Impairment of CCR6+ and CXCR3+ Th Cell Migration in HIV-1 Infection Is Rescued by Modulating Actin Polymerization

Abstract

CD4+ T cell repopulation of the gut is rarely achieved in HIV-1–infected individuals who are receiving clinically effective antiretroviral therapy. Alterations in the integrity of the mucosal barrier have been indicated as a cause for chronic immune activation and disease progression. In this study, we present evidence that persistent immune activation causes impairment of lymphocytes to respond to chemotactic stimuli, thus preventing their trafficking from the blood stream to peripheral organs. CCR6+ and CXCR3+ Th cells accumulate in the blood of aviremic HIV-1–infected patients on long-term antiretroviral therapy, and their frequency in the circulation positively correlates to levels of soluble CD14 in plasma, a marker of chronic immune activation. Th cells show an impaired response to chemotactic stimuli both in humans and in the pathogenic model of SIV infection, and this defect is due to hyperactivation of cofilin and inefficient actin polymerization. Taking advantage of a murine model of chronic immune activation, we demonstrate that cytoskeleton remodeling, induced by okadaic acid, restores lymphocyte migration in response to chemokines, both in vitro and in vivo. This study calls for novel pharmacological approaches in those pathological conditions characterized by persistent immune activation and loss of trafficking of T cell subsets to niches that sustain their maturation and activities.

Insight on the regulation of chemokine activities

“…While effective antiretroviral therapy (ART) is able to restore the number of circulating CD4 + T‐cells, only a partial repopulation of Th17 cells is observed in the gut of the majority of treated patients, leading to a modest reduction in the levels of markers of chