AIDS and Cancer Virus Program

Biography

Claes Ohlen received his Ph.D. from the Karolinska Institute, Stockholm, Sweden 1992. His graduate work focused on mouse studies of T and NK cells in tumor and transplantation models, as well as genetic and biochemical studies of antigen presentation for T cells. After a post-doc position at Oxford University, UK, Dr. Ohlen 1994 joined Phil Greenberg's group at Department of Immunology, University of Washington/Fred Hutchinson Cancer Research Center, Seattle, as a Senior Fellow to study basic questions of T cell tolerance and autoimmunity. He joined the faculty of Department of Immunology, University of Washington, 1997 as an Acting Instructor and became Assistant Research Professor 2001. In 2001 Dr Ohlen was also appointed Assistant Director, Immunology Core, Center for AIDS Research, National Primate Research Center, University of Washington, Seattle, WA. In 2004, Dr. Ohlen was recruited to the AIDS and Cancer Virus Program at SAIC/Frederick National Laboratory for Cancer Research and joined the program in January 2005 as a Senior Scientist/Principal Investigator (PI) and Head, Retroviral Immunology Section.

Research Description

The overall goal for our laboratory is a better understanding of antiviral T cell responses and their potential for control of primate lentiviral infection, seeking improved prevention and treatment of AIDS virus infection using a rhesus macaque model.

Control of HIV and SIV infection by adaptive immune responses is considered to be mediated by both antibodies and CD8+ T cells. Studies of passive transfer of neutralizing antibodies have shown that humoral responses are capable of mediating protection from infection. However, because the breadth and titers of neutralizing antibodies required for protection are considerably higher than achieved by current vaccine protocols, much interest and effort during recent years has focused on T cell based vaccines. Understanding the nature of effective antiviral T cell responses remains an important objective, but despite much effort, the nature and mechanism(s) of protective T cell responses against primate lentiviruses remain obscure. T cells are implicated in viral control by studies demonstrating correlations between cellular responses and control of viral replication, studies on viral escape in T cell epitopes, and studies involving in vivo depletion of CD8+ lymphocytes. However, these data only indirectly implicate T cell responses in such control, and do not define the nature of the cells or effector mechanisms responsible.

To address the role of CD8+ T cells in viral control, our laboratory is pursuing a program of both in vitro and in vivo studies of T cell mediated virus suppression. Our in vivo macaque studies involve various approaches based on adoptive transfer of ex vivo-expanded SIV specific autologous T cells, and their ability to provide protection from acute infection. The in vivo studies have generated a number of critical questions regarding homing, persistence and mechanism of viral suppression by T cells. We address these basic questions in vitro because they are important and unresolved immunological issues in their own right, but also because the research supports our in vivo effort by identifying cells to use in adoptive transfer experiments. The system allows us to screen effector clones with different functional and cell surface phenotype, measuring inhibition of viral spread (using flow cytometry and staining for intracellular SIV gag) and viral replication (using RT PCR to measure viral RNA in supernatants) as readout.

We also study the mechanism(s) behind the clonal differences in SIV susceptibility of CD4+ T cells generated from individual animals that we have observed, with the aim to discover new mechanisms for virus resistance, potentially leading to novel therapy approaches.

These studies address the role of SIV specific T cells in protection against AIDS virus, and the immunobiology of HIV/SIV infection.

Key Collaborators

• Dr. Mark Connors, NIH
• Dr. Michele Di Mascio, NIH
• Dr. Mario Roederer, NIH
• Dr. Barbara Felber, NIH
• Dr. George Pavlakis, NIH
• Dr. Carl June, University of Pennsylvania
• Dr. Luis Giavedoni, Southwest National Primate Research Center
• Dr. Francois Villinger, Emory University

