Primary Appointment:
 Microbiology & Immunology

GEBS Cluster Affiliations:
 IMV - Immunology, Microbiology, and Virology
 NS - Neuroscience
 

Link to Laboratory Web Page

Link to Laboratory Server

University of Rochester
School of Medicine and Dentistry
601 Elmwood Ave, Box 672
Rochester, New York 14642

Phone: (585) 275-3216
Fax: (585) 473-2361
E-Mail: stephen_dewhurst@urmc.rochester.edu

Viral vectors and vaccine development for HIV/AIDS; Mechanisms of neuronal apoptosis in HIV/AIDS; Salivary gland gene therapy studies

Viral vectors and vaccine development for HIV/AIDS: We are examining novel methods for the generation of vaccines for HIV/AIDS. Ongoing studies include experiments designed to test the efficacy of novel herpesvirus vector systems (cytomegalovirus, HSV amplicon vectors) in mice, as well as exploratory studies aimed at the development of selectively targeted virus vector systems with an ability to target dendritic cells. The latter studies involve the use of phage display libraries to identify peptides capable of allowing viral particles to enter human cells, including dendritic cells. These peptides will be used to retarget adenovirus vectors, and also to mediate the internalization and uptake of bacteriophage vectors in human cells.

Mechanisms of neuronal apoptosis in HIV/AIDS: We are examining the role of NF-kB activation in neuronal survival in neuroAIDS. Related studies focus on the effect of glycogen synthase kinase 3-b activation on neuronal survival and function, and on the development of novel methods for the delivery of viral vectors into the central nervous system.

Salivary gland gene therapy studies: Human herpesvirus (HHV)-7 infects almost all adults and is a constitutive inhabitant of human saliva; the virus can also be found in human salivary gland tissues. We are therefore interested in HHV-7, with a long-term view towards the development of the virus, or viral components, for use in salivary gland gene transfer applications. We are also analyzing several novel gene products encoded by HHV-6 and -7 (including a putative viral opioid receptor and a potential viral immunoregulatory gene).

Fan, S., C. A. Maguire, et al  "Valproic acid enhances gene expression from viral gene transfer vectors." J Virol Methods 125(1): 23-33. 2005.
   
Gorantla, S., K. Santos, et al. "Human dendritic cells transduced with herpes simplex virus amplicons encoding human immunodeficiency virus type 1 (HIV-1) gp120 elicit adaptive immune responses from human cells engrafted into NOD/SCID mice and confer partial protection against HIV-1 challenge." J Virol 79(4): 2124-32, 2005.
   
Jin, N., A. D. Kovacs, et al. "Opposite effects of lithium and valproic acid on trophic factor deprivation-induced glycogen synthase kinase-3 activation, c-Jun expression and neuronal cell death." Neuropharmacology 48(4): 576-83, 2005.

Perry, S. W., J. P. Norman, et al. "HIV-1 transactivator of transcription protein induces mitochondrial hyperpolarization and synaptic stress leading to apoptosis." J Immunol 174(7): 4333-44, 2005.

Renda MJ, Bradel-Tretheway B, Planelles V, Bambara RA, Dewhurst S. Inhibition of HIV Type 1 Replication Using Lentiviral-Mediated Delivery of Mutant tRNA(Lys3)A58U. AIDS Res Hum Retroviruses. 20:1324-34, 2004.

Fan S, Ramirez SH, Garcia TM, Dewhurst S. Dishevelled promotes neurite outgrowth in neuronal differentiating neuroblastoma 2A cells, via a DIX-domain dependent pathway. Brain Res Mol Brain Res. 132:38-50, 2004.

Caserta MT, McDermott MP, Dewhurst S, Schnabel K, Carnahan JA, Gilbert L, Lathan G, Lofthus GK, Hall CB. Human herpesvirus 6 (HHV6) DNA persistence and reactivation in healthy children. J Pediatr. 145:478-84, 2004.

Hall CB, Caserta MT, Schnabel KC, Boettrich C, McDermott MP, Lofthus GK, Carnahan JA, Dewhurst S. Congenital infections with human herpesvirus 6 (HHV6) and human herpesvirus 7 (HHV7). J Pediatr. 2004 Oct;145(4):472-7.

Diamond TL, Roshal M, Jamburuthugoda VK, Reynolds HM, Merriam AR, Lee KY, Balakrishnan M, Bambara RA, Planelles V, Dewhurst S, Kim B. Macrophage tropism of HIV-1 depends on efficient cellular dNTP utilization by reverse transcriptase. J Biol Chem. 279:51545-53, 2004

Ramirez SH, Fan S, Maguire CA, Perry S, Hardiek K, Ramkumar V, Gelbard HA, Dewhurst S, Maggirwar SB. Activation of adenosine A2A receptor protects sympathetic neurons against nerve growth factor withdrawal. J Neurosci Res. 77:258-69, 2004.

Zhen Z, Bradel-Tretheway BG, Dewhurst S, Bidlack JM. Transient overexpression of kappa and mu opioid receptors using recombinant adenovirus vectors. J Neurosci Methods 136:133-9, 2004.

Latchney LR, Fallon MA, Culp DJ, Gelbard HA, Dewhurst S. Immunohistochemical Assessment of Fractalkine, Inflammatory Cells, and Human Herpesvirus 7 in Human Salivary Glands. J Histochem Cytochem. 52:671-682, 2004.

Dou H, Birusingh K, Faraci J, Gorantla S, Poluektova LY, Maggirwar SB, Dewhurst S, Gelbard HA, Gendelman HE. Neuroprotective activities of sodium valproate in a murine model of human immunodeficiency virus-1 encephalitis. J Neurosci. 23:9162-70, 2003.

Diamond TL, Souroullas G, Weiss KK, Lee KY, Bambara RA, Dewhurst S, Kim B. Mechanistic understanding of an altered fidelity simian immunodeficiency virus reverse transcriptase mutation, V148I, identified in a pig-tailed macaque J Biol Chem. 278:29913-24, 2003.

Bradel-Tretheway BG, Zhen Z, Dewhurst S. Effects of codon-optimization on protein expression by the human herpesvirus 6 and 7 U51 open reading frame. J Virol Methods 111:145-56, 2003.

Wang X, Messerle M, Sapinoro R, Santos K, Hocknell PK, Jin X, Dewhurst S. Murine cytomegalovirus abortively infects human dendritic cells, leading to expression and presentation of virally vectored genes J. Virol. 77:7182-7192, 2003.

Wang X, Wiley RD, Evans TG, Bowers WJ, Federoff HJ, Dewhurst S. Cellular immune responses to helper-free HSV-1 amplicon particles encoding HIV-1 gp120 are enhanced by DNA priming. Vaccine 21:2288-2297, 2003

Richards J, Abend J, Miller M, Chakraborty-Sett S, Dewhurst S, Whetter L. A peptide containing a novel FPGN CD40-binding sequence enhances adenoviral infection of murine and human dendritic cells. Eur. J. Biochem. 270: 2287-2294, 2003.

Richards J, Miller M, Abend J, Koide A, Koide S, Dewhurst S. Engineered fibronectin type III domain with a RGDWXE sequence binds with enhanced affinity and specificity to human alphaV beta3 integrin. J. Mol. Biol. 326:1475-1488, 2003.

Hocknell PK, Wiley RW, Wang X, Evans TG, Bowers WJ, Hanke T, Federoff HJ, Dewhurst, S. Expression of human immunodeficiency virus-1 gp120 from herpes simplex virus-1 derived amplicons results in potent, specific and durable cellular and humoral immune responses. J. Virol. 76:5565-5580, 2002.

Skrincosky D, Willis RA, Hocknell PK, Frelinger JG, Mirandola P, Wang X, Dewhurst S. Epitope mapping of human herpesvirus-7 gp65 using monoclonal antibodies. Arch. Virol. 146:1705-1722, 2001.

