Perivascular macrophages in the neonatal macaque brain undergo massive necroptosis after simian immunodeficiency virus infection

Abstract

We previously showed that rhesus macaques neonatally infected with simian immunodeficiency virus (SIV) do not develop SIV encephalitis (SIVE) and maintain low brain viral loads despite having similar plasma viral loads compared to SIV-infected adults. We hypothesize that differences in myeloid cell populations that are the known target of SIV and HIV in the brain contribute to the lack of neonatal susceptibility to lentivirus-induced encephalitis. Using immunohistochemistry and immunofluorescence microscopy, we examined the frontal cortices from uninfected and SIV-infected infant and adult macaques (n = 8/ea) as well as adults with SIVE (n = 4) to determine differences in myeloid cell populations. The number of CD206+ brain perivascular macrophages (PVMs) was significantly greater in uninfected infants than in uninfected adults and was markedly lower in SIV-infected infants while microglia numbers were unchanged across groups. CD206+ PVMs, which proliferate after infection in SIVinfected adults, did not undergo proliferation in infants. While virtually all CD206+ cells in adults are also CD163+, infants have a distinct CD206 single-positive population in addition to the double-positive population commonly seen in adults. Notably, we found that more than 60% of these unique CD206+CD163− PVMs in SIV-infected infants were positive for cleaved caspase-3, an indicator of apoptosis, and that nearly 100% of this subset were concomitantly positive for the necroptosis marker receptorinteracting protein kinase-3 (RIP3). These findings show that distinct subpopulations of PVMs found in infants undergo programmed cell death instead of proliferation following SIV infection, which may lead to the absence of PVM-dependent SIVE and the limited size of the virus reservoir in the infant brain.

Heterogeneity and developmental dynamics of LYVE-1 perivascular macrophages distribution in the mouse brain

“…40 Interestingly, zebrafish BAMs are CD206 þ /LYVE-1 þ , and in NHP, CD206 þ PVMs respond to viral infections. [41][42][43] An across-species molecular and anatomical comparison of BAMs in general, and of BrLyVMs specifically, is expected to yield important insights about the evolution and ontogeny of these cells, and about their functional roles.…”

Downregulation of CCR5 on brain perivascular macrophages in simian immunodeficiency virus‐infected rhesus macaques

“…No change was found between UI and infected neonates in the number of CCR5-positive cells (Figure 1f); however, numbers were significantly lower in infants than adults as reported by Delery et al (2019). Due to extremely low CCR5 expression in uninfected and infected neonates/infants and the complexity of macrophage subsets in neonatal SIV infection, neonates were not investigated further in this study (Bohannon et al, 2020).…”

Heterogeneity and developmental dynamics of LYVE-1 perivascular macrophages distribution in the mouse brain

“…Zebrafish BAMs comprise mainly MMs 35,36 , and to a lesser extent PVMs and CPMs 37 . Interestingly, zebrafish BAMs are CD206 + /LYVE-1 + , and in NHP, CD206 + PVMs respond to viral infections 38,39 . An across-species molecular and anatomical comparison of BAMs in general, and of BrLyVMs specifically, is expected to yield important insights about the evolution and ontogeny of these cells, and about their functional roles.…”