Recent Publications

1. Minang JT, Trivett MT, Barsov EV, Del Prete GQ, Trubey CM, Thomas JA, Gorelick RJ, Piatak M Jr, Ott DE, Ohlen C: TCR triggering transcriptionally downregulates CCR5 expression on rhesus macaque CD4+ T cells with no measurable effect on susceptibility to SIV infection. Virology 409(1):132-140, 2011. Epub 2010 Oct 28. PMID: 21035160
2. Bolton DL, Minang JT, Trivett MT, Song K, Tuscher JJ, Li Y, Piatak M Jr, O’Connor D, Lifson JD, Roederer M, Ohlen C: Trafficking, persistence, and activation state of adoptively transferred allogeneic and autologous SIV-specific CD8+ T cell clones during acute and chronic infection of rhesus macaques. J Immunol 184(1):303-314, 2010. Epub 2009 Nov 30. PMID: 19949089.
3. Minang JT, Trivett MT, Bolton DL, Trubey CM, Estes JD, Li Y, Smedley J, Pung R, Rosati M, Jalah R, Pavlakis GN, Felber BK, Piatak M Jr, Roederer M, Lifson JD, Ott D, Ohlen C: Distribution, persistence and efficacy of adoptively transferred central and effector memory-derived autologous SIV-specific CD8+ T cell clones in rhesus macaques during acute infection. J Immunol 184(1):315-326, 2010. Epub 2009 Nov 30. PMID: 19949091.
4. Tjernlund A, Zhu J, Laing K, Diem K, McDonald D, Vazquez J, Cao J, Ohlen C, McElrath MJ, Picker L, Corey L: In situ detection of Gag-specific CD8+ cells in the GI tract of SIV infected Rhesus macaques. Retrovirology 7:1-14, 2010. Epub 2010 Feb 16. PMID: 20158906 PMCID: PMC2834607.
5. Patel V, Valentin A, Kulkarni V, Rosati M, Bergamaschi C, Jalah R, Alicea C, Minang JT, Trivett MT, Ohlen C, Zhao J, Robert-Guroff M, Khan AS, Draghia-Akli R, Felber BK, Pavlakis GN: Long-lasting humoral and cellular immune responses and mucosal dissemination after intramuscular DNA immunization. Vaccine 28(30):4827-36, 2010. Epub 2010 May 6. PMID: 20451642
6. Minang JT, Trivett MT, Coren LV, Barsov EV, Piatak MJr, Ott DE, Ohlen C: Nef-mediated MHC class I down-regulation unmasks clonal differences in virus suppression by SIV-specific CD8+ T cells independent of IFN-gamma and CD107a responses. Virology 391:130-139, 2009.
7. Rice J, Dossett ML, Ohlen C, Buchan SL, Kendall TJ, Dunn SN, Stevenson FK, Greenberg PD: DNA fusion gene vaccination mobilizes effective anti-leukemic cytotoxic T lymphocytes from a tolerized repertoire. Eur J Immunol 38(8):2118-2130, 2008.
8. Teague RM, Greenberg PD, Fowler C, Huang MZ, Tan X, Morimoto J, Dossett ML, Huseby ES, Ohlen C: Peripheral CD8+ T cell tolerance to self-proteins is regulated proximally at the T cell receptor. Immunity 28(5):662-674, 2008.
9. Minang JT, Barsov EV, Yuan F, Trivett MT, Piatak M, Lifson JD, Ott DE, Ohlen C: Efficient inhibition of SIV replication in rhesus CD4+ T-cell clones by autologous immortalized SIV-specific CD8+ T-cell clones. Virology 372:430-441, 2008.
10. Minang JT, Trivett MT, Coren LV, Barsov EV, Piatak MJr, Chertov O, Chertova E, Ott DE, Ohlen C: The Mamu B 17-restricted SIV Nef IW9 to TW9 mutation abrogates correct epitope processing and presentation without loss of replicative fitness. Virology 375:307-314, 2008.
11. Morimoto J, Tan X, Teague RM, Ohlen C, Greenberg PD: Induction of tolerance in CD8+ T cells to a transgenic autoantigen expressed in the liver does not require cross-presentation. J Immunol 178(11):6849-6860, 2007.
12. Kraft AR, Krux F, Schimmer S, Ohlen C, Greenberg PD, Dittmer U: CpG oligodeoxynucleotides allow for effective adoptive T-cell therapy in chronic retroviral infection. Blood 109:2982-2984, 2007.
13. Andersen H, Barsov EV, Trivett MT, Trubey CM, Giavedoni LD, Lifson JD, Ott DE, Ohlen C: Transduction with human telomerase reverse transcriptase immortalizes a rhesus macaque CD8+ T cell clone with maintenance of surface marker phenotype and function. AIDS Res Hum Retroviruses 23:456-465, 2007.
14. Teague RM, Sather BD, Sacks JA, Huang MZ, Dossett ML, Morimoto J, Tan X, Sutton SE, Cooke MP, Ohlen C, Greenberg PD: Interleukin-15 rescues tolerant CD8+ T cells for use in adoptive immunotherapy of established tumors. Nature Med 12(3):335-41, 2006.
15. Dittmer U, He H, Messer RJ, Schimmer S, Olbrich AR, Ohlen C, Greenberg PD, Stromnes IM, Iwashiro M, Sakaguchi S, Evans LH, Peterson KE, Yang G, Hasenkrug KJ: Functional impairment of CD8(+) T cells by regulatory T cells during persistent retroviral infection. Immunity 20(3):293-303, 2004.

Staffing

• Victor Ayala, Ph.D., Postdoctoral Fellow
• Matthew T. Trivett, Research Associate II
• Sumiti Jain, Post-doctoral Fellow