Monocyte/macrophage trafficking in acquired immunodeficiency syndrome encephalitis: Lessons from human and nonhuman primate studies

Abstract

Here the authors discuss evidence in human and animal models supporting two opposing views regarding the pathogenesis of human immunodeficiency virus (HIV) in the central nervous system (CNS): (1) HIV infection in the CNS is a compartmentalized infection, with the virus-infected macrophages entering the CNS early, infecting resident microglia and astrocytes, and achieving a state of latency with evolution toward a fulminant CNS infection late in the course of disease; or alternatively, (2) events in the periphery lead to altered monocyte/macrophage (MΦ) homeostasis, with increased CNS invasion of infected and/or uninfected MΦs. Here the authors have reevaluated evidence presented in the favor of the latter model, with a discussion of phenotypic characteristics distinguishing normal resident microglia with those accumulating in HIV encephalitis (HIVE). CD163 is normally expressed by perivascular MΦs but not resident microglia in normal CNS of humans and rhesus macaques. In agreement with other studies, the authors demonstrate expression of CD163 by brain MΦs in HIVE and simian immunodeficiency virus encephalitis (SIVE). CNS tissues from HIV-sero positive individuals with HIVE or HIV-associated progressive multifocal leukoencephalopathy (PML) were also examined. In HIVE, the authors further demonstrate colocalization of CD163 and CD16 (FcγIII recptor) gene expression, the latter marker associated with HIV infection of monocyte in vivo and permissivity of infection. Indeed, CD163 + MΦs and microglia are often productively infected in HIVE CNS. In SIV infected rhesus macaques, CD163 + cells accumulate perivascularly, within nodular lesions and the parenchyma in animals with encephalitis. Likewise, parenchymal microglia and perivascular MΦs are CD163 + in HIVE. In contrast to HIVE, CD163 + perivascular and parenchymal MΦs in HIV-associated PML were only associated with areas of demyelinating lesions. Interestingly, SIV-infected rhesus macaques whose viral burden was predominantly at 1 × 10 6 copies/ml or greater developed encephalitis. To further investigate the relationship between CD163 + /CD16 + MΦs/microglia in the CNS and altered homeostasis in the periphery, the authors performed flow-cytometric analyses of peripheral blood

SIV Encephalitis Lesions Are Composed of CD163+ Macrophages Present in the Central Nervous System during Early SIV Infection and SIV-Positive Macrophages Recruited Terminally with AIDS

“…69 We observed an increased rate of recruitment of perivascular macrophages in SIVE animals compared with SIVnoE animals from 20 to 49 dpi, which may represent perivascular cuffing in the CNS; more important, we suggest that the increased recruitment of perivascular macrophages before endstage disease may predict which animals will develop SIVE terminally with AIDS. The accumulation of macrophages and perivascular macrophages with HIV and SIV infection contributing to metabolic encephalopathy has been implicated in glial and neuronal perturbation and ultimately CNS disease, 43 through the simple increase in traffic of monocytes to the CNS 10,15,37,44,70 (the release of toxic proteins, cytokines, and chemokines, 37,71 as well as possibly viral proteins).…”

“…5,7 MAC387 þ macrophages are rarely found to be productively infected. 9,13,14,25,37 The timing of monocyte and macrophage entry into the CNS and the role of macrophage subsets mediating the progression or resolution of CNS inflammation due to HIV and SIV infection are not well defined.…”

Extracellular ATP induces the rapid release of HIV-1 from virus containing compartments of human macrophages

“…Although whether bone marrow-associated precursor cells and circulating monocytes harbor HIV-1 in vivo is controversial (45), infection of resident tissue macrophages has been observed both in seropositive individuals and in macaques experimentally infected with simian immunodeficiency virus (SIV) (5). In particular, infected macrophages and microglia represent, together with astrocytes, the dominant productively infected cell types in the central nervous system (46)(47)(48), where they constitute an immunologic sanctuary poorly reached by antiretroviral agents (7,13,49).…”

Architecture and Regulation of the HIV-1 Assembly and Holding Compartment in Macrophages

“…HIV-1-infected macrophages produce virus at a lower rate than CD4 ϩ T cells but remain viable for weeks or months as a result of HIV-1 suppression of apoptosis and are thus considered a viral reservoir (4,18). Moreover, macrophages and microglia play important roles in HIV-1-related neurological disorders (10). Macrophage clearance of microorganisms that may become opportunistic pathogens in AIDS declines as macrophage function is impaired by HIV-1 infection, implying a central role for these cells in HIV-1 pathogenesis (17,23).…”