Severer nodular lesion in white matter than in gray matter in simian immunodeficiency virus-infected monkey, but not closely correlated with viral infection

Abstract

Immune cell accumulation and white matter anomaly are common features of HIV (human immunodeficiency virus) -infected patients in combination antiretroviral therapy (cART) era. Neuroimaging tests on cART treated patients displayed prominent diffuse white matter lesions. Notably, immune cell nodular lesion (NL) was a conspicuous type of pathological change in HIV/SIV (simian immunodeficiency virus) infected brain before cART. Therefore, we used SIV infected brain to investigate the distribution of those NLs in gray and white matters. We found a significant higher number of NLs in white matter than that in gray matter. However, virus infection correlated with macrophage NLs but not with microglia NLs, especially in white matter. In addition, NLs interrupted white matter integrity more severely, since even tiny nodules could disconnect nerve fibers in white matter tracts. In the gray matter with dense myelinated axons, NLs obviously encroached those fibers; in the area of few myelinated axons, small nodules well co-localized with extracellular matrix between neurons.

Significant higher‐level C‐C motif chemokine ligand 2/3 and chemotactic power in cerebral white matter than grey matter in rat and human

“…Apart from higher number of PC in the WM, we also observed nodular lesions formed by microglia nodules (MN) that were more prevalent in the WM than in the GM of the SIV-infected brain (Zhang et al, 2019), suggesting involvement of microglia in virus-induced WM injury as reported by many other studies (Borrajo et al, 2021;Wallet et al, 2019). The formation of MN in normal appearing WM was also observed in early stage of MS, which occurred before T-cell infiltration (Singh et al, 2013).…”

“…In our recent study, we also observed that the number of MNs was significantly higher in the WM than in the GM in SIV-infected brains (Zhang et al, 2019). Surprisingly, no infected cells were found in a numerous MNs, inferring microglial aggregation was not directly associated with viral infection.…”

“…In fact, activation of microglia and formation of MNs in normal appearing WM were also observed in an early stage of the MS (Singh et al., 2013). Note worthily, even small number of nodules inside WM tracts may dramatically distort axon bundles (Zhang et al., 2019), and positive correlation between microglia activation–aggregation and disruption of nerve fibers paranodal apparatus have been observed in MS cases, as well as in optic nerve pathological changes in glaucoma (Bordone et al., 2017; Howell et al., 2010; Singh et al., 2013). Nevertheless, our current findings help to explain why infiltration of monocytes and T cells into the WM is more serious than their infiltration into the GM, and why more microglia nodular lesions in the WM than in the GM in MS and HIV/SIV‐infected brains.…”

“…Coincidently, we recently observed in simian immunodeficiency virus (SIV)‐infected brain that the number of perivascular macrophage cuffing (PC)—cells therein probably derived from infiltrated monocytes—in WM was significantly higher than in GM (Zhang et al., 2019). On the other hand, robust T‐cell infiltration in WM of multiple sclerosis (MS) cases (Zephir, 2018) suggested a higher chemoattractant power of WM on T cells as well.…”

“…We have shown in a previous study that the WM in SIV-infected brain, wherein more PCs were observed in comparison with the GM, could recruit more monocytes (Zhang et al, 2019). In HIV-infected brain, the PCs built up at an early stage of infection, according to a case report of an iatrogenic HIV-infected patient who died 15 days after accidental inoculation of the virus (Davis et al, 1992).…”