Jonah Sacha, Ph.D.

Research Overview:

Dr. Sacha’s laboratory is engaged in research in three distinct, but related areas of T cell biology.

The obstacle of sequence diversity in vaccine design:

Viral sequence diversity is the Achilles’ heel of traditional vaccine approaches.  For example, the influenza vaccine must change yearly in anticipation of the predominant circulating viral strains, which differ from one another by only 1-2%.  The problem of viral diversity is exponentially larger in pathogens such as HIV, where co-circulating HIV strains can differ from each other by up to 35%.  Indeed, the extraordinary sequence variation of HIV poses one of the greatest hurdles to vaccine development.  New vaccine modalities are desperately needed to overcome this formidable obstacle.  We are currently designing and testing novel approaches to solve the problem of viral sequence diversity.

Endogenous retroviruses in human disease:

The genome of every human being contains endogenous retroviruses (ERVs), which are the genetic fossil remains of ancient retroviral infections that integrated into germ line cells.  These fixed retroviral sequences account for ~8% of the entire human genome and are inherited from parent to offspring like cellular genes. Although normally quiescent, ERVs can become active and are targeted by the cellular immune response during infection with pathogens such as EBV and HIV and in disease states like cancer. Because ERV-specific immune responses may arise only during pathological processes and are currently understudied, their role in immunity is likely greatly underappreciated.  We are currently exploring the role of ERVs in pathogenesis and immunity.

CD4+ T cells in retroviral infections

Cellular immune responses are a critical component for containing the replication of retroviruses such as HIV. While the role of CD8+ T cells in AIDS virus infection is well documented from CD8+ T cell-mediated viral escape and CD8 depletion studies, much less is known about antiviral CD4+ T cell responses. However, understanding the precise immunological role played by CD4+ T cells during retroviral infections will likely provide insight into the components of an effective immune response and is a key step in facilitating rational vaccine design.  We are actively pursuing how CD4+ T cells contribute to the control of retroviruses despite being the targets of the virus.

Biography:

Dr. Sacha graduated cum laude from the University of Missouri-Columbia in 2003 with a B.A. in German and B.S. in Biology.  After receiving his Ph.D. in Microbiology & Immunology from the University of Wisconsin-Madison in 2007, he joined the faculty at UW-Madison where he researched the characteristics of effective retrovirus-specific CD8+ and CD4+ T cells.  In 2011, he joined the Oregon Health & Science University and has appointments in the Vaccine & Gene Therapy Institute and Pathobiology & Immunology Division of the Oregon National Primate Research Center.



Sacha Laboratory Link (click here)

Publications:

1: Sacha JB, Kim IJ, Chen L, Ullah JH, Goodwin DA, Simmons HA, Schenkman DI, von Pelchrzim F, Gifford RJ, Nimityongskul FA, Newman LP, Wildeboer S, Lappin PB, Hammond D, Castrovinci P, Piaskowski SM, Reed JS, Beheler KA, Tharmanathan T, Zhang N, Muscat-King S, Rieger M, Fernandes C, Rumpel K, Gardner JP 2nd, GebhardDH, Janies J, Shoieb A, Pierce BG, Trajkovic D, Rakasz E, Rong S, McCluskie M, Christy C, Merson JR, Jones RB, Nixon DF, Ostrowski MA, Loudon PT, Pruimboom-Brees IM, Sheppard NC. Vaccination with cancer- and HIV infection-associated endogenous retrotransposable elements is safe and immunogenic.
J Immunol. 2012 Aug 1; 189(3): 1467-79. PMCID: PMC3401319

2: Vojnov L, Martins MA, Bean AT, Veloso de Santana MG, Sacha JB, Wilson NA, Bonaldo MC, Galler R, Stevenson M, Watkins DI. The majority of freshly sorted< simian immunodeficiency virus (SIV)-specific CD8(+) T cells cannot suppress viral replication in SIV-infected macrophages. J Virol.2012 Apr; 86(8): 4682-7. PMCID: PMC3318662

3: Burwitz BJ, Sacha JB, Reed JS, Newman LP, Norante FA, Bimber BN, Wilson NA, Watkins DI, O'Connor DH. Pyrosequencing reveals restricted patterns of CD8+ T cell escape-associated compensatory mutations in simian immunodeficiency virus. J Virol. 2011 Dec; 85(24): 13088-96. PMCID: PMC3233179

4: Vojnov L, Bean AT, Peterson EJ, Chiuchiolo MJ, Sacha JB, Denes FS, Sandor M, Fuller DH, Fuller JT, Parks CL, McDermott AB, Wilson NA, Watkins DI. DNA/Ad5 vaccination with SIV epitopes induced epitope-specific CD4? T cells, but few subdominant epitope-specific CD8? T cells. Vaccine. 2011 Oct 6; 29(43): 7483-90. PMCID: PMC3186839

5: Reynolds MR, Sacha JB, Weiler AM, Borchardt GJ, Glidden CE, Sheppard NC, Norante FA, Castrovinci PA, Harris JJ, Robertson HT, Friedrich TC, McDermott AB, Wilson NA, Allison DB, Koff WC, Johnson WE, Watkins DI. The TRIM5{alpha} genotype of rhesus macaques affects acquisition of simian immunodeficiency virus SIVsmE660 infection after repeated limiting-dose intrarectal challenge. J Virol. 2011 Sep; 85(18): 9637-40. PMCID: PMC3165772

