Sacha Laboratory

 Sacha Laboratory Staff | OHSU Vaccine and Gene Therapy Institute

Welcome to the Sacha Laboratory, located in the Vaccine & Gene Therapy Institute and Oregon National Primate Research Center at the Oregon Health & Science University. We are a dedicated team of scientists working towards ameliorating human suffering by solving the AIDS epidemic and improving clinical care.

Sacha Laboratory

Overview

With more than 20 million dead and greater than 30 million currently infected with HIV, development of a prophylactic HIV vaccine is a top global health priority.  However, despite 30 years of intense research there is no vaccine.  The enormous sequence diversity of HIV remains one of the top challenges to be overcome in developing an effective prophylactic vaccine (see illustration below).  My laboratory aims to determine which antigens should be targeted to overcome the formidable obstacle of HIV viral sequence diversity.  Thus, we are actively exploring four distinct, but related areas of immunity to highly variable pathogens such as HIV.

 An illustrative example of the extreme diversity of HIV versus influenza, which demonstrates the need for new vaccine approaches.

An illustrative example of the extreme diversity of HIV versus influenza, which demonstrates the need for new vaccine approaches.  From Korber et al., British Medical Bulletin, 2001.

Research

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.  Although normally quiescent, ERVs are active and targeted by the immune response during infection with pathogens such as HIV and in disease states like cancer. Because ERV-specific immune responses arise only during pathological processes, they may represent an alternate, stable target for vaccine-induced immunity.  We are exploring the role of ERVs in immunity to disease to understand how to exploit these germ-line sequences for protecting the host from viral infection and disease.

 An endogenous retrovirus genome is pictured.  These proviruses are present in the germ line DNA of all mammals, accounting for an astounding 8% of the human genome.  Some of the proviruses are still able to produce proteins, raising the possibility that t

An endogenous retrovirus genome is pictured.  These proviruses are present in the germ line DNA of all mammals, accounting for an astounding 8% of the human genome.  Some of the proviruses are still able to produce proteins, raising the possibility that they be targeted by the immune system during pathological processes.

 

GvHD

The durable HIV functional cure of Timothy Brown (aka "The Berlin Patient") and the transient HIV remission oberved in the Boston Patients indicate that stem cell transplants may be able to deplete HIV reservoirs and control HIV replication. Graft-versus-host disease (GvHD) is a common side effect of stem cell transplants and such immunity may be resposible for the remarkable lack of HIV seen in these transplant recipients. To determine how GvHD impacts HIV, we have established a physiologically relevant model of allogeneic stem cell transplantation and are actively studying GvHD as a means to attack HIV. These studies will also help improve cancer therapy by determining how to maintain the positive effect of graft-versus-tumor immunity while minimizing the unwanted effects of GvHD.

 

The number of stem cell (bone marrow) transplant procedures increases each year. Our model will also help improve quality of living of patients undergoing stem cell transplants by reducing GvHD while maintianing the protective graft-versus-tumor effect.

 

The number of stem cell (bone marrow) transplant procedures increases each year. Our model will also help improve quality of living of patients undergoing stem cell transplants by reducing GvHD while maintianing the protective graft-versus-tumor effect.

 

Sequence diversity

Viral sequence diversity is the Achilles’ heel of traditional vaccine approaches and poses one of the greatest hurdles to vaccine development.  New, unconventional 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.  An example of one approach is shown below.

An example of an alternate target for vaccination:  HIV-induced degradation of  the innate antiviral APOBEC protein.  (A)  HIV infectes a target cell and (B) produces the Vif protein.  (C)  Vif targets APOBEC to the proteasome for destruction.  However, b

An example of an alternate target for vaccination:  HIV-induced degradation of  the innate antiviral APOBEC protein.  (A)  HIV infectes a target cell and (B) produces the Vif protein.  (C)  Vif targets APOBEC to the proteasome for destruction.  However, because proteasomal degradation generates CD8+ T cell epitopes, (D) HIV-infected cells are marked by a significant increase in MHC-I bound APOBEC-derived CD8+ T cells.  A vaccine targeting this could theoretically defeat the sequence diversity of HIV.

 

MHC-E

Major histocompatibility complex (MHC) class I alleles are the most diverse loci in the human population. Indeed, over 8,500 MHC-I alleles exist. In contrast, only two HLA-E molecules exist, raising the possibility of a truly universal vaccine, with which every vaccinated individual would mount identical HLA-E restricted CD8+ T cell responses. We are actively investigating the novel characteristics of MHC-E to understand how to mobilize this remarkable immune molecule for vaccines against variable pathogens.

