TY - JOUR
T1 - Inhibition of retrograde transport limits polyomavirus infection in vivo
AU - Maru, Saumya
AU - Jin, Ge
AU - Desai, Dhimant
AU - Amin, Shantu
AU - Shwetank,
AU - Lauver, Matthew D.
AU - Lukacher, Aron E.
N1 - Funding Information:
We acknowledge the technical support of Jade Vogel, Nate Sheaffer, and Joe Bednarczyk of the Flow Cytometry Core Facility of the Penn State College of Medicine. We thank Laura Cos and Jessica Wingate from the Comparative Medicine diagnostic laboratory at the Penn State College of Medicine for performing serum creatinine and BUN assays. This work was supported by NIH grants R01 NS088367 and R01 NS092662 (to A.E.L.)
Publisher Copyright:
© 2017 Maru et al.
PY - 2017/11/1
Y1 - 2017/11/1
N2 - Polyomaviruses (PyVs) silently infect most humans, but they can cause life-threatening diseases in immunocompromised individuals. The JC polyomavirus (JCPyV) induces progressive multifocal leukoencephalopathy, a severe demyelinating disease in multiple sclerosis patients receiving immunomodulatory therapy, and BK polyomavirus (BKPyV)-associated nephropathy is a major cause of kidney allograft failure. No effective anti-PyV agents are available. Several compounds have been reported to possess anti-PyV activity in vitro, but none have shown efficacy in clinical trials. Productive PyV infection involves usurping the cellular retrograde vesicular transport pathway to enable endocytosed virions to navigate to the endoplasmic reticulum where virion uncoating begins. Compounds inhibiting this pathway have been shown to reduce infection by simian virus 40 (SV40), JCPyV, and BKPyV in tissue culture. In this study, we investigated the potential of Retro-2.1, a retrograde transport inhibitor, to limit infection by mouse polyomavirus (MuPyV) in vivo. We found that Retro-2.1 significantly reduced MuPyV levels in the kidney during acute infection without affecting renal function or the MuPyV-specific CD8 T cell response. To approximate the clinical setting of PyV resurgence in immunocompromised hosts, we showed that antibody-mediated depletion of T cells in persistently infected mice elevated MuPyV levels in the kidney and that Retro-2.1 blunted this increase in virus levels. In summary, these data indicate that inhibition of retrograde vesicular transport in vivo controls infection in a natural PyV mouse model and supports development of these compounds as potential therapeutic agents for individuals at risk for human PyV-associated diseases.
AB - Polyomaviruses (PyVs) silently infect most humans, but they can cause life-threatening diseases in immunocompromised individuals. The JC polyomavirus (JCPyV) induces progressive multifocal leukoencephalopathy, a severe demyelinating disease in multiple sclerosis patients receiving immunomodulatory therapy, and BK polyomavirus (BKPyV)-associated nephropathy is a major cause of kidney allograft failure. No effective anti-PyV agents are available. Several compounds have been reported to possess anti-PyV activity in vitro, but none have shown efficacy in clinical trials. Productive PyV infection involves usurping the cellular retrograde vesicular transport pathway to enable endocytosed virions to navigate to the endoplasmic reticulum where virion uncoating begins. Compounds inhibiting this pathway have been shown to reduce infection by simian virus 40 (SV40), JCPyV, and BKPyV in tissue culture. In this study, we investigated the potential of Retro-2.1, a retrograde transport inhibitor, to limit infection by mouse polyomavirus (MuPyV) in vivo. We found that Retro-2.1 significantly reduced MuPyV levels in the kidney during acute infection without affecting renal function or the MuPyV-specific CD8 T cell response. To approximate the clinical setting of PyV resurgence in immunocompromised hosts, we showed that antibody-mediated depletion of T cells in persistently infected mice elevated MuPyV levels in the kidney and that Retro-2.1 blunted this increase in virus levels. In summary, these data indicate that inhibition of retrograde vesicular transport in vivo controls infection in a natural PyV mouse model and supports development of these compounds as potential therapeutic agents for individuals at risk for human PyV-associated diseases.
UR - http://www.scopus.com/inward/record.url?scp=85041503013&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85041503013&partnerID=8YFLogxK
U2 - 10.1128/mSphere.00494-17
DO - 10.1128/mSphere.00494-17
M3 - Article
AN - SCOPUS:85041503013
SN - 2379-5042
VL - 2
JO - mSphere
JF - mSphere
IS - 6
M1 - e00494-17
ER -