6: Payne RP, Kløverpris H, Sacha JB, Brumme Z, Brumme C, Buus S, Sims S, Hickling S, Riddell L, Chen F, Luzzi G, Edwards A, Phillips R, Prado JG, Goulder PJ. Efficacious early antiviral activity of HIV Gag- and Pol-specific HLA-B 2705-restricted CD8+ T cells. J Virol. 2010 Oct; 84(20): 10543-57. PMCID: PMC2950555

7: Sacha JB, Buechler MB, Newman LP, Reed J, Wallace LT, Loffredo JT, Wilson NA, Watkins DI. Simian immunodeficiency virus-specific CD8+ T cells recognize Vpr-and Rev-derived epitopes early after infection. J Virol. 2010 Oct; 84(20): 10907-12. PMCID: PMC2950557

8: Bonaldo MC, Martins MA, Rudersdorf R, Mudd PA, Sacha JB, Piaskowski SM, Costa Neves PC, Veloso de Santana MG, Vojnov L, Capuano S 3rd, Rakasz EG, Wilson NA, Fulkerson J, Sadoff JC, Watkins DI, Galler R. Recombinant yellow fever vaccine< virus 17D expressing simian immunodeficiency virus SIVmac239 gag induces SIV-specific CD8+ T-cell responses in rhesus macaques. J Virol. 2010 Apr; 84(7): 3699-706. PMCID: PMC2838090

9: Sacha JB, Watkins DI. Synchronous infection of SIV and HIV in vitro for virology, immunology and vaccine-related studies. Nat Protoc. 2010 Feb; 5(2): 239-46. PMCID: PMC2936483

10: Maness NJ, Wilson NA, Reed JS, Piaskowski SM, Sacha JB, Walsh AD, Thoryk E, Heidecker GJ, Citron MP, Liang X, Bett AJ, Casimiro DR, Watkins DI. Robust, vaccine-induced CD8(+) T lymphocyte response against an out-of-frame epitope. J Immunol. 2010 Jan 1; 184(1): 67-72. PMCID: PMC2881682

11: Vojnov L, Reed JS, Weisgrau KL, Rakasz EG, Loffredo JT, Piaskowski SM, Sacha JB, Kolar HL, Wilson NA, Johnson RP, Watkins DI. Effective simian immunodeficiency virus-specific CD8+ T cells lack an easily detectable, shared characteristic. J Virol. 2010 Jan; 84(2): 753-64. PMCID: PMC2798340

12: Maness NJ, Sacha JB, Piaskowski SM, Weisgrau KL, Rakasz EG, May GE, Buechler MB, Walsh AD, Wilson NA, Watkins DI. Novel translation products from simian immunodeficiency virus SIVmac239 Env-encoding mRNA contain both Rev and cryptic T-cell epitopes. J Virol. 2009 Oct; 83(19): 10280-5. PMCID: PMC2748035

13: Sacha JB, Giraldo-Vela JP, Buechler MB, Martins MA, Maness NJ, Chung C, Wallace LT, León EJ, Friedrich TC, Wilson NA, Hiraoka A, Watkins DI. Gag- and Nef-specific CD4+ T cells recognize and inhibit SIV replication in infected macrophages early after infection. Proc Natl Acad Sci U S A. 2009 Jun 16; 106(24): 9791-6. PMCID: PMC2687996

14: Migueles SA, Osborne CM, Royce C, Compton AA, Joshi RP, Weeks KA, Rood JE, Berkley AM, Sacha JB, Cogliano-Shutta NA, Lloyd M, Roby G, Kwan R, McLaughlin M, Stallings S, Rehm C, O'Shea MA, Mican J, Packard BZ, Komoriya A, Palmer S, Wiegand AP, Maldarelli F, Coffin JM, Mellors JW, Hallahan CW, Follman DA, Connors M. Lytic granule loading of CD8+ T cells is required for HIV-infected cell elimination associated with immune control. Immunity. 2008 Dec 19; 29(6): 1009-21. PMCID: PMC2622434

15: Sacha JB, Reynolds MR, Buechler MB, Chung C, Jonas AK, Wallace LT, Weiler AM, Lee W, Piaskowski SM, Soma T, Friedrich TC, Wilson NA, Watkins DI. Differential antigen presentation kinetics of CD8+ T-cell epitopes derived from the same viral protein. J Virol. 2008 Sep; 82(18): 9293-8. PMCID: PMC2546915

16: Sacha JB, Chung C, Reed J, Jonas AK, Bean AT, Spencer SP, Lee W, Vojnov L, Rudersdorf R, Friedrich TC, Wilson NA, Lifson JD, Watkins DI. Pol-specific CD8+ T cells recognize simian immunodeficiency virus-infected cells prior to Nef-mediated major histocompatibility complex class I downregulation. J Virol. 2007 Nov; 81(21): 11703-12. PMCID: PMC216877

17: Sacha JB, Chung C, Rakasz EG, Spencer SP, Jonas AK, Bean AT, Lee W, Burwitz BJ, Stephany JJ, Loffredo JT, Allison DB, Adnan S, Hoji A, Wilson NA, Friedrich TC, Lifson JD, Yang OO, Watkins DI. Gag-specific CD8+ T lymphocytes recognize infected cells before AIDS-virus integration and viral protein expression. J Immunol. 2007 Mar 1; 178(5): 2746-54. PubMed PMID: 17312117

18: Tewari K, Sacha JB, Gao X, Suresh M. Effect of chronic viral infection on epitope selection, cytokine production, and surface phenotype of CD8 T cells and the role of IFN-gamma receptor in immune regulation. J Immunol. 2004 Feb 1; 172(3): 1491-500. PubMed PMID: 14734726

 

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