Main Research Themes

CMV INHIBITION BY ARTEMISININ-DERIVED DIMERS

We have shown that artemisinin-derived dimers inhibit human CMV replication significantly more that artemsinin-derived monomers, a pattern that has been observed in inhibition of cancer cell lines. Current work focuses in identifying mechanisms of CMV inhibition by these compounds and their effects on cell-signaling pathways

MODELS OF ANTI-VIRAL COMBINATION THERAPY

We performed extensive analysis of CMV inhibition using combination of known CMV inhibitors. Using several models for analysis of drug combination we have shown that the slope parameter is an important factor in distinguishing between classes of CMV inhibitors and for analyzing the outcome of drug combination.

ROLE OF WNT PATHWAY IN CMV REPLICATION

We have shown that in contrast to other herpesviruses (such as EBV and KSHV) CMV infection of human foreskin fibroblasts results in inhibition of the WNT pathway.

CMV CONTROL BY NOD1 and NOD2

We have shown that NOD1 and NOD2 recognize CMV and restrict virus replication. We are studying mechanisms of CMV control by NOD1 and NOD2, and the effects of their polymorphisms on virus replication.

IDENTIFY NOVEL CMV INHIBITORS USING HTS

We recently completed a high-throughput screening of more than 400,000 compounds with NCATS and identified several scaffolds that inhibit CMV. Work in our lab is characterizing these new agents.

Clinical trials

Phase III, randomized, placebo-controlled, blinded investigation of six weeks vs. six months of oral valganciclovir therapy in infants with symptomatic congenital cytomegalovirus infection (CASG 112) (DMID Protocol Number: 06-0046)
Status: closed for enrolled, manuscript submitted

Evaluation of the pharmacokinetics and pharmacodynamics of ganciclovir in premature infants receiving treatment for cytomegalovirus infection (DMID Protocol Number: 11-0067)
Status: open for enrollment

A phase II randomized and controlled investigation of six weeks of oral valganciclovir therapy in infants and children with congenital CMV infection and hearing loss (DMID Protocol Number: 11-0069)
Status: starting soon

Selected Publications

Mukhopadhyay R, Venkatadri R, Katsnelson J, Arav-Boger R. Digitoxin suppresses human cytomegalovirus replication via Na(+), K(+)/ATPase α1 subunit-dependent AMPK and autophagy activation. J Virol. 2018 Jan 10. pii: JVI.01861-17. doi: 10.1128/JVI.01861-17. [Epub ahead of print] PubMed PMID: 29321306.

Aronoff DM, Correa H, Rogers LM, Arav-Boger R, Alcendor DJ. Placental pericytes and cytomegalovirus infectivity: Implications for HCMV placental pathology and congenital disease. Am J Reprod Immunol. 2017 Sep;78(3). doi: 10.1111/aji.12728. Epub 2017 Jul 25. PubMed PMID: 28741727; PubMed Central PMCID: PMC5561471.

Gniadek TJ, Forman MT, Martin I, Arav-Boger R, Valsamakis A. The effect of a genetic variant on quantitative real-time PCR in a case of disseminated adenovirus infection. Diagn Microbiol Infect Dis. 2017 Jun 1. pii: S0732-8893(17)30173-6. doi: 10.1016/j.diagmicrobio.2017.05.013. [Epub ahead of print] PubMed PMID: 28629877.

Forman MS, Vaidya D, Bolorunduro O, Diener-West M, Pass RF, Arav-Boger R. Cytomegalovirus Kinetics Following Primary Infection in Healthy Women. J Infect Dis. 2017 May 15;215(10):1523-1526. doi: 10.1093/infdis/jix188. PubMed PMID: 28431127; PubMed Central PMCID: PMC5461424.

Cui X, Adler SP, Schleiss MR, Arav-Boger R, Demmler Harrison GJ, McVoy MA. Cytomegalovirus Virions Shed in Urine Have a Reversible Block to Epithelial Cell Entry and Are Highly Resistant to Antibody Neutralization. Clin Vaccine Immunol. 2017 Jun 5;24(6). pii: e00024-17. doi: 10.1128/CVI.00024-17. Print 2017 Jun. PubMed PMID: 28404573.