A schematic of the HLA-E molecule. MHC-E is highly monomorphic and expressed in nearly every nucleated cell in the body. Although MHC-E has been traditionally viewed as negative receptor for innate NK cells, we have found that MHC-E also possess a previou

A schematic of the HLA-E molecule. MHC-E is highly monomorphic and expressed in nearly every nucleated cell in the body. Although MHC-E has been traditionally viewed as negative receptor for innate NK cells, we have found that MHC-E also possess a previously underappreciated ability to bind diverse peptide for presentation to CD8+ T cells in adaptive immunity.

Opportunities

Postdoctoral Fellows: Postdoctoral fellows with expertise in immunology and/or virology should submit a copy of their CV to Dr. Sacha.

Graduate Students:  Graduate students are the lifeblood of the laboratory and the future of the field. If you are a current Molecular Microbiology & Immunology graduate student interested in rotating in the Sacha laboratory, please contact Dr. Sacha.

If you are interested in graduate studies at OHSU, we encourage you to apply to the Department of Molecular Microbiology & Immunology.

Undergraduates:  We are currently recruiting motivated, bright young individuals interested in pursuing a career in research or medicine. 

If you attend one of the many Portland area undergraduate institutions please contact Dr. Sacha to discuss the possibility of joining the laboratory.

If you attend an institution outside the Portland area and are interested in a summer research position, please apply to the ONPRC Undergraduate Summer Fellowship Program.

Research Technician:  All of our technician positions are currently filled.  Check back later for any new openings.

Publications

Fujita T, Burwitz BJ, Chew GM, Reed JS, Clayton K, Ostrowski M, Ishii N, Sacha JB†, and Ndhlovu LC†. Expansion of dysfunctional Tim-3 expressing effector memory CD8+ T cells during SIV infection of rhesus macaques. Journal of Immunology, 2014 Dec 1;193(11):5576-83. †Indicates co-senior authors.

Burwitz BJ, Reed JS, Hammond KB, Ericson A, Richter Y, Golomb G, and Sacha JB. Liposomal alendronate depletion of monocytes and macrophages in the nonhuman primate model of human disease. Journal of Leukocyte Biology, 2014 Sep;96(3):491-501.

Michaud HA, Sengupta D, de Mulder M, Deeks SG, Martin JN, Kobie JJ, Sacha JB, Nixon DF. Cutting Edge: An antibody recognizing ancestral endogenous virus glycoproteins mediates antibody dependent cellular cytotoxicity on HIV-1 infected cells. Journal of Immunology, 2014 Aug 15;193(4):1544-8.

Alzhanova D, Hammarlund E, Reed J, Meermeier E, Rawlings S, Ray CA, Edwards DM, Bimber B, Legasse A, Planer S, Sprague J, Axthelm MK, Pickup DJ, Lewinsohn DM, Gold MC, Wong SW, Sacha JB, Slifka MK, Frueh K. T cell inactivation by poxviral B22 family proteins increases viral virulence. PLoS Pathog. 2014 May 15;10(5):e1004123. PMCID: PMC4022744

Burwitz BJ, Wu HL, Reed JS, Newman LP, Bimber BN, Nimiyongskul FA, Leon EJ, Maness NJ, Friedrich TC, Masaru Yokoyama, Hinonori Sato, Tetsuro Matano, O'Connor DH, and Sacha JB. Tertiary mutations stabilize

CD8+ T lymphocyte escape-associated compensatory mutations following transmission of simian immunodeficiency virus. Journal of Virology, 2014 Mar;88(6):3598-604. PMCID: PMC3957937.

Michaud HA, de Mulder M, SenGupta D, Deeks SG, Martin JN, Pilcher CD, Hecht FM, Sacha JB, Nixon DF. Trans-activation, post-transcriptional maturation, and induction of antibodies to HERV-K (HML-2) envelope transmembrane protein in HIV-1 infection. Retrovirology. 2014 Jan 28;11:10.

Sheppard NC, Jones RB, Burwitz BJ, Nimityongskul FA, Newman LP, Buechler MB, Reed JS, Piaskowski SM, Weisgrau KL, Castrovinci PA, Wilson NA, Ostrowski MA, Park B, Nixon DF, Rakasz EG, Sacha JB. Vaccination against endogenous retrotransposable element consensus sequences does not protect rhesus macaques from SIVsmE660 infection and replication. PLoS One. 2014 Mar 20;9(3):e92012.

