Cofilin hyperactivation in HIV infection and targeting the cofilin pathway using an anti-α 4 β 7 integrin antibody.

Autor: He S; Key Laboratory of AIDS Immunology of National Health Commission, Department of Laboratory Medicine, The First Affiliated Hospital, China Medical University, Shenyang, Liaoning 110001, P. R. China.; Key Laboratory of AIDS Immunology, Chinese Academy of Medical Sciences, Shenyang, Liaoning 110001, P. R. China.; National Center for Biodefense and Infectious Diseases, School of Systems Biology, George Mason University, Manassas, VA 20110, USA., Fu Y; Key Laboratory of AIDS Immunology of National Health Commission, Department of Laboratory Medicine, The First Affiliated Hospital, China Medical University, Shenyang, Liaoning 110001, P. R. China.; Key Laboratory of AIDS Immunology, Chinese Academy of Medical Sciences, Shenyang, Liaoning 110001, P. R. China.; National Center for Biodefense and Infectious Diseases, School of Systems Biology, George Mason University, Manassas, VA 20110, USA., Guo J; National Center for Biodefense and Infectious Diseases, School of Systems Biology, George Mason University, Manassas, VA 20110, USA., Spear M; National Center for Biodefense and Infectious Diseases, School of Systems Biology, George Mason University, Manassas, VA 20110, USA., Yang J; National Center for Biodefense and Infectious Diseases, School of Systems Biology, George Mason University, Manassas, VA 20110, USA., Trinité B; Department of Basic Science, New York University College of Dentistry, New York, NY 10010, USA., Qin C; Key Laboratory of AIDS Immunology of National Health Commission, Department of Laboratory Medicine, The First Affiliated Hospital, China Medical University, Shenyang, Liaoning 110001, P. R. China.; Key Laboratory of AIDS Immunology, Chinese Academy of Medical Sciences, Shenyang, Liaoning 110001, P. R. China.; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou 310003, P. R. China., Fu S; Key Laboratory of AIDS Immunology of National Health Commission, Department of Laboratory Medicine, The First Affiliated Hospital, China Medical University, Shenyang, Liaoning 110001, P. R. China.; Key Laboratory of AIDS Immunology, Chinese Academy of Medical Sciences, Shenyang, Liaoning 110001, P. R. China.; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou 310003, P. R. China., Jiang Y; Key Laboratory of AIDS Immunology of National Health Commission, Department of Laboratory Medicine, The First Affiliated Hospital, China Medical University, Shenyang, Liaoning 110001, P. R. China.; Key Laboratory of AIDS Immunology, Chinese Academy of Medical Sciences, Shenyang, Liaoning 110001, P. R. China.; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou 310003, P. R. China., Zhang Z; Key Laboratory of AIDS Immunology of National Health Commission, Department of Laboratory Medicine, The First Affiliated Hospital, China Medical University, Shenyang, Liaoning 110001, P. R. China.; Key Laboratory of AIDS Immunology, Chinese Academy of Medical Sciences, Shenyang, Liaoning 110001, P. R. China.; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou 310003, P. R. China., Xu J; Key Laboratory of AIDS Immunology of National Health Commission, Department of Laboratory Medicine, The First Affiliated Hospital, China Medical University, Shenyang, Liaoning 110001, P. R. China.; Key Laboratory of AIDS Immunology, Chinese Academy of Medical Sciences, Shenyang, Liaoning 110001, P. R. China.; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou 310003, P. R. China., Ding H; Key Laboratory of AIDS Immunology of National Health Commission, Department of Laboratory Medicine, The First Affiliated Hospital, China Medical University, Shenyang, Liaoning 110001, P. R. China.; Key Laboratory of AIDS Immunology, Chinese Academy of Medical Sciences, Shenyang, Liaoning 110001, P. R. China.; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou 310003, P. R. China., Levy DN; Department of Basic Science, New York University College of Dentistry, New York, NY 10010, USA., Chen W; Mucosal Immunology Section, NIDCR, NIH, Bethesda, MD 20892, USA., Petricoin E 3rd; Center for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, VA 20110, USA., Liotta LA; Center for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, VA 20110, USA., Shang H; Key Laboratory of AIDS Immunology of National Health Commission, Department of Laboratory Medicine, The First Affiliated Hospital, China Medical University, Shenyang, Liaoning 110001, P. R. China.; Key Laboratory of AIDS Immunology, Chinese Academy of Medical Sciences, Shenyang, Liaoning 110001, P. R. China.; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou 310003, P. R. China., Wu Y; National Center for Biodefense and Infectious Diseases, School of Systems Biology, George Mason University, Manassas, VA 20110, USA.
Jazyk: angličtina
Zdroj: Science advances [Sci Adv] 2019 Jan 09; Vol. 5 (1), pp. eaat7911. Date of Electronic Publication: 2019 Jan 09 (Print Publication: 2019).
DOI: 10.1126/sciadv.aat7911
Abstrakt: A functional HIV cure requires immune reconstitution for lasting viremia control. A major immune dysfunction persisting in HIV infection is the impairment of T helper cell migration and homing to lymphoid tissues such as GALTs (gut-associated lymphoid tissues). ART (antiretroviral therapy) does not fully restore T cell motility for tissue repopulation. The molecular mechanism dictating this persistent T cell dysfunction is not understood. Cofilin is an actin-depolymerizing factor that regulates actin dynamics for T cell migration. Here, we demonstrate that blood CD4 T cells from HIV-infected patients ( n = 193), with or without ART, exhibit significantly lower levels of cofilin phosphorylation (hyperactivation) than those from healthy controls ( n = 100; ratio, 1.1:2.3; P < 0.001); cofilin hyperactivation is also associated with poor CD4 T cell recovery following ART. These results suggest an HIV-mediated systemic dysregulation of T cell motility that cannot be repaired solely by ART. We further demonstrate that stimulating blood CD4 T cells with an anti-human α 4 β 7 integrin antibody can trigger signal transduction and modulate the cofilin pathway, partially restoring T cell motility in vitro . However, we also observed that severe T cell motility defect caused by high degrees of cofilin hyperactivation was not repairable by the anti-integrin antibody, demonstrating a mechanistic hindrance to restore immune functions in vivo. Our study suggests that cofilin is a key molecule that may need to be therapeutically targeted early for T cell tissue repopulation, immune reconstitution, and immune control of viremia.
Databáze: MEDLINE
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