Jonah B. Sacha
Viral sequence diversity is the Achilles' heel of traditional vaccine approaches to HIV and poses one of the greatest hurdles to vaccine development. The Sacha laboratory aims to determine which antigens should be targeted to overcome the formidable obstacle of HIV viral sequence diversity. Thus, we are actively exploring three distinct, but related areas of immunity to highly variable pathogens such as HIV:
CD4+ T cells
While the role of CD8+ T cells in AIDS virus infection is well documented, 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 provide insight into the components of an effective immune response and is a key step in facilitating rational vaccine design. Furthermore, CD4+ T cells are able to tolerate extensive sequence diversity in their target epitopes, raising the possibility they might be particularly effective in immunity to hyper-variable pathogens. We are actively pursuing how CD4+ T cells contribute to the control of genetically diverse pathogens like retroviruses.
Non-HIV targets for protection: Endogenous Retroviruses: 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.
A rare subset of infected individuals will contain viral replication to undetectable levels and do not progress to AIDS even without antiretroviral treatment. These rare individuals offer a glimpse into effective anti-AIDS virus immunity. Interestingly, some of these individuals will spontaneously lose the ability to control the virus. We are studying the breakthrough virus in these individuals to delineate correlates of protection from infection with a chronic virus like HIV.
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.
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. J. Virol. 84(20):10543-10557.
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):239-246.
Sacha JB, Giraldo-Vela JP, Buechler MB, Martins MA, Maness NJ, Chung C, Wallace LT, León EJ, Friedrich TC, Wilson NA, Hiraoka A, and Watkins DI (2009). 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. 106:9791-9796.
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, and Connors M (2008). Lytic granule loading of CD8+ T cells is required for HIV-infected cell elimination associated with immune control. Immunity. 29(6):1009-1021.
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. J. Immunol. 178:2746-2754.
Burwitz BJ, Giraldo-Vela JP, Reed J, Newman LP, Bean AT, Nimityongskul FA, Castrovinci PA, Maness NJ, Leon EJ, Rudersdorf R, and Sacha JB (2012). CD8+ and CD4+ cytotoxic T cell escape mutations precede breakthrough SIVmac239 viremia in an elite controller. Retrovirology. Nov 6;9:91. doi: 10.1186/1742-4690-9-91.
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, Priumboom-Brees IM, and Sheppard NC (2012). Vaccination with cancer-and HIV infection-associated endogenous retrotransposable elements is safe and immunogenic. J. Immunol. 189(3):1467-1479. doi:10.4049/jimmunol.1200079. Epub 2012 Jun 27.
Champiat S, Garrison KI, 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, and Nixon DF. T Cells target APOBEC3 proteins in HIV-1-infected humans and SIV-infected Indian Rhesus macaques. J. Virol. 2013 Mar 27.