Keywords:

HIV, SIV, cytotoxic CD8+ T cells, effector and memory T cells, cytokines

My research area in the Laboratory of Dr. Peter Katsikis explores the function of virus-specific cytotoxic CD8+ T cells, cells that play a key role in controlling viral infection. I am specifically interesting in the phenotype, survival and function of HIV-specific CD8+ T cells from HIV-infected individuals. Although killer CD8+ T cells can control the replication of HIV for some time, these cells ultimately fail to prevent the progression to AIDS. My research investigates why these HIV-specific CD8+ T cells fail and how this failure can be overcome. We have recently found that HIV-specific CD8+ T cells are very susceptible to Fas/CD95-induced apoptosis and can be killed by HIV-infected cells.  This increased susceptibility to apoptosis may affect their ability to behave as serial killers and ultimately impair the anti-viral function. Furthermore, this increased death susceptibility may also be the cause for the lack of terminal differentiation of HIV-specific effector memory CD8+ T cells, which potentially adds to the functional defect of these cells. Currently I am examining in more detail why these cells have decreased survival at the molecular level, which will allow us to understand how these cells become sensitive to apoptosis and how viral infection induces this. Furthermore, we have shown that the cytokine Interleukin 15 (IL-15) can decrease apoptosis susceptibility and increase effector function of HIV-specific CD8+ T cells in vitro. In a pilot in vivo trial, we demonstrated that IL-15 can dramatically increase the numbers of CD8+ T cells and natural killer (NK) cells in the blood of in SIV-infected non-human primates. These data enabled us to now start a new study aiming to examine whether IL-15 treatment in vivo can increase the function and survival of SIV-specific CD8+ T cells during acute and chronic SIV infection. These studies may ultimately lead to clinical trials that examine whether IL-15 can enhance the effector function and decrease the apoptosis sensitivity of HIV-specific CD8+ T cells from HIV-individuals.

1. Muller, Y., H. Wollf, E. Weirenga, and G. Jung.  Induction of abortive and productive proliferation in resting human T-lymphocytes via CD3 and CD28.  Immunology 97:280-286, 1999.

2. Mueller, Y.M., S. De Rosa, J.A. Hutton, J. Witek, M. Roederer, J.D. Altman, and P.D. Katsikis. Increased CD95/Fas induced apoptosis of HIV-specific CD8+ T cells. Immunity,15:871-72,2001.

3. Cocca, B.A., S.N. Seal, P. D'Agnillo, Y.M. Mueller, P.D. Katsikis, J. Rauch, M. Weigert, and M.Z. Radic. Structural basis for autoantibody recognition of phosphatidylserine-2 glycoprotein I and apoptotic cells. PNAS, 98:13826-13831, 2001.

4. Halstead, E.S., Y.M. Mueller, J.D. Altman, and P.D. Katsikis. In vivo stimulation of CD137 broadens primary antiviral CD8+ T cell responses.  Nature Immunology, 3: 536-541, 2002.

5. Mueller, Y.M., D.E. Cramer, Y. Huang, B.G. Exner, and S.T. Ildstad.  Hematopoietic stem cells from the marrow of mice treated with FLT3 ligand are significantly expand-ed but exhibit reduced engraftment potential. Transplantation, 73: 1177-85, 2002.

6. Xu, H., B.G. Exner, D.E. Cramer, M.K. Tanner, Y.M. Mueller, and S.T. Ildstad.  CD8+, αβ-TCR+ and γδ-TCR+ Cells in the recipient hematopoietic environment mediate resistance to engraftment of allogeneic donor bone marrow.  J. Immunol., 168: 1636-1643, 2002.

7. Mueller, Y.M., V. Makar, P. Bojczuk, J. Witek, and P.D. Katsikis.  IL-15 enhances the function and inhibits CD95/Fas-induced apoptosis of human CD4+ and CD8+ effector memory T cells.  International Immunology 15: 49-58, 2003.

8. Maldonado, A., Y.M. Mueller, P. Thomas, P. Bojczuk, C. O’Connors, and P.D. Katsikis.  Decreased effector memory CD45RA+CD62L- CD8+ T cells and increased central memory CD45RA-CD62L+ CD8+ T cells in peripheral blood of rheumatoid arthritis patients.  Arthritis Research 5: R91-R96, 2003.

9. Mueller, Y.M., P. Bojczuk, E.S. Halstead, A.H.J. Kim, J. Witek, J.D. Altman, and P.D. Katsikis.  IL-15 enhances survival and function of HIV-specific CD8+ T cells.  Blood,101: 1024-29, 2003.

10. Petrovas, C., Y.M. Mueller, I.D. Dimitriou, P.M. Bojczuk, K.C. Mounzer, J. Witek, J.D. Altman, and P.D. Katsikis.  HIV-specific CD8(+) T cells exhibit markedly reduced levels of Bcl-2 and Bcl-x(L).  J. Immunol. 172: 4444-53, 2004.

11. Petrovas, C., Y.M. Mueller, and P.D. Katsikis.  HIV-specific CD8+ T cells: Serial killers condemned to die?  Curr. HIV Res., Apr 2(2): 153-162, 2004.

12. Kim, A.H., I.D. Dimitriou, M.C. Holland, D. Mastellos, Y.M. Mueller, J.D. Altman, J.D. Lambris, and P.D. Katsikis.  Complement C5a receptor is essential for the optimal generation of antiviral CD8+ T cell responses.  J Immunol 173:2524-9, 2004.

13. Petrovas, C, Y.M.Mueller, and P.D. Katsikis.  Apoptosis of HIV-specific CD8+ T cells: an HIV evasion strategy.  Cell Death Differ. Apr 1; [Epub ahead of print], 2005.

14. Naguib, N.N., Y.M. Mueller, P.M. Bojczuk, M.P. Rossi, P.D. Katsikis and Y.Gogotsi. Effect of Carbon Nanofiber Structure on Binding of Antibodies.  Nanotechnology 16:567-71, 2005.

15. Mueller, Y.M., C. Petrovas, P.M. Bojczuk, I.D. Dimitriou, B. Beer, P. Silvera, F. Villinger, J.S. Cairns, M.G. Lewis and P.D. Katsikis.  IL-15 increases effector memory CD8+ T cells and NK cells in SIV-infected macaques.  J Virol 79: 4877-85, 2005.