Holdhoff M, Guner G, Rodriguez FJ, Hicks JL, Zheng Q, Forman MS, Ye X, Grossman SA, Meeker AK, Heaphy CM, Eberhart CG, De Marzo AM, Arav-Boger R. Absence of cytomegalovirus in glioblastoma and other high-grade gliomas by real-time PCR, immunohistochemistry and in situ hybridization. Clin Cancer Res. 2016 Dec 29. pii: clincanres.1490.2016. doi: 10.1158/1078-0432.CCR-16-1490. [Epub ahead of print] PubMed PMID: 28034905.

Fan YH, Roy S, Mukhopadhyay R, Kapoor A, Duggal P, Wojcik GL, Pass RF, Arav-Boger R. Role of nucleotide-binding oligomerization domain 1 (NOD1) and its variants in human cytomegalovirus control in vitro and in vivo. Proc Natl Acad Sci U S A. 2016 Nov 29;113(48):E7818-E7827. PubMed PMID: 27856764; PubMed Central PMCID: PMC5137695.

Avery RK, Arav-Boger R, Marr KA, Kraus E, Shoham S, Lees L, Trollinger B, Shah P, Ambinder R, Neofytos D, Ostrander D, Forman M, Valsamakis A. Outcomes in Transplant Recipients Treated With Foscarnet for Ganciclovir-Resistant or Refractory Cytomegalovirus Infection. Transplantation. 2016 Oct;100(10):e74-80. doi: 10.1097/TP.0000000000001418. PubMed PMID: 27495775; PubMed Central PMCID: PMC5030152.

Mukhopadhyay R, Roy S, Venkatadri R, Su YP, Ye W, Barnaeva E, Mathews Griner L, Southall N, Hu X, Wang AQ, Xu X, Dulcey AE, Marugan JJ, Ferrer M, Arav-Boger R. Efficacy and Mechanism of Action of Low Dose Emetine against Human Cytomegalovirus. PLoS Pathog. 2016 Jun 23;12(6):e1005717. doi: 10.1371/journal.ppat.1005717. PubMed PMID: 27336364; PubMed Central PMCID: PMC4919066.

Barger-Kamate B, Forman M, Sangare CO, Haidara AS, Maiga H, Vaidya D, Djimde A, Arav-Boger R. Effect of artemether-lumefantrine (Coartem) on cytomegalovirus urine viral load during and following treatment for malaria in children. J Clin Virol. 2016 Feb 11;77:40-45. doi: 10.1016/j.jcv.2016.02.006. [Epub ahead of print] PubMed PMID: 26895228.

Sue PK, Salazar-Austin NM, McDonald OG, Rishi A, Cornish TC, Arav-Boger R. Cytomegalovirus Enterocolitis in Immunocompetent Young Children: A Report of Two Cases and Review of the Literature. Pediatr Infect Dis J. 2016 Feb 9. [Epub ahead of print] PubMed PMID: 26862673.

Kapoor A, Fan YH, Arav-Boger R. Bacterial Muramyl Dipeptide (MDP) Restricts Human Cytomegalovirus Replication via an IFN-β-Dependent Pathway. Sci Rep. 2016 Feb 2;6:20295. doi: 10.1038/srep20295. PubMed PMID: 26830977; PubMed Central PMCID: PMC4735818.

Fox JM, Moynihan JR, Mott BT, Mazzone JR, Anders NM, Brown PA, Rudek MA, Liu JO, Arav-Boger R, Posner GH, Civin CI, Chen X. Artemisinin-derived dimer ART-838 potently inhibited human acute leukemias, persisted in vivo, and synergized with antileukemic drugs. Oncotarget. 2016 Jan 12. doi: 10.18632/oncotarget.6896. [Epub ahead of print] PubMed PMID: 26771236.

Roy S, Liu F, Arav-Boger R. Human Cytomegalovirus Inhibits the PARsylation Activity of Tankyrase-A Potential Strategy for Suppression of the Wnt Pathway. Viruses. 2015 Dec 29;8(1). pii: E8. doi: 10.3390/v8010008. PubMed PMID: 26729153; PubMed Central PMCID: PMC4728568.

Arav-Boger R. Strain Variation and Disease Severity in Congenital Cytomegalovirus Infection: In Search of a Viral Marker. Infect Dis Clin North Am. 2015 Sep;29(3):401-14. doi: 10.1016/j.idc.2015.05.009. Epub 2015 Jul 4. Review. PubMed PMID: 26154664; PubMed Central PMCID: PMC4552582.

