Faculty

Simon M. Barratt-Boyes, BVSc, PhD Associate Professor, Department of Infectious Diseases and Microbiology and Department of Immunology, School of Medicine (Secondary Appointment) E-mail: smbb@pitt.edu Phone: 412-383-7537 Address: Center for Vaccine Research 9046 BST3 3501 Fifth Avenue Pittsburgh, PA  15260

Education

BVSc; Massey University, New Zealand; 1984
PhD; University of California, Davis; 1993

Research Interests

Dendritic cell dynamics in viral infections; vector-based vaccines for viral infections

Research Summary

	Figure caption: Dendritic cells expressing green fluorescent protein via recombinant adenovirus transduction are localized in the T cell-rich region of the lymph node after injection in a monkey
	Figure caption:Human dendritic cells stained with antibodies to CD11c (blue) and early endosomal antigen (red). Image courtesy of S. Gleason

Our research broadly focuses on the immunology of infectious diseases. A lot of our work focuses on dendritic cells (DC), which are critical in the initiation of immune responses to pathogens. The animal model we primarily study is the simian model of human immunodeficiency virus infection, being simian immunodeficiency virus or SIV, although we do basic immunology work using human cells. There are three major lines of investigation currently ongoing in the lab.

Dendritic cell dynamics in healthy and virus-infected rhesus macaques: Studies in the human show that the two main subsets of DC, myeloid DC (mDC) and plasmacytoid DC (pDC), are lost from the circulation in individuals with HIV infection associated with progression to disease. The mechanism of DC loss is undefined but is believed to be associated with migration to tissues or cell death. We have shown that mDC and pDC are lost from the blood and lymphoid tissues in monkeys with AIDS, validating this model for the study of DC dynamics in HIV infection. Most recently we have critically addressed the issue of pDC dynamics in acute SIV infection. We found that pDC were present in normal numbers in bone marrow but were lost from blood and lymph nodes within days of intravenous infection. Underlying pDC loss was a profound mobilization of pDC from bone marrow into blood and subsequent influx into lymph nodes. In lymph nodes pDC were activated, apoptotic, and frequently infected with virus. Nevertheless, pDC were functionally normal with respect to cytokine production. We have concluded from this work that migration and death both contribute to pDC depletion, with influx into lymph nodes bringing cells into an environment favoring their death by infection or apoptosis. Currently we are evaluating the effect of antiretroviral therapy on DC dynamics during the transition from acute to chronic infection. A developing project in the lab in collaboration with Ted Ross is the study of DC dynamics in influenza virus infection, particularly in mice and primates infected with highly pathogenic avian influenza virus.

Dendritic cell- and vector-based immunotherapy: There is a lot of interest in using DC as antigen-presenting cells to deliver viral or tumor-associated antigens to T cells in immunotherapy. We have developed an mRNA approach to transfect monkey and human DC with viral antigens and have demonstrated that nucleofection with mRNA is a superior method for introducing transgenes into primary DC lines and for subsequent stimulation of virus-specific T cells. Adenoviral vectors are also potent vehicles for transducing DC and have been used to great effect as vaccines when given directly to monkeys or human volunteers. We have used recombinant adenoviral vectors as vaccines for SIV infection and for highly pathogenic avian influenza virus infection. Currently we are using adenovirus-5 and 35-based vectors in combination as an immunotherapy for monkeys that are infected with SIV and treated with antiretroviral drugs to control virus load. These studies have revealed that Ad5- and 35-based immunotherapy is very effective at increasing the breadth of T cell response to virus but does not improve the breadth or quality of immunity in monkeys with chronic SIV infection.

Dendritic cell capture of cell-associated antigens: We have studied the interaction of DC with other cells and have shown that DC capture antigens from living cells and cross-present peptides from these antigens to cytotoxic T cells, a process known as ‘nibbling’. Work in the lab is currently looking at how the different sources of cellular antigens – from live cells or apoptotic cells – affects the process and efficiency of antigen capture. These studies involve confocal and live-cell imaging assays in collaboration with the Center for Biologic Imaging.

