TY - JOUR
T1 - An oral form of methylglyoxal-bis-guanylhydrazone reduces monocyte activation and traffic to the dorsal root ganglia in a primate model of HIV-peripheral neuropathy
AU - Lakritz, Jessica R.
AU - Yalamanchili, Samshita
AU - Polydefkis, Michael J.
AU - Miller, Andrew D.
AU - McGrath, Michael S.
AU - Williams, Kenneth C.
AU - Burdo, Tricia H.
N1 - Funding Information:
This work was funded by NIH/NINDS RO1 NS040237 (awarded to KC Williams), R01. The conflict of interest statement is correct. NS082116 (awarded to TH Burdo), and U19MH08183 (awarded to MS McGrath). We would like to thank Pathologica for providing MGBG and Wedgwood Pharmacy for formulating MGBG and the placebo. We would also like to thank the veterinary staff at the NEPRC and TNRPC for the animal care and for assisting with necropsies and tissue collection.
Publisher Copyright:
© 2017, Journal of NeuroVirology, Inc.
PY - 2017/8/1
Y1 - 2017/8/1
N2 - Peripheral neuropathy (PN) is a major comorbidity of HIV infection that is caused in part by chronic immune activation. HIV-PN is associated with infiltration of monocytes/macrophages to the dorsal root ganglia (DRG) causing neuronal loss and formation of Nageotte nodules. Here, we used an oral form of methylglyoxal-bis-guanylhydrazone (MGBG), a polyamine biosynthesis inhibitor, to specifically reduce activation of myeloid cells. MGBG is selectively taken up by monocyte/macrophages in vitro and inhibits HIV p24 expression and DNA viral integration in macrophages. Here, MGBG was administered to nine SIV-infected, CD8-depleted rhesus macaques at 21 days post-infection (dpi). An additional nine SIV-infected, CD8-depleted rhesus macaques were used as untreated controls. Cell traffic to tissues was measured by in vivo BrdU pulse labeling. MGBG treatment significantly diminished DRG histopathology and reduced the number of CD68+ and CD163+ macrophages in DRG tissue. The number of recently trafficked BrdU+ cells in the DRG was significantly reduced with MGBG treatment. Despite diminished DRG pathology, intraepidermal nerve fiber density (IENFD) did not recover after treatment with MGBG. These data suggest that MGBG alleviated DRG pathology and inflammation.
AB - Peripheral neuropathy (PN) is a major comorbidity of HIV infection that is caused in part by chronic immune activation. HIV-PN is associated with infiltration of monocytes/macrophages to the dorsal root ganglia (DRG) causing neuronal loss and formation of Nageotte nodules. Here, we used an oral form of methylglyoxal-bis-guanylhydrazone (MGBG), a polyamine biosynthesis inhibitor, to specifically reduce activation of myeloid cells. MGBG is selectively taken up by monocyte/macrophages in vitro and inhibits HIV p24 expression and DNA viral integration in macrophages. Here, MGBG was administered to nine SIV-infected, CD8-depleted rhesus macaques at 21 days post-infection (dpi). An additional nine SIV-infected, CD8-depleted rhesus macaques were used as untreated controls. Cell traffic to tissues was measured by in vivo BrdU pulse labeling. MGBG treatment significantly diminished DRG histopathology and reduced the number of CD68+ and CD163+ macrophages in DRG tissue. The number of recently trafficked BrdU+ cells in the DRG was significantly reduced with MGBG treatment. Despite diminished DRG pathology, intraepidermal nerve fiber density (IENFD) did not recover after treatment with MGBG. These data suggest that MGBG alleviated DRG pathology and inflammation.
KW - Dorsal root ganglia
KW - HIV
KW - Monocyte
KW - Peripheral neuropathy
KW - Polyamine biosynthesis inhibitor
KW - Rhesus
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U2 - 10.1007/s13365-017-0529-9
DO - 10.1007/s13365-017-0529-9
M3 - Article
C2 - 28462488
AN - SCOPUS:85018269334
SN - 1355-0284
VL - 23
SP - 568
EP - 576
JO - Journal of neurovirology
JF - Journal of neurovirology
IS - 4
ER -