Hansen SG, Piatak M, Ventura AB, Hughes CM, Gilbride RM, Ford JC, Burwitz BJ, Planer SL, TurnerJM, Legasse AW, Axthelm MK, Edlefsen PT, Nelson JA, Fr¸h K, Estes JD, Sacha JB, Lifson JD, and Picker LJ. Immune clearance of highly pathogenic SIV infection. Nature. 2013 Oct 3;502(7469):100-4.

Jaworski JP, Kobie J, Brower Z, Malherbe DC, Landucci G, Sutton WF, Guo B, Reed JS, Leon EJ, Engelmann F, Zheng B, Legasse A, Park B, Dickerson M, Lewis AD, Colgin LM, Axthelm M, Messaoudi I,Sacha JB, Burton DR, Forthal DN, Hessell AJ, Haigwood NL. Neutralizing polyclonal IgG present during acute infection prevents rapid disease onset in simian-human immunodeficiency virus SHIVSF162P3-infected infant rhesus macaques. Journal of Virology. 2013 Oct;87(19):10447-59.

Hansen SG, Sacha JB, Hughes CM, Ford JC, Burwitz BJ, Scholz I, Gilbride RM, Gilliam AN, Lewis MS, Ventura AB, Xu G, Malouli D, Richards R, Whizin N, Reed JS, Hammond KB, Fischer M, Turner JM, Legasse AW, Axthelm MK, Edlefsen PT, Nelson JA, Lifson JD, Frueh K, and Picker LJ. Cytomegalovirus Vectors Violate CD8+ T Cell Epitope Recognition Paradigms. Science. 2013 May 24;340(6135):1237874.

Champiat S, Garrison KE, Raposo RA, Burwitz BJ, Reed J, Tandon R, York VA, Newman LP, Nimityongskul FA, Wilson NA, Almeida RR, Martin JN, Deeks SG, Rosenberg MG, Wiznia AA, Spotts GE, Pilcher CD, Hecht FM, Ostrowski MA, Sacha JB†, Nixon DF†. T Cells Target APOBEC3 Proteins in HIV-1-infected Humans and SIV- infected Indian Rhesus Macaques. Journal of Virology. 2013 Jun;87(11):6073-80. †Indicates co-senior authors.

1Kloverpris HN, Payne RP, Sacha JB, Rasaiyaah JT, Chen F, Takiguchi M, Yang OO, Towers GJ, Goulder P, Prado JG. Early antigen presentation of protective HIV-1 KF11Gag and KK10Gag epitopes from incoming viral particles facilitates rapid recognition of infected cells by specific CD8+ T cells. Journal of Virology. 2013 Mar; 87(5):2628-38.

Jones RB, Garrison KE, Mujib S, Mihajlovic V, Aidarus N, Hunter DV, Martin E, John VM, Zhan W, Faruk NF, Gyenes G, Sheppard NC, Priumboom-Brees IM, Goodwin DA, Chen L, Rieger M, Muscat-King S, Loudon PT, Stanley C, Holditch SJ, Wong JC, Clayton K, Duan E, Song H, Xu Y, SenGupta D, Tandon R, Sacha JB, Brockman MA, Benko E, Kovacs C, Nixon DF, Ostrowski MA. HERV-K(HML-2)-specific CD8+ T cells recognize and eliminate cells infected with globally diverse HIV-1, HIV-2, and SIV primary isolates. Journal of Clinical Investigation. 2012 Dec 3;122(12):4473-89

Burwitz BJ, Giraldo-Vela JP, Reed J, Newman LP, Bean AT, Nimityongskul FA, Castrovinci PA, Maness NJ, Leon EJ, Rudersdorf R, Sacha JB. CD8+ and CD4+ cytotoxic T cell escape mutations precede breakthrough SIVmac239 viremia in an elite controller. Retrovirology. 2012 Nov 6;9:91. PMCID: 3496649

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, Gebhard DH, 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. Journal of Immunology. 2012 Aug 1;189(3):1467-79. PMCID: PMC3401319

1Vojnov L, Martins MA, Beat 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. Journal of Virology. 2012 Apr;86(8):4682-7. PMCID: PMC3318662

Burwitz BJ†, Sacha JB†, Reed J, Newman LP, Norante FA, Bimber BN, Wilson NA, Watkins DI, and O'Connor DH (2011). Pyrosequencing reveals restricted patterns of CD8+ T cell escape associated compensatory mutations in SIV. Journal of Virology. Dec;85(24):13088-96. †Indicates co-first authors.

