I have been involved in immunology research at Case Western Reserve University since 1994. I received my PhD from the laboratory of Dr. Michael Lederman in 2014 where I investigated treated, HIV-infected patients who had no detectible plasma virus but did not recover their CD4 T cell numbers. I then joined the laboratory of Dr. Donald Anthony as a post-doc in the Department of Medicine/Infectious Disease. I have since secured independent funding through the Cleveland VA Medical Center and I am studying inflammation in chronic viral infections and in aging in various patient cohorts. Currently, I have a dual appointment as a Research Health Scientist at the Cleveland VA Medical Center and as an Assistant Professor in the Department of Pathology at Case Western Reserve University.
The current research goals I am pursuing relate to understanding the underlying impact of inflammation on the development of immune exhaustion and senescence in the elderly. People with chronic viral infections and older aged individuals share many of the same comorbidities including cardiovascular disease, cancer, and liver disease. Comorbidities increase with age and in HIV-infected patients. HIV infected and elderly patients also demonstrate evidence of immune senescence and exhaustion that has been associated with immune dysfunction. Results from my research will provide a growing need nationwide to advance our understanding and develop therapeutic strategies in the aging population with and without chronic viral infection.
We study cellular immunology concentrating on chronic viral infections (HIV, HCV, SARS-CoV2) and inflammation in aging. We primarily study human blood cells and plasma to examine the effects of chronic inflammation on health, the mechanisms by which the immune system maintains homeostasis, and how inflammation disrupts the ability of the immune system to reestablish homeostasis after infection and during aging. We have extensive experience in immunological research in the fields of autoimmunity, T cell-specific adaptive immune responses, B-cell antibody responses, cytokines, innate immunity, inflammation, viral infection, and cellular biology. We use cell culture, ELISAs, ELISPOT assays, Cytokine and Antibody Multiplex assays (MSD, Luminex, ELLA), and flow cytometry to test our hypothesizes.
Research Information
Research Interests
Drivers of immune activation and inflammation in HIV disease
It is clear that ongoing immune activation and inflammation are associated with poor disease prognosis in HIV infection. Specifically, elevated plasma levels of IL-6 are a strong predictor of morbid outcomes in HIV infection. What drives this immune activation and inflammation is not clear. Latent HIV persists even in patients that have controlled viral replication with therapy for decades and have no detectible circulating virus. If patients discontinue taking ART, HIV rebounds and viral levels rise. Researchers speculated that low level viral replication drove the increased plasma levels of IL-6. We demonstrated that HIV is not a major driver of increased plasma IL-6 levels (Shive et al, JAIDS, 2012). We and others speculate that translocation of microbial products from the damaged gut during chronic HIV infections likely drives much of the immune activation and inflammation observed in chronic HIV infection. IL-6 and soluble CD14 (sCD14) are elevated in treated HIV infection and are associated with increased mortality and morbidity in HIV-infected patients. CD14, a marker on monocytes, is a co-receptor for lipopolysaccharide (LPS), a cell membrane component of gram negative bacteria. HIV researchers were beginning to use plasma sCD14 as an indicator of microbial translocation in HIV. We showed that, although LPS is a potent monocyte activator that binds to CD14 and induces release of sCD14, other TLR ligands and inflammatory cytokines such as IL-6 and IL-1b can induce the release of sCD14. We suggested that sCD14 should be considered a marker of monocyte activation that does not necessarily reflect monocyte activation by LPS (Shive et al, AIDS, 2015).
1. Carey L. Shive, Angélique Biancotto, Nicholas T. Funderburg, Heather A. Pilch-Cooper, Hernan Valdez, Leonid Margolis, Scott F. Sieg, Grace A. McComsey, Benigno Rodriguez, Michael M. Lederman. HIV-1 Is Not a Major Driver of Increased Plasma IL-6 Levels in Chronic HIV-1 Disease. Journal of Acquired Immune Deficiency Syndromes. 2012, 61(2):145-152.
2. Carey L. Shive, Wei Jiang, Donald D. Anthony, Michael M. Lederman. Soluble CD14 is a non-specific marker of monocyte activation. AIDS. 2015, 29(10):1263-1265.
3. Michael L. Freeman, Carey L. Shive, Thao P. Nguyen, Souheil-Antoine Younes, Soumya Panigrahi, Michael M. Lederman. Cytokines and T-Cell Homeostasis in HIV Infection. The Journal of Infectious Diseases (Supplement article) 2016, 214(S2):S51–7
4. Souheil-Antoine Younes, Michael L. Freeman, Joseph C. Mudd, Carey L. Shive, Arnold Reynaldi, Soumya Panigrahi, Jacob D. Estes, Claire Deleage, Carissa Lucero, Jodi Anderson, Timothy W. Schacker, Miles P. Davenport, Joseph M. McCune, Peter W. Hunt, Sulggi A. Lee, Sergio Serrano-Villar, Robert L. Debernardo, Jeffrey M. Jacobson, David H. Canaday, Rafick-Pierre Sekaly, Benigno Rodriguez, Scott F. Sieg, Michael M. Lederman. IL-15 promotes activation and expansion of CD8+ T cells in HIV-1 infection. The Journal of Clinical Investigation, 2016 Jul 1;126(7):2745-56.