Recent Publications

• Barratt-Boyes, S.M., Soloff, A.C., Gao, W., Nwanegbo, E., Liu, X., Rajakumar, P.A., Brown, K.N., Robbins, P.D., Murphey-Corb, M., Day, R.D. & Gambotto, A. (2006). Broad cellular immunity with robust memory responses to simian immunodeficiency virus following serial vaccination with adenovirus 5- and 35-based vectors. J. Gen. Virol. 87: 139-149.

• Gao, W., Soloff, A.C., Lu, X., Montecalvo, A., Nguyen, D.C., Matsuoka, Y., Robbins, P.D., Swayne, D.E., Donis, R.O., Katz, J.M., Barratt-Boyes, S.M., & Gambotto, A. (2006). Protection in mice and poultry from lethal H5N1 avian influenza through adenovirus-based immunization. J. Virol. 80: 1959-1964.

• Barratt-Boyes, S.M., Brown, K.N., Melhem, N., Soloff, A.C., & Gleason, S.M. (2006). Understanding and exploiting dendritic cells in human immunodeficiency virus infection using the nonhuman primate model. Immunol. Rev. 36:265-74.

• Brown, K.N., Trichel, A. & Barratt-Boyes, S.M. (2007) Parallel loss of myeloid and plasmacytoid dendritic cells from blood and lymphoid tissues in simian AIDS. J. Immunol. 178: 6958-6967.

• Melhem, N.M., Liu, X.D., Boczowski, D., Gilboa, E. & Barratt-Boyes, S.M. (2007) Robust CD4+ and CD8+ T cell responses to SIV using mRNA-transfected dendritic cells expressing autologous viral antigen. Eur. J. Immunol. 37: 2164-2173.

• Gambotto, A., Barratt-Boyes, S.M., de Jong, M.D., Neumann, G., & Kawaoka, Y. (2008) Human infection with highly pathogenic H5N1 influenza virus. The Lancet 371: 1464-1475.

• Qin, S., Sui, Y., Soloff, A.C., Junecko, B.A., Kirschner, D.E., Murphey-Corb, M., Watkins, S.C., Tarwater, P.M., Pease, J.E., Barratt-Boyes, S.M., & Reinhart, T.A. (2008) Chemokine and cytokine mediated loss of regulatory T cells in lymph nodes during pathogenic simian immunodeficiency virus infection. J. Immunol. 180: 5530-5536.

• Melhem, N.M., Liu, X.D., Gleason, S.M., Liu, X. & Barratt-Boyes, S.M. (2008) High-level antigen expression and sustained antigen presentation in dendritic cells nucleofected with wild-type vial mRNA but not DNA. Clin. Vacc. Immunol. 15: 1337-1344.

• Wijewardana, V., Brown, K.N. & Barratt-Boyes, S.M. (2009) Studies of plasmacytoid dendritic cell dynamics in simian immunodeficiency virus infection of nonhuman primates provide insight into HIV pathogenesis. Current HIV Res. 7: 23-29.

• Barratt-Boyes, S.M. & Brown, K.N. (2009) Surface phenotype and rapid quantification of blood dendritic cell subsets in the rhesus macaque. J Med Primatol In press.

• Brown, K.N., Wijewardana, V., Liu, X. & Barratt-Boyes, S.M. (2009) Rapid influx and death of plasmacytoid dendritic cells in lymph nodes mediate depletion in acute simian immunodeficiency virus infection. PLoS Pathogens May 2009, 5: e1000413

• Soloff, A.C., Liu, X, Gao, W., Day, R.D., Gambotto, A. & Barratt-Boyes, S.M. (2009) Adenovirus 5 and 35-based immunotherapy enhances the strength but not breadth or quality of immunity during chronic SIV infection. European Journal of Immunology (In press).

Dr. Barratt-Boyes' Lab

Staff