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Perivascular macrophages are the primary cell type productively infected by simian immunodeficiency virus in the brains of macaques: implications for the neuropathogenesis of AIDS.

Williams KC, Corey S, Westmoreland SV, Pauley D, Knight H, deBakker C, Alvarez X, Lackner AA - J. Exp. Med. (2001)

Bottom Line: However, the identification of distinct subpopulations of monocyte/macrophages that carry virus to the brain and that sustain infection within the central nervous system (CNS) has not been examined.We further demonstrate that although productive viral infection of the CNS occurs early, thereafter it is not easily detectable until terminal AIDS.The biology of perivascular macrophages, including their rate of turnover and replacement by peripheral blood monocytes, may explain the timing of neuroinvasion, disappearance, and reappearance of virus in the CNS, and questions the ability of the brain to function as a reservoir for productive infection by HIV/SIV.

View Article: PubMed Central - PubMed

Affiliation: Division of Comparative Pathology, New England Regional Primate Research Center, Harvard Medical School, Southborough, Massachusetts 01772, USA. kenneth_williams@hms.harvard.edu

ABSTRACT
The macrophage is well established as a target of HIV and simian immunodeficiency virus (SIV) infection and a major contributor to the neuropathogenesis of AIDS. However, the identification of distinct subpopulations of monocyte/macrophages that carry virus to the brain and that sustain infection within the central nervous system (CNS) has not been examined. We demonstrate that the perivascular macrophage and not the parenchymal microglia is the primary cell productively infected by SIV. We further demonstrate that although productive viral infection of the CNS occurs early, thereafter it is not easily detectable until terminal AIDS. The biology of perivascular macrophages, including their rate of turnover and replacement by peripheral blood monocytes, may explain the timing of neuroinvasion, disappearance, and reappearance of virus in the CNS, and questions the ability of the brain to function as a reservoir for productive infection by HIV/SIV.

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Accumulation of perivascular macrophages in the CNS of SIV-infected macaques. Images for individual channels (CD11b, green; Glut-1, red; and CD14, blue) are shown on the left and the merged image combining all three channels plus the DIC image are shown on the right. CD11b+ (green) and CD14+ (blue) perivascular macrophages (blue-green) accumulate around a CNS vessel (Glut-1, red) in an SIVE lesion. Parenchymal microglia that are CD11b+CD14− (green) outside of the lesion area maintain a reticular network, although their morphology has changed as a result of activation. Bar, 10 μM.
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Figure 6: Accumulation of perivascular macrophages in the CNS of SIV-infected macaques. Images for individual channels (CD11b, green; Glut-1, red; and CD14, blue) are shown on the left and the merged image combining all three channels plus the DIC image are shown on the right. CD11b+ (green) and CD14+ (blue) perivascular macrophages (blue-green) accumulate around a CNS vessel (Glut-1, red) in an SIVE lesion. Parenchymal microglia that are CD11b+CD14− (green) outside of the lesion area maintain a reticular network, although their morphology has changed as a result of activation. Bar, 10 μM.

Mentions: Although it has not been demonstrated in vivo, it is possible that parenchymal microglia can upregulate CD14 as has been demonstrated in vitro 53. For this reason, and to further investigate the cell types infected in the CNS, we performed multilabel confocal microscopy of normal CNS and CNS from SIV-infected animals with SIVE. Confocal microscopy for CD11b and CD14 combined with Glut-1 for CNS endothelium confirmed that these markers are differentially expressed on brain macrophage populations in vivo: CD11b expression was found on parenchymal microglia and perivascular macrophages whereas CD14 expression was limited to perivascular macrophages (Fig. 5). CD11b expression on parenchymal microglia revealed a reticular network of cells throughout the brain. Parenchymal microglia in the brain of animals with SIVE have morphology consistent with activated cells and express activation antigens including HLA-DR, CD16, and CD69 (data not shown). However, these activated parenchymal microglia maintain their reticular network in the CNS white matter and do not express detectable CD14 (Fig. 5 and Fig. 6). Thus, they can be differentiated from perivascular macrophages 3839555657. In agreement with the immunohistochemical observations, the number of perivascular macrophages was low in the normal CNS and increased in the CNS of animals with SIVE (Fig. 6). These confocal microscopy studies also clearly show the intimate association of both parenchymal microglia and perivascular macrophages with Glut-1+ CNS endothelial cells (Fig. 5). Perivascular macrophages wrap around the vessels while parenchymal microglia have foot processes that contact vessels forming part of the blood–brain barrier 1517.


Perivascular macrophages are the primary cell type productively infected by simian immunodeficiency virus in the brains of macaques: implications for the neuropathogenesis of AIDS.

Williams KC, Corey S, Westmoreland SV, Pauley D, Knight H, deBakker C, Alvarez X, Lackner AA - J. Exp. Med. (2001)

Accumulation of perivascular macrophages in the CNS of SIV-infected macaques. Images for individual channels (CD11b, green; Glut-1, red; and CD14, blue) are shown on the left and the merged image combining all three channels plus the DIC image are shown on the right. CD11b+ (green) and CD14+ (blue) perivascular macrophages (blue-green) accumulate around a CNS vessel (Glut-1, red) in an SIVE lesion. Parenchymal microglia that are CD11b+CD14− (green) outside of the lesion area maintain a reticular network, although their morphology has changed as a result of activation. Bar, 10 μM.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2193403&req=5

Figure 6: Accumulation of perivascular macrophages in the CNS of SIV-infected macaques. Images for individual channels (CD11b, green; Glut-1, red; and CD14, blue) are shown on the left and the merged image combining all three channels plus the DIC image are shown on the right. CD11b+ (green) and CD14+ (blue) perivascular macrophages (blue-green) accumulate around a CNS vessel (Glut-1, red) in an SIVE lesion. Parenchymal microglia that are CD11b+CD14− (green) outside of the lesion area maintain a reticular network, although their morphology has changed as a result of activation. Bar, 10 μM.
Mentions: Although it has not been demonstrated in vivo, it is possible that parenchymal microglia can upregulate CD14 as has been demonstrated in vitro 53. For this reason, and to further investigate the cell types infected in the CNS, we performed multilabel confocal microscopy of normal CNS and CNS from SIV-infected animals with SIVE. Confocal microscopy for CD11b and CD14 combined with Glut-1 for CNS endothelium confirmed that these markers are differentially expressed on brain macrophage populations in vivo: CD11b expression was found on parenchymal microglia and perivascular macrophages whereas CD14 expression was limited to perivascular macrophages (Fig. 5). CD11b expression on parenchymal microglia revealed a reticular network of cells throughout the brain. Parenchymal microglia in the brain of animals with SIVE have morphology consistent with activated cells and express activation antigens including HLA-DR, CD16, and CD69 (data not shown). However, these activated parenchymal microglia maintain their reticular network in the CNS white matter and do not express detectable CD14 (Fig. 5 and Fig. 6). Thus, they can be differentiated from perivascular macrophages 3839555657. In agreement with the immunohistochemical observations, the number of perivascular macrophages was low in the normal CNS and increased in the CNS of animals with SIVE (Fig. 6). These confocal microscopy studies also clearly show the intimate association of both parenchymal microglia and perivascular macrophages with Glut-1+ CNS endothelial cells (Fig. 5). Perivascular macrophages wrap around the vessels while parenchymal microglia have foot processes that contact vessels forming part of the blood–brain barrier 1517.

Bottom Line: However, the identification of distinct subpopulations of monocyte/macrophages that carry virus to the brain and that sustain infection within the central nervous system (CNS) has not been examined.We further demonstrate that although productive viral infection of the CNS occurs early, thereafter it is not easily detectable until terminal AIDS.The biology of perivascular macrophages, including their rate of turnover and replacement by peripheral blood monocytes, may explain the timing of neuroinvasion, disappearance, and reappearance of virus in the CNS, and questions the ability of the brain to function as a reservoir for productive infection by HIV/SIV.

View Article: PubMed Central - PubMed

Affiliation: Division of Comparative Pathology, New England Regional Primate Research Center, Harvard Medical School, Southborough, Massachusetts 01772, USA. kenneth_williams@hms.harvard.edu

ABSTRACT
The macrophage is well established as a target of HIV and simian immunodeficiency virus (SIV) infection and a major contributor to the neuropathogenesis of AIDS. However, the identification of distinct subpopulations of monocyte/macrophages that carry virus to the brain and that sustain infection within the central nervous system (CNS) has not been examined. We demonstrate that the perivascular macrophage and not the parenchymal microglia is the primary cell productively infected by SIV. We further demonstrate that although productive viral infection of the CNS occurs early, thereafter it is not easily detectable until terminal AIDS. The biology of perivascular macrophages, including their rate of turnover and replacement by peripheral blood monocytes, may explain the timing of neuroinvasion, disappearance, and reappearance of virus in the CNS, and questions the ability of the brain to function as a reservoir for productive infection by HIV/SIV.

Show MeSH
Related in: MedlinePlus