5. Michael L. Freeman, Joseph C. Mudd, Carey L. Shive, Souheil-Antoine Younes, Soumya Panigrahi, Scott F. Sieg, Sulggi A. Lee, Peter W. Hunt, Leonard H. Calabrese, Sara Gianella, Benigno Rodriguez, Michael M. Lederman. CD8 T-Cell Expansion and Inflammation Linked to CMV Coinfection in ART-treated HIV Infection. Clinical Infectious Diseases. September 2015
Factors and mechanisms that contribute to immune failure in treated HIV-infected patients
Low numbers of peripheral CD4 T cells in HIV-infected patients are associated with increased morbidity and death, even in patients that have controlled virus with antiretroviral therapy. It is not clear why some patients with undetectable virus are still unable to recover their CD4 T cell numbers. We characterized these immune failure patients and found that all maturation subsets of CD4 T cells were decreased, as were naïve CD8 T cell numbers. Immune failure patients had elevated plasma levels of soluble factors of inflammation, such as IL-6 and sCD14, and coagulation (D-dimers), increased T cell activation, and increased cycling of CD4 memory T cells (Lederman et al, JID, 2011). We expanded on these studies and examined the in vitro effects of inflammatory cytokines on uninfected T cells and found that IL-1b and IL-6 caused a decrease in the expression of the IL-7 receptor alpha chain, CD127 (Shive et al, JID, 2014). This could contribute to the reduced numbers of naïve T cells in immune failure patients. We also found that IL-1b and IL-6 caused increased turn-over of memory CD4 T cells as was observed in the immune failure patients (Shive et al, JID, 2014).
6. Michael Lederman, Leonard Calabrese, Nicholas Funderburg, Brian Clagett, Kathy Medvik, Hector Bonilla, Barbara Gripshover, Robert Salata, Alan Taege, Michelle Lisgaris, Grace McComsey, Elizabeth Kirchner, Jane Baum, Carey Shive, Robert Asaad, Robert KKalayjian, Scott Sieg, and Benigno Rodriguez. Immunologic Failure Despite Suppressive Antiretroviral Therapy Is Related to Activation and Turnover of Memory CD4 Cells. Journal of Infectious Diseases. 2011, 204: 1217-26.
7. Carey L. Shive, Joseph C. Mudd, Nicholas T. Funderburg, Scott F. Sieg, Benjamin Kyi, Doug A. Bazdar, Davide Mangioni, Andrea Gori, Jeffrey M. Jacobson, Ari D. Brooks, Jeffrey Hardacre, John Ammori, Jacob D. Estes, Timothy W. Schacker, Benigno Rodriguez, and Michael M. Lederman. Inflammatory Cytokines Drive CD4 T cell Cycling and Impaired Responsiveness to Interleukin-7: Implications for Immune Failure in HIV Disease. Journal of Infectious Diseases. 2014, 210 (4): 619-629.
The effect of adjuvants on the immune response
Understanding the effects of adjuvants is critical to design effective vaccines. Using a mouse model of Multiple Sclerosis, experimental autoimmune encephalomyelitis (EAE), and neonatal tolerance, we examined the effects of adjuvant on the immune response in EAE and the balance between Th1 and Th2 cells. Pertussis toxin is often used in models of EAE to induce the clinical manifestations of the disease. We found that pertussis toxin enhanced the production of cytokines and caused the clonal expansion of autoreactive T cells (Shive et al, Eur.J.Immunol, 2000). We demonstrated that in EAE, the microbial product (pertussis toxin) acts on antigen presenting cells of the innate immune system and contributes to disease by the induction of high frequencies of autoantigen-specific Th1 cells despite the clonal expansion of autoantigen-specific Th2 cells that were induced by injection of autoreactive peptide in Incomplete Freud’s Adjuvant (IFA) (Hofstetter et al, J. Immunol., 2002) (Heeger et al, J. Immunol, 2000). We also examined the influence of adjuvant on neonatal tolerance (Hofstetter et al, J. Neuroimmunology, 2007) and in older aged mice (Ebhard et al, Cellular Immunology, 2002).
8. Shive CL, Hofstetter HH, Shaw C, and Forsthuber TG. The enhanced antigen-specific production of cytokines induced by pertussis toxin is due to clonal expansion of T cells and not to altered effector functions of long-term memory cells. Eur.J.Immunol. 2000, 30:2422-2431.
9. Hofstetter, H., Shive C.L., Ebhardt, M. and T.G. Forsthuber. Pertussis toxin modulates the immune response to neuroantigens injected in incomplete Freunds adjuvant: Induction of Th1 cells and experimental autoimmune encephalomyelitis in the presence of high frequencies of Th2 cells. The Journal of Immunology. 2002, 169:117-125.
10. Heeger PS, Forsthuber TG, Shive CL, Brekert E, Genain C, Hofstetter HH, Karulin A, and Lehmann PV. Revisiting tolerance induced by autoantigen in incomplete Freund’s adjuvant. The Journal of Immunology. 2000, 164:5771-5781.
11. Harald H. Hofstetter, Andra Kovalovsky, Carey L. Shive, Paul V. Lehmann, Thomas G. Forsthuber. Neonatal induction of myelin-specific Th1/Th17 immunity does not result in experimental autoimmune encephalomyelitis and can protect against the disease in adulthood. Journal of Neuroimmunology. 2007, 187; 20-30.
12. Monika B. Ebhardt, Carey L. Shive, Rocio Guardia, Laurent Gapin, Bernhard O. Boehm, and Thomas G. Forsthuber. Immunological adjuvants efficiently induce antigen-specific T cell responses in old mice: implications for vaccine adjuvant development in aged individuals. Cellular Immunology. 2002, 215; 87–97.
External Appointments
Research Health Scientist; Cleveland VA Medical Center
Geriatric Research, Education and Clinical Center (GRECC) Investigator