McClain L, Zhi Y, Cheng H, Ghosh A, Piazza P, Yee MB, Kumar S, Milosevic J, Bloom DC, Arav-Boger R, Kinchington PR, Yolken R, Nimgaonkar V, D'Aiuto L. Broad-spectrum non-nucleoside inhibitors of human herpesviruses. Antiviral Res. 2015 Sep;121:16-23. doi: 10.1016/j.antiviral.2015.06.005. Epub 2015 Jun 12. PubMed PMID: 26079681; PubMed Central PMCID: PMC4536133.

Hsu AJ, Dabb A, Arav-Boger R. Autoinduction of voriconazole metabolism in a child with invasive pulmonary aspergillosis. Pharmacotherapy. 2015 Apr;35(4):e20-6. doi: 10.1002/phar.1566. PubMed PMID: 25884532.

Roy S, He R, Kapoor A, Forman M, Mazzone JR, Posner GH, Arav-Boger R. Inhibition of human cytomegalovirus replication by artemisinins: effects mediated through cell cycle modulation. Antimicrob Agents Chemother. 2015 Jul;59(7):3870-9. doi: 10.1128/AAC.00262-15. Epub 2015 Apr 13. PubMed PMID: 25870074; PubMed Central PMCID: PMC4468661.

Kimberlin DW, Jester PM, Sánchez PJ, Ahmed A, Arav-Boger R, Michaels MG, Ashouri N, Englund JA, Estrada B, Jacobs RF, Romero JR, Sood SK, Whitworth MS, Abzug MJ, Caserta MT, Fowler S, Lujan-Zilbermann J, Storch GA, DeBiasi RL, Han JY, Palmer A, Weiner LB, Bocchini JA, Dennehy PH, Finn A, Griffiths PD, Luck S, Gutierrez K, Halasa N, Homans J, Shane AL, Sharland M, Simonsen K, Vanchiere JA, Woods CR, Sabo DL, Aban I, Kuo H, James SH, Prichard MN, Griffin J, Giles D, Acosta EP, Whitley RJ; National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group. Valganciclovir for symptomatic congenital cytomegalovirus disease. N Engl J Med. 2015 Mar 5;372(10):933-43. doi: 10.1056/NEJMoa1404599. PubMed PMID: 25738669; PubMed Central PMCID: PMC4401811.

Cai H, Wang HY, Venkatadri R, Fu DX, Forman M, Bajaj SO, Li H, O'Doherty GA, Arav-Boger R. Digitoxin analogues with improved anticytomegalovirus activity. ACS Med Chem Lett. 2014 Jan 25;5(4):395-9. doi: 10.1021/ml400529q. eCollection 2014 Apr 10. PubMed PMID: 24900847; PubMed Central PMCID: PMC4027591.

Roy S, Arav-Boger R. New cell-signaling pathways for controlling cytomegalovirus replication. Am J Transplant. 2014 Jun;14(6):1249-58. doi: 10.1111/ajt.12725. Epub 2014 May 19. Review. PubMed PMID: 24839861; PubMed Central PMCID: PMC4280670.

Kapoor A, Forman M, Arav-Boger R. Activation of Nucleotide Oligomerization Domain 2 (NOD2) by Human Cytomegalovirus Initiates Innate Immune Responses and Restricts Virus Replication. PLoS One. 2014 Mar 26;9(3):e92704. doi: 10.1371/journal.pone.0092704. eCollection 2014. PubMed PMID: 24671169; PubMed Central PMCID: PMC3966837.

Cai H, Kapoor A, He R, Venkatadri R, Forman M, Posner GH, Arav-Boger R. In vitro combination of anti-cytomegalovirus compounds acting through different targets: role of the slope parameter and insights into mechanisms of Action. Antimicrob Agents Chemother. 2014 Feb;58(2):986-94. doi: 10.1128/AAC.01972-13. Epub 2013 Nov 25. PubMed PMID: 24277030; PubMed Central PMCID: PMC3910867.

He R, Forman M, Mott BT, Venkatadri R, Posner GH, Arav-Boger R. Unique and highly selective anticytomegalovirus activities of artemisinin-derived dimer diphenyl phosphate stem from combination of dimer unit and a diphenyl phosphate moiety. Antimicrob Agents Chemother. 2013 Sep;57(9):4208-14. doi: 10.1128/AAC.00893-13. Epub 2013 Jun 17. PubMed PMID: 23774439; PubMed Central PMCID: PMC3754318.

