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

Abstract

Macrophage recruitment to the central nervous system (CNS) during AIDS pathogenesis is poorly understood. We measured the accumulation of brain perivascular (CD163 þ ) and inflammatory (MAC387 þ ) macrophages in SIV-infected monkeys. Monocyte progenitors were 5-bromo-2 0 -deoxyuridine (BrdU) labeled in bone marrow, and CNS macrophages were labeled serially with fluorescent dextrans injected into the cisterna magna. MAC387 þ macrophages accumulated in the meninges and choroid plexus in early inflammation and in the perivascular space and SIV encephalitis (SIVE) lesions late. CD163 þ macrophages accumulated in the perivascular space and SIVE lesions with late inflammation. Most of the BrdU þ cells were MAC387 þ ; however, CD163 þ BrdU þ macrophages were present in the meninges and choroid plexus with AIDS. Most (81.6% AE 1.8%) of macrophages in SIVE lesions were present in the CNS before SIVE lesion formation. There was a 2.9-fold increase in SIVp28 þ macrophages entering the CNS late compared with those entering early (P < 0.05). The rate of CD163 þ macrophage recruitment to the CNS inversely correlated with time to death (P < 0.03) and increased with SIVE. In SIVE animals, soluble CD163 correlated with CD163 þ macrophage recruitment (P Z 0.02). Most perivascular macrophages that comprise SIVE lesions and multinucleated giant cells are present in the CNS early, before SIVE lesions are formed. Most SIV-infected macrophages traffic to the CNS terminally with AIDS.

Insights into End-Organ Injury in HIV Infection

“…The findings of Nowlin et al 3 are of great interest to CNS macrophage biologists as well as immunologists studying acute and chronic inflammation. Early during SIV infection, Nowlin et al 3 reported most cells to be MAC387 þ recently recruited monocytes/macrophages.…”

“…Nowlin et al 3 used straightforward multilabel immunohistochemical approaches to assess macrophage populations and their turnover in the choroid plexus, meninges, perivascular space, and parenchymal lesions (when present in animals with SIVE). The method also allowed comparison of the rates of turnover in early acute inflammation and in the later inflammation as the animals developed AIDS and CNS lesions.…”

“…Consistent with the observations from the bone marrow during inflammation, most BrdU þ cells were also MAC387 þ . During the late stages of inflammation, Nowlin et al 3 found macrophage accumulation primarily in the perivascular space and in SIVE lesions, not in the meninges and choroid plexus. It is likely that the meninges and choroid plexus have cells trafficking through them in late stages of inflammation, thereby decreasing accumulation.…”

“…These newly described intriguing observations have not been reported in either a lentiviral infection model or a nonhuman primate model, underlining the fact that CNS inflammation is a dynamic process. Nowlin et al 3 reported an increased ratio of CD163 þ (with phenotype of M2 alternatively activated macrophages 6 )/MAC387 þ macrophages (that might have an M1 phenotype) in the CNS of animals with SIVE.…”

“…Early during SIV infection, Nowlin et al 3 reported most cells to be MAC387 þ recently recruited monocytes/macrophages. As expected, most of these cells were detected in the meninges and the choroid plexus (which appeared to have trafficking kinetics similar to the blood than to the CNS compartments).…”