Send to

Choose Destination
Sci Adv. 2019 Jan 9;5(1):eaat7911. doi: 10.1126/sciadv.aat7911. eCollection 2019 Jan.

Cofilin hyperactivation in HIV infection and targeting the cofilin pathway using an anti-α4β7 integrin antibody.

He S1,2,3, Fu Y1,2,3, Guo J3, Spear M3, Yang J3, Trinité B4, Qin C1,2,5, Fu S1,2,5, Jiang Y1,2,5, Zhang Z1,2,5, Xu J1,2,5, Ding H1,2,5, Levy DN4, Chen W6, Petricoin E 3rd7, Liotta LA7, Shang H1,2,5, Wu Y3.

Author information

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.
Department of Basic Science, New York University College of Dentistry, New York, NY 10010, USA.
Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou 310003, P. R. China.
Mucosal Immunology Section, NIDCR, NIH, Bethesda, MD 20892, USA.
Center for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, VA 20110, USA.


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 α4β7 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.

Supplemental Content

Full text links

Icon for PubMed Central
Loading ...
Support Center