Mott BT, He R, Chen X, Fox JM, Civin CI, Arav-Boger R, Posner GH. Artemisinin-derived dimer phosphate esters as potent anti-cytomegalovirus (anti-CMV) and anti-cancer agents: a structure-activity study. Bioorg Med Chem. 2013 Jul 1;21(13):3702-7. doi: 10.1016/j.bmc.2013.04.027. Epub 2013 Apr 22. PubMed PMID: 23673218; PubMed Central PMCID: PMC3685872.

Kapoor A, He R, Venkatadri R, Forman M, Arav-Boger R. Wnt modulating agents inhibit human cytomegalovirus replication. Antimicrob Agents Chemother. 2013 Jun;57(6):2761-7. doi: 10.1128/AAC.00029-13. Epub 2013 Apr 9. PubMed PMID: 23571549; PubMed Central PMCID: PMC3716142.

D'Aiuto L, Di Maio R, Heath B, Raimondi G, Milosevic J, Watson AM, Bamne M, Parks WT, Yang L, Lin B, Miki T, Mich-Basso JD, Arav-Boger R, Sibille E, Sabunciyan S, Yolken R, Nimgaonkar V. Human induced pluripotent stem cell-derived models to investigate human cytomegalovirus infection in neural cells. PLoS One. 2012;7(11):e49700. doi: 10.1371/journal.pone.0049700. Epub 2012 Nov 27. PubMed PMID: 23209593; PubMed Central PMCID: PMC3507916.

Kapoor A, Cai H, Forman M, He R, Shamay M, Arav-Boger R. Human cytomegalovirus inhibition by cardiac glycosides: evidence for involvement of the HERG gene. Antimicrob Agents Chemother. 2012 Sep;56(9):4891-9. doi: 10.1128/AAC.00898-12. Epub 2012 Jul 9. PubMed PMID: 22777050; PubMed Central PMCID: PMC3421849.

Forman M, Valsamakis A, Arav-Boger R. Dried urine spots for detection and quantification of cytomegalovirus in newborns. Diagn Microbiol Infect Dis. 2012 Aug;73(4):326-9. doi: 10.1016/j.diagmicrobio.2012.04.009. Epub 2012 Jun 1. PubMed PMID: 22658885; PubMed Central PMCID: PMC3396794.

He R, Park K, Cai H, Kapoor A, Forman M, Mott B, Posner GH, Arav-Boger R. Artemisinin-derived dimer diphenyl phosphate is an irreversible inhibitor of human cytomegalovirus replication. Antimicrob Agents Chemother. 2012 Jul;56(7):3508-15. doi: 10.1128/AAC.00519-12. Epub 2012 Apr 30. PubMed PMID: 22547612; PubMed Central PMCID: PMC3393438.

Arav-Boger R, Wojcik GL, Duggal P, Ingersoll RG, Beaty T, Pass RF, Yolken RH. Polymorphisms in Toll-like receptor genes influence antibody responses to cytomegalovirus glycoprotein B vaccine. BMC Res Notes. 2012 Mar 13;5:140. doi: 10.1186/1756-0500-5-140. PubMed PMID: 22414065; PubMed Central PMCID: PMC3317442.

He R, Mott BT, Rosenthal AS, Genna DT, Posner GH, Arav-Boger R. An artemisinin-derived dimer has highly potent anti-cytomegalovirus (CMV) and anti-cancer activities. PLoS One. 2011;6(8):e24334. doi: 10.1371/journal.pone.0024334. Epub 2011 Aug 31. PubMed PMID: 21904628; PubMed Central PMCID: PMC3164168.

He R, Sandford G, Hayward GS, Burns WH, Posner GH, Forman M, Arav-Boger R. Recombinant luciferase-expressing human cytomegalovirus (CMV) for evaluation of CMV inhibitors. Virol J. 2011 Jan 26;8:40. doi: 10.1186/1743-422X-8-40. PubMed PMID: 21269468; PubMed Central PMCID: PMC3041771.

Murthy S, Hayward GS, Wheelan S, Forman MS, Ahn JH, Pass RF, Arav-Boger R. Detection of a single identical cytomegalovirus (CMV) strain in recently seroconverted young women. PLoS One. 2011 Jan 10;6(1):e15949. doi: 10.1371/journal.pone.0015949. PubMed PMID: 21264339; PubMed Central PMCID: PMC3018470.

Arav-Boger R, He R, Chiou CJ, Liu J, Woodard L, Rosenthal A, Jones-Brando L, Forman M, Posner G. Artemisinin-derived dimers have greatly improved anti-cytomegalovirus activity compared to artemisinin monomers. PLoS One. 2010 Apr 28;5(4):e10370. doi: 10.1371/journal.pone.0010370. PubMed PMID: 20442781; PubMed Central PMCID: PMC2860993.

Jacobson LM, Milstone AM, Zenilman J, Carroll KC, Arav-Boger R. Daptomycin therapy failure in an adolescent with methicillin-resistant Staphylococcus aureus bacteremia. Pediatr Infect Dis J. 2009 May;28(5):445-7. doi: 10.1097/INF.0b013e3181927891. PubMed PMID: 19295462.

Arav-Boger R. Treatment for Kaposi sarcoma herpesvirus: great challenges with promising accomplishments. Virus Genes. 2009 Apr;38(2):195-203. doi: 10.1007/s11262-008-0325-y. Epub 2009 Jan 13. Review. PubMed PMID: 19139983.

Arav-Boger R, Boger YS, Foster CB, Boger Z. The use of artificial neural networks in prediction of congenital CMV outcome from sequence data. Bioinform Biol Insights. 2008 May 29;2:281-9. PubMed PMID: 19812782; PubMed Central PMCID: PMC2735958.

Arav-Boger R, Pass R. Viral load in congenital cytomegalovirus infection. Herpes. 2007 Jun;14(1):17-22. Review. PubMed PMID: 17848214.

Zong JC, Arav-Boger R, Alcendor DJ, Hayward GS. Reflections on the interpretation of heterogeneity and strain differences based on very limited PCR sequence data from Kaposi's sarcoma-associated herpesvirus genomes. J Clin Virol. 2007 Sep;40(1):1-8. Epub 2007 Aug 14. Review. PubMed PMID: 17698410; PubMed Central PMCID: PMC2084348.

Reif S, Arav-Boger R, Diamant S, Burstein Y, Fatal A. Shwachman--Diamond syndrome associated with autoimmune phenomena. J Med. 1999;30(3-4):259-65. PubMed PMID: 17312679.

Arav-Boger R, Battaglia CA, Lazzarotto T, Gabrielli L, Zong JC, Hayward GS, Diener-West M, Landini MP. Cytomegalovirus (CMV)-encoded UL144 (truncated tumor necrosis factor receptor) and outcome of congenital CMV infection. J Infect Dis. 2006 Aug 15;194(4):464-73. Epub 2006 Jul 7. PubMed PMID: 16845629.

Arav-Boger R, Foster CB, Zong JC, Pass RF. Human cytomegalovirus-encoded alpha -chemokines exhibit high sequence variability in congenitally infected newborns. J Infect Dis. 2006 Mar 15;193(6):788-91. Epub 2006 Feb 8. PubMed PMID: 16479512.

Arav-Boger R, Zong JC, Foster CB. Loss of linkage disequilibrium and accelerated protein divergence in duplicated cytomegalovirus chemokine genes. Virus Genes. 2005 Aug;31(1):65-72. PubMed PMID: 15965610.

Arav-Boger R, Shapiro TA. Molecular mechanisms of resistance in antimalarial chemotherapy: the unmet challenge. Annu Rev Pharmacol Toxicol. 2005;45:565-85. Review. PubMed PMID: 15822189.

Arav-Boger R, Pass RF. Diagnosis and management of cytomegalovirus infection in the newborn. Pediatr Ann. 2002 Nov;31(11):719-25. Review. PubMed PMID: 12455480.

Arav-Boger R, Willoughby RE, Pass RF, Zong JC, Jang WJ, Alcendor D, Hayward GS. Polymorphisms of the cytomegalovirus (CMV)-encoded tumor necrosis factor-alpha and beta-chemokine receptors in congenital CMV disease. J Infect Dis. 2002 Oct 15;186(8):1057-64. Epub 2002 Sep 30. PubMed PMID: 12355354.

Arav-Boger R, Reif S, Bujanover Y. Portal vein thrombosis caused by protein C and protein S deficiency associated with cytomegalovirus infection. J Pediatr. 1995 Apr;126(4):586-8. PubMed PMID: 7699538.