With more than 20 million dead and greater than 30 million currently infected with HIV, development of a prophylactic HIV vaccine or immunotherapies to achieve durable antiretroviral therapy (ART)-free HIV remission is a top global health priority.  However, despite 30 years of intense research there is no vaccine or curative therapies, and new vaccine approaches and therapeutic treatments are urgently needed. The Sacha laboratory aims to identify novel immune responses and therapeutic approaches for use in prophylactic HIV vaccines and HIV-remission inducing treatments. Specifically, we are engaged in the following areas of research:

Non-classical T cells

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 MHC-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.

Allogeneic stem cell transplantation

The durable HIV functional cure of Timothy Brown (aka "The Berlin Patient") and the transient HIV remission observed 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 responsible for the remarkable lack of HIV 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 how to harness gvhd as a means to attack HIV, similar to the protective graft-versus-tumor effect in cancer patients. 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.

Negative checkpoint inhibitors

Chronic antigen stimulation induces phenotypic and functional changes to T cells defined by the coordinated up-regulation of a series of negative checkpoint receptors (ncrs) that eventually result in T cell exhaustion and failure to contain pathogen replication.  Given the central role of ncrs in modulating the duration and magnitude of cellular immune responses, they are ideal targets for immunotherapy. Therefore, we have expanded the Tim-3:Gal-9 NCR axis into nonhuman primates, and pioneered the identification of TIGIT as a novel NCR in both SIV-infected nonhuman primates and HIV-infected humans. We are currently developing and testing new reagents targeted to these NCR pathways, which give new directions to vaccines and therapies aimed at reversing T cell exhaustion in the setting of chronic antigen stimulation such as HIV and neoplasia. Opposite to this goal, targeting these NCR pathways to induce T cell anergy will provide novel therapies to dampen pathogenic cellular immune responses, such as those found in graft-versus-host disease following allogeneic stem cell transplantation.

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 Medical 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 both the Vaccine & Gene Therapy Institute and Oregon National Primate Research Center.

Key Publications

Ericsen AJ, Lauck M, Mohns MS, DiNapoli SR, Mutschler JP,Greene JM, Weinfurter JT, Lehrer-Brey G, Prall TM, Gieger SM, Buechler CR,Crosno KA, Peterson EJ, Reynolds MR, Wiseman RW, Burwitz BJ, Estes JD, SachaJB, Friedrich TC, Brenchley JM, O'Connor DH. Microbial Translocation andInflammation Occur in Hyperacute Immunodeficiency Virus Infection and Compromise Host Control of Virus Replication. PLoS Pathog. 2016 Dec7;12(12):e1006048. doi: 10.1371/journal.ppat.1006048. [PMID: 27926931]

Burwitz BJ, Malouli D, Bimber BN, Reed JS, Ventura AB,Hancock MH, Uebelhoer LS, Bhusari A, Hammond KB, Espinosa Trethewy RG, Klug A,Legasse AW, Axthelm MK, Nelson JA, Park BS, Streblow DN, Hansen SG, Picker LJ,Früh K, Sacha JB. Cross-Species Rhesus Cytomegalovirus Infection of CynomolgusMacaques. PLoS Pathog. 2016 Nov 9;12(11):e1006014. doi:10.1371/journal.ppat.1006014. [PMID: 27829026]

Greene JM, Dash P, Roy S, McMurtrey C, Awad W, Reed JS,Hammond KB, Abdulhaqq S, Wu HL, Burwitz BJ, Roth BF, Morrow DW, Ford JC, Xu G,Bae JY, Crank H, Legasse AW, Dang TH, Greenaway HY, Kurniawan M, Gold MC,Harriff MJ, Lewinsohn DA, Park BS, Axthelm MK, Stanton JJ, Hansen SG, PickerLJ, Venturi V, Hildebrand W, Thomas PG, Lewinsohn DM, Adams EJ, Sacha JB. MR1-restrictedmucosal-associated invariant T (MAIT) cells respond to mycobacterialvaccination and infection in nonhuman primates. Mucosal Immunol. 2016 Oct 19.doi: 10.1038/mi.2016.91. [PMID: 27759023]

Sturgill ER, Malouli D, Hansen SG, Burwitz BJ, Seo S,Schneider CL, Womack JL, Verweij MC, Ventura AB, Bhusari A, Jeffries KM,Legasse AW, Axthelm MK, Hudson AW, Sacha JB, Picker LJ, Früh K.Natural KillerCell Evasion Is Essential for Infection by Rhesus Cytomegalovirus. PLoS Pathog.2016 Aug 31;12(8):e1005868. doi: 10.1371/journal.ppat.1005868. [PMID: 27580123]

Abdel-Mohsen M, Chavez L, Tandon R, Chew GM, Deng X, DaneshA, Keating S, Lanteri M, Samuels ML, Hoh R, Sacha JB, Norris PJ, Niki T,Shikuma CM, Hirashima M, Deeks SG, Ndhlovu LC, Pillai SK.Human Galectin-9 Is aPotent Mediator of HIV Transcription and Reactivation. PLoS Pathog. 2016 Jun2;12(6):e1005677. doi: 10.1371/journal.ppat.1005677. [PMID: 27253379]

Hessell AJ, Jaworski JP, Epson E, Matsuda K, Pandey S, Kahl C, Reed J, Sutton WF, Hammond KB, Legasse A, Planer S, Stanton J, Pegu A, Chen X, Axthelm M, Lewis A, Hirsch VM, Graham BS, Mascola JR, Sacha JB, Haigwood NL. Early short-term treatment with neutralizing human monoclonal antibodies intercepts viral reservoir establishment in SHIV-exposed newborn macaques. Nature Medicine. 2016 Apr;22(4):362-8.

Hansen SG, Wu HL, Burwitz BJ, Hughes CM, Hammond KB, Ventura AB, Reed JS, Gilbride RM, Ainslie E, Morrow DW, Ford JC, Selseth AN, Pathak R, Malouli D, Legasse AW, Axthelm MK, Nelson JA, Gillespie GM, Walters LC, Brackenridge S, Sharpe HR, Lopez CA, Früh K, Korber BT, McMichael AJ, Gnanakaran S, Sacha JB†, Picker LJ†. Broadly targeted CD8+ T cell responses restricted by major histocompatibility complex-E. Science. 2016 Feb 12;351(6274):714-20. †Indicates co-senior authors.

Wu HL, Leon EJ, Wallace LT, Nimiyongskul FA, Buechler MB, Newman LP, Castrovinci PA, Johnson RP, Gifford RJ, Jones RB, Sacha JB. Identification and spontaneous immune targeting of an endogenous retrovirus K envelope protein in the indian rhesus macaque model of human disease. Retrovirology. 2016 Jan 15;13:6.

Chew GM, Fujita T, Webb GM, Burwitz BJ, Wu HL, Reed JS, Hammond KB, Clayton KL, Ishii N, Abdel-Mohsen M, Liegler T, Mitchell BI, Hecht FM, Ostrowski M, Shikuma CM, Hansen SG, Maurer M, Korman AJ, Deeks SG, Sacha JB†,Ndhlovu LC†. TIGIT marks exhausted T cells, correlates with disease progression, and serves as a target for immune restoration in HIV and SIV Infection.  PLoS Pathogens. 2016 Jan 7;12(1):e1005349. †Indicates co-senior authors.

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.

See a full listing of Dr. Sacha's publications.

Sacha Laboratory web page