Yvonne Mueller Assistant Professor, Microbiology and Immunology Manager, Flow Cytometry Core Facility Ph.D., Ludwig-Maximilians-University Munich, Germany, 1998 2900 Queen Lane Philadelphia, PA 19129 Tel: 215-991-8386 Fax: 215-848-2271 Email: Yvonne.mueller@drexelmed.edu

Keywords:

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

Virus-specific cytotoxic CD8+ T cells play a key role in controlling viral infection. In HIV and SIV infection, these killer CD8+ T cells can indeed control the replication of the virus for some time; however, ultimately these cells fail to prevent the progression to AIDS.

The focus of our research is why these virus-specific CD8+ T cells fail to control HIV and SIV replication while other virus-specific CD8+ T cells directed against e.g. CMV are functional. Additionally, we are investigating strategies to overcome this functional failure. We are therefore investigating the phenotype, survival and function of these HIV- and SIV-specific CD8+ T cells from HIV-infected individuals and SIV-infected non-human primates.

We have recently found that HIV- and SIV-specific CD8+ T cells are very susceptible to Fas/CD95-induced apoptosis and can be killed by HIV-infected cells, which up-regulate Fas/CD95-Ligand. 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. We have shown in SIV-infected animals that these defects appear early during infection and seem to be antigen dependent. In in vitro studies with PBMC from HIV-infected humans and SIV-infected non-human primates, we have shown that the pro-inflammatory cytokine Interleukin 15 (IL-15) can decrease apoptosis susceptibility and increase effector function of HIV- and SIV-specific CD8+ T cells in vitro. In in vivo studies, we have furthermore demonstrated that IL-15 can dramatically increase the numbers of CD8+ T cells and natural killer (NK) cells in the blood of non-human primates during acute and chronic SIV-infection. However, when IL-15 is given in during the first four weeks of acute SIV infection, viral set point is increased up to 3 log compared to untreated animals due probably to increased SIV-target population.

In upcoming studies, we will further explore what determines the viral set point in SIV infection. The model of IL-15 treatment during acute SIV infection will allow us now to examine how increased activation of the immune system may alter SIV infection during acute infection and how this influence the viral set point.  Further studies will elucidate a potential beneficial effect of IL-15 during chronic SIV infection. Additional studies will focus on the molecular pathways responsible for the increased apoptosis sensitivity of HIV- and SIV-specific CD8+ T cells and how IL-15 prevents this.

Selected Publications

1. 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.

2. 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.

3. 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.

4. 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.

5. 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.

6. 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.

7. 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.

8. 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.

9. 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.

10. Petrovas, C, Y.M.Mueller, and P.D. Katsikis. Apoptosis of HIV-specific CD8+ T cells: an HIV evasion strategy. Cell Death Differ. 12: Suppl 1:859-70, 2005.

11. 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.

12. Petrovas C, Mueller YM, Dimitriou ID, Altork SR, Banerjee A, Sklar PA, Mounzer KC, Altman JD, Katsikis PD. Increased mitochondrial mass characterizes the survival defect of HIV-specific CD8+ T cells. Blood 109:2505-13, 2007.

13. Mueller, Y. M., Petrovas, C., Do, D. H., Altork, S. R., Fischer-Smith, T., Rappaport, J., Altman, J. D., Lewis, M. G. and P. D. Katsikis. Early establishment and antigen dependence of SIV-specific CD8+ T cell defects. J. Virology, 81: 10861-10868, 2007.

14. Petrovas, C., Mueller, Y. M., Altork, S. R., Jacobson, J. M., Pitsakis, P. G., Mounzer, K. C., Altman, J. D., and P. D. Katsikis.  Actin integrity is indispensable for CD95/Fas-induced apoptosis of HIV-specific CD8+ T cells. Apoptosis, 12: 2175-2186, 2007.

15. Mueller, Y. M., Do, D. H., Altork, S. R., Artlett, C. M., Gracely, E. J., Katsetos, C. D., Legido, A., Villinger, F., Altman, J. D., Brown, C. R., Lewis, M. G., and P. D., Katsikis.  IL-15 treatment during acute SIV infection increases viral set point and accelerates disease progression. J. Immunol., 180: 350-360, 2008.