- perivascular macrophages and resident macrophages expressing the pan-macrophage markers CD68 or HAM-56. The presence and number of MAC387+ monocyte/macrophages in the CNS correlated with the development of HIVE in humans and severity of SIVE in monkeys. About one third of the MAC387+ monocyte/macrophages in CNS lesions were BrdU+ consistent with them being recently emigrated from bone marrow. Myeloid-related protein 8 (MRP8) expression, characteristic of later stage of disease, was not detected in macaques. By contrast, we detected MAC387+MRP8+ macrophages that were negative for CD68, CD163 and HIV p24 in lesions in HIVE patients, corresponding to a chronic, early to late inflammatory stage of these lesions. MAC387+ cells were CD14+ and CD16+ but CD68-. This was in contrast to CD68+ and HAM-56+ resident macrophages, and CD163+CD68+ perivascular macrophages. The MAC387+ monocyte/macrophages were not productively infected suggesting that they are more likely immune macrophages and/or potential reservoirs of latent virus in contrast to CD163+CD68+ perivascular macrophages. These results further demonstrate that the formation of HIV and SIV encephalitic lesions is an active process occurring throughout disease. This ongoing process involves recruitment/accumulation of at least three subsets of macrophages: non-productively infected inflammatory MAC387+ monocyte/macrophages that are not normally in the CNS, CD163+ perivascular macrophages and CD68+ HAM-56+ resident macrophages, the latter two of which are present in the CNS in non-pathogenic conditions and are reservoirs for productive viral replication.

National Institute of Health (NIH)
National Center for Research Resources (NCRR)
Primate Research Center Grants (P51)
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Special Emphasis Panel (ZRR1-CM-8 (01))
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Tulane University
Obstetrics & Gynecology
Schools of Medicine
New Orleans
United States
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