Barbara Shacklett, Ph.D.
Areas of investigation
Our research group focuses on cell-mediated immune responses to HIV and other viruses in mucosal tissues, and trafficking of lymphoid cells to mucosal tissues and the central nervous system.
Most studies of antiviral immunity have focused on peripheral blood. However, the majority of lymphocytes are harbored in lymphoid tissues throughout the body. Mucosal lymphoid tissues serve as a portal of entry for HIV and as a site of active viral replication and CD4+ T-cell depletion. Therefore, studies of mucosal immunity are of particular importance for our understanding of HIV pathogenesis. Understanding the induction of antiviral immunity at mucosal surfaces is also of great relevance for vaccine development, as the majority of HIV transmission occurs through sexual contact.
We have established methods to detect antigen-specific T cells in mucosal tissues using clinical samples obtained by minimally invasive methods. We use a combination of approaches including flow cytometry, cellular immunology, and molecular biology, to study the trafficking patterns and effector functions of antigen-specific T cells. These translational research projects involve active collaborations with clinicians at UC Davis Medical Center and the University of California, San Francisco.
- Development of methods and approaches to study antiviral immunity in mucosal tissues during natural infection (i.e., HIV) and after vaccination
- Identification of HIV and CMV-specific CD8+ T cells in gut-associated lymphoid tissue
- Development of live, attenuated simian immunodeficiency viruses to study correlates of protective immunity to HIV/SIV in nonhuman primates
Questions addressed in ongoing studies
- What are the effector functions of antiviral T-cells in mucosal tissues?
- What is the relationship between CD8+ T cell frequency and HIV viral load in tissues?
- What molecules (i.e., integrins, chemokines) are involved in the trafficking of antigen-specific T cells to mucosal tissues and to the central nervous system?
- How do immunization routes correlate with the induction of antiviral T cell responses in tissues?
Quigley MF, Abel K, Miller CJ, Zuber B, Sandberg JK, Shacklett BL. Perforin expression in the gastrointestinal mucosa is limited to acute simian immunodeficiency virus infection. Journal of Virology 80:3083-7. 2006
Critchfield JW, Lemongello D, Walker DH, Garcia JC, Asmuth DM, Pollard RB, Shacklett BL. Multifunctional HIVgag specific CD8+ T-cell responses in rectal mucosa and PBMC during chronic HIV-1 infection. Journal of Virology 81:5460-71
Emu, B., Sinclair, E., Hatano, H., Ferre, A., Shacklett, B.L., Martin, J.N., McCune, J.M, and Deeks, S.G. (2008), HLA Class I-Restricted T Cell Responses May Contribute to the Control of HIV Infection, but Such Responses are Not Always Necessary for Long-term Virus Control, Journal of Virology 82:5398-407. PMID: 18353945
Critchfield, J.W., Young, D.H., Hayes, T.L., Braun, J.V., Garcia, J.C., Pollard, R.B., and Shacklett, B.L. (2008), Magnitude and Complexity of Rectal Mucosa HIV-1-Specific CD8+ T-cell Responses During Chronic Infection Reflect Clinical Status. PLoS ONE 2008;3(10):e3577. PMID: 18974782.
Ferre, A.L., Hunt, P., Critchfield, J.W., Young, D.H., Morris, M.M., Garcia, J.C., Pollard, R.B., Yee, H.F., Martin, J.N., Deeks, S.G., and Shacklett, B.L. (2009), Mucosal Immune Responses to HIV-1 in Elite Controllers: A Potential Correlate of Immune Control. Blood 113(17):3978-89. PMID: 19109229.
Ferre, A.L., Lemongello, D., Hunt, P.W., Morris, M.M., Yee, H.F., Jr., Martin, J.N., Garcia, J.C., Pollard, R.B., Deeks, S.G., and Shacklett, B.L. (2010), Immunodominant HIV-Specific CD8+ T-Cell Responses Are Common to Blood and Gastrointestinal Mucosa, and Gag-Specific Responses Dominate in Rectal Mucosa of HIV Controllers. Journal of Virology 84(19):10354-65. PMID: 20668079.
Ferre, A.L., Hunt, P.W., McConnell, D.H., Morris, M.M., Garcia, J.C., Pollard, R.B., Deeks, S.G., and Shacklett, B.L. (2010), HIV Controllers With HLA-DRB1*13 and DQB1*06 Have Strong, Polyfunctional Mucosal CD4+ T-cell Responses. Journal of Virology, in press (published online ahead of print, August 18, 2010). PMID:20719952.
Hatano, H., Hayes, T.L., Dahl, V., Sinclair, E., Lee, T.H., Hoh, R., Lampiris, H., Palmer, S., Hunt, P.W., McCune, J.M., Martin, J.N., Busch, M.P., Shacklett, B.L., and Deeks, S.G. (2010), A randomized, controlled trial of Raltegravir intensification in antiretroviral-treated, HIV-infected patients with suboptimal CD4+ T-cell response. Journal of Infectious Diseases, in press.
Review articles and commentaries
Shacklett B.L. (2006). Understanding the lucky few: The conundrum of HIV-exposed, seronegative individuals. Current HIV/AIDS Reports, 3(1):26-31.
Shacklett B.L. (2008). Mucosal immunity to HIV: a review of recent literature. Current Opinion in HIV and AIDS, 3:541-547. PMID: 19373019.
Shacklett, B.L. (2009). Cell-mediated immunity to HIV in the female reproductive tract. Invited review, Journal of Reproductive Immunology, PMID: 19857902.
Shacklett, B.L. (2010), Immune responses to HIV and SIV in mucosal tissues: "location, location, location". Current Opinion in HIV and AIDS 5:128-34.
Shacklett, B.L., and Anton, P.A. (2010), HIV infection and gut mucosal immune function: Updates on pathogenesis with implications for management and intervention. Current Infectious Disease Reports 12:19-27. PMID: 20174448.
Shacklett B.L. and Nixon DF (2006), Methods for detection of antigen-specific T cells by Enzyme-linked immunospot assay (ELISPOT), Ch. 28 in: ASM Manual of Molecular and Clinical Laboratory Immunology, 7th Edition, B. Detrick, R.G. Hamilton and S.D. Douglas, Eds., ASM Press, 1374 pp. , ISBN No. 978-1-55581-364-2.
Shacklett B.L. (2007), HIV Infection of the Gastrointestinal Tract, in: Latent Infection by HIV-1 and Related Lentiviruses: New Approaches and Treatment Challenges, A. Brown, Ed., Research Signpost, Trivandrum, pp. 67-82, ISBN No. 978-81-308-0189-6.
Shacklett, B.L., Lemongello, D., and Critchfield, J.W. (2008), Isolating mucosal lymphocytes from biopsy tissue for cellular immunology assays, Ch. 23 in: HIV Protocols, 2nd Ed., V.R. Prasad and G.V. Kalpana, Eds., Humana Press, in press, ISBN No. 978-1-58829-859-1. (Listed in PubMed as Methods Mol Biol. 2009;485:347-56. PMID: 19020836
Shacklett, B.L., Lemongello, D., and Critchfield, J.W. (2008), Quantifying HIV-1-specific CD8+ T-cell responses using ELISPOT and cytokine flow cytometry, Ch. 24 in: HIV Protocols, 2nd Ed., V.R. Prasad and G.V. Kalpana, Eds., Humana Press, ISBN No. 978-1-58829-859-1. (Listed in PubMed asMethods Mol Biol. 2009;485:359-74. PMID: 19020837.