Ramirez SH, Sanchez JF, Dimitri CA, Gelbard HA, Dewhurst S, Maggirwar SB. Neurotrophins prevent HIV Tat-induced neuronal apoptosis via a nuclear factor-kappaB (NF-kappaB)-dependent mechanism. J. Neurochem. 78:874-889, 2001.

Tong N, Sanchez JF, Maggirwar SB, Ramirez SH, Guo H, Dewhurst S, Gelbard HA. Activation of glycogen synthase kinase (GSK)-3 beta by platelet activating factor mediates migration and cell death in cerebellar granule neurons. Eur J Neurosci. 13:1913-1922, 2001

Bal HP, Chroboczek J, Schoehn G, Ruigrok RW, Dewhurst S. Adenovirus type 7 penton - Purification of soluble pentamers from Escherichia coli and development of an integrin-dependent gene delivery system. Eur J Biochem. 267:6074-6081, 2000.

Skrincosky D, Hocknell P, Whetter L, Secchiero P, Chandran B, Dewhurst S. Identification and analysis of a novel heparin-binding glycoprotein encoded by human herpesvirus 7. J Virol. 74:4530-40, 2000.

Maggirwar SB, Ramirez S, Tong N, Gelbard HA, Dewhurst S. Functional interplay between nuclear factor-kappaB and c-Jun integrated by coactivator p300 determines the survival of nerve growth factor-dependent PC12 cells. J. Neurochem. 74:527-39, 2000.

Tong N, Perry SW, Zhang Q, James HJ, Guo H, Brooks A, Bal H, Kinnear SA, Fine S, Epstein LG, Dairaghi D, Schall TJ, Gendelman HE, Dewhurst S, Sharer LR, Gelbard HA. Neuronal fractalkine expression in HIV-1 encephalitis: roles for macrophage recruitment and neuroprotection in the central nervous system. J. Immunol. 164:1333-9, 2000.

Maggirwar SM, Tong N, Ramirez S, Gelbard HA, Dewhurst S. HIV-1 Tat mediated activation of glycogen synthase kinase-3 beta contributes to Tat-mediated neurotoxicity. J Neurochem 73:578-586, 1999.

Dominguez G, Dambaugh TR, Stamey FR, Dewhurst S, Inoue I, Pellett PE. Human herpesvirus 6B genome sequence: coding content and comparison with human herpesvirus 6A. J Virol 73:8040-8051, 1999.

Maggirwar SM, Sarmiere PD, Dewhurst S, Freeman RS. Nerve growth factor-dependent activation of NF-kappaB contributes to survival of sympathetic neurons. J Neurosci 18:10356-10365, 1998.

Deng H, Dewhurst, S. Functional identification and analysis of cis-acting sequences which mediate genome cleavage and packaging in human herpesvirus 6. J Virol 72:320-329, 1998.

Selected Review Articles

Dewhurst S. Human herpesvirus type 6 and human herpesvirus type 7 infections of the central nervous system. Herpes. 2004 Jun;11 Suppl 2:105A-111A. Review.

Perry SW, Dewhurst S, Bellizzi MJ, Gelbard HA. Tumor necrosis factor-alpha in normal and diseased brain: Conflicting effects via intraneuronal receptor crosstalk? J Neurovirol. 8:611-24, 2002.

Caserta MT, Mock DJ, Dewhurst S. Human herpesvirus 6. Clin. Infect. Dis. 33:829-833, 2001.

Dewhurst SL, da Cruz RL, Whetter L. Pathogenesis and treatment of HIV-1 infection: recent developments (Y2K update). Front Biosci. 5:D30-49, 2000.

Whetter L, Ojukwu I, Novembre F, Dewhurst S. Pathogenesis of simian immunodeficiency virus infection. J Gen Virol 80:1557-1568, 1999.

Dewhurst S, Skrincosky D, van Loon N. Human herpesvirus 7. Expert Reviews in Molecular Medicine, 1997.