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 (2011). TRIM5a genotype of rhesus macaques affects acquisition of SIVsmE660 infection after repeated limiting-dose intrarectal challenge. Journal of Virology. 85(18): 9637-40.

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 (2011). 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.

Sacha JB, Buechler MB, Newman LP, Reed J, Wallace LT, Wilson NA, and Watkins DI. (2010) SIV-specific CD8+ T cells recognize Vpr- and Rev-derived epitopes early after infection. Journal of Virology. 84(20):10543-57.

Payne RP, Kloverpris H, Sacha JB, Buus S, Sims S, Hickling S, Riddell L, Chen F, Luzzi G, Edwards A, Prado JG, Goulder PJ (2010). Efficacious antiviral activity of HLA-B*2705-restricted CD8+ T cells is associated with early recognition of HIV-infected cells and not to a superior functional CD8+ T cell profile.Journal of Virology. 84(20) 10907-12.

Bonaldo MC, Martins MA, Rudersdorf R, Mudd PM, Sacha JB, Piaskowski SM, da Costa Neves PC, Veloso de Santana MG, Vojnov L, Capuano III S, Rakasz EG, Wilson NA, Fulkerson J, Sadoff JC, Watkins DI, Galler R (2010). Recombinant yellow fever vaccine virus 17D expressing SIVmac239 Gag induces SIV-specific CD8+ T cell responses in rhesus macaques. Journal of Virology. 84(7): 3699 - 3706.

Maness NJ, Wilson NA, Reed J, Piaskowski SM, Sacha JB, Walsh AD, Thoryk E, Heidecker GJ, Citron MP, Liang X, Bett AJ, Casimiro DR, and Watkins DI (2010). Robust vaccine-induced CD8+ T lymphocyte response against an out of frame epitope. Journal of Immunology. 84: 67-72

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

Vojnov L, Reed JS, Weisgrau KL, Piaskowski SM, Rakasz EG, Loffredo JT, Sacha JB, Wilson NA, Johnson RP, Watkins DI (2010). Effective SIV-specific CD8+ T cells lack an easily detectable, shared characteristic.Journal of Virology. 84: 753-764.

Maness NJ, Sacha JB, Piaskowski SM, Weisgrau KL, Rakasz EG, May GE, Buechler MB, Wilson NA, Watkins DI (2009). Novel translation products from the SIVmac239 Env encoding mRNA contain both Rev and cryptic T cell epitopes. Journal of Virology. 83: 10280-10285.

Sacha JB, Giraldo-Vela JP, Buechler MB, Martins MA, Maness NJ, Chung C, Wallace LT, LeÛn EJ, Friedrich TC, Wilson NA, Hiraoka A, Watkins DI (2009). Gag- and Nef-specific CD4+ T cells recognize and inhibit SIV replication in infected macrophages early after infection. Proceedings of the National Academy of Sciences of the USA. 106:9791-6.

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 (2008). Lytic granule loading of CD8+ T cells is required for HIV-infected cell elimination associated with immune control. Immunity. 29(6):1009-21

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 (2008). Differential antigen presentation kinetics of CD8+ T cell epitopes derived from the same viral protein. Journal of Virology. 82:9293-8.

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 (2007). Pol-specific CD8+ T cells recognize simian immunodeficiency virus-infected cells prior to nef-mediated major histocompatibility complex class I downregulation. Journal of Virology 81:11703-12.

Sacha JB, Chung C, Rakasz EG, Spencer SP, Jonas AK, Bean AT, Lee W, Burwitz B, Stephany J, Loffredo JT, Allison DB, Adnan A, Hoji A, Wilson N, Friedrich TC, Lifson JD, Yang OO, Watkins DI (2007). Gag-specific CD8+ T lymphocytes recognize infected cells before AIDS-virus integration and protein expression.Journal of Immunology. 178:2746-54.

Tewari KV†, Sacha J†, Gao X, and Suresh M (2004). Effect of chronic viral Infection on epitope selection, cytokine production, and surface phenotype of CD8+ T cells and the role of IFN-γ receptor in immune regulation. Journal of Immunology. 172: 1491 – 1500. †Indicates co-first authors.

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