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

Abstract

We demonstrate an HIV-mediated dysregulation of cofilin in CD4 T cells and propose therapeutics to restore T cell motility.

Cofilin, an intracellular marker for HIV‐associated CD4 T‐cell motility dysregulation, shed light on the mechanisms of incomplete immune reconstitution in the patients with HIV

“…These studies demonstrated that the resting CD4 T cells from the patients with HIV carried significantly higher levels of active cofilin and that the hyperactivated cofilin was likely associated with immune activation in the patients with HIV . Consistent with these studies, the He et al study used a large cohort to more conclusively demonstrate a direct linkage between cofilin hyperactivation and the impairment of CD4 T‐cell migration. The authors used R10015, a cofilin kinase inhibitor, to quantify direct effects of cofilin hyperactivation on T‐cell motility and found that a 50% reduction in cofilin phosphorylation could cause a 20% to 40% decrease in T‐cell migration.…”

“…Cofilin is a major cell motility engine that drives T‐cell motility for cell circulation and homing to lymphoid and nonlymphoid tissues . In the He et al study, the authors found that cofilin phosphorylation was markedly reduced, thereby becoming hyperactivated, in the peripheral blood resting CD4 T cells of the patients with HIV vs healthy controls. In addition, cofilin hyperactivation persisted in patients with HIV on ART and was associated with poor CD4 T‐cell recovery in these patients.…”

“…In the recent issue of Science Advances , He et al conducted a study to investigate cofilin phosphorylation and the motility of peripheral blood CD4 T cells in a large cohort of HIV (n = 193) vs healthy controls (n = 100). Cofilin is an actin‐depolymerizing factor that depolymerizes filamentous actin (F‐actin) and is inactivated by phosphorylation.…”

“…They also used anti‐human α4β7 integrin antibody to modulate the cofilin activity and found that the motility of blood resting CD4 T cells from the patients with HIV was partially restored. Thus, He et al suggested that cofilin would represent a potential target for therapeutic intervention to restore T‐cell motility for T‐cell tissue repopulation and immune reconstitution in patients with HIV.…”

“…CD4 T cells are heterogeneous population consisting of several subsets such as follicular helper T (Tfh), Th1, Th2, Th9, Th17, and regulatory T cells. The He et al study solely focused on resting blood CD4 T cells that would contain all CD4 subpopulations. Because the majority of HIV infection occurs in lymphoid tissue, it will be interesting to study the role of T‐cell motility in specific tissue CD4 subpopulations and their relationship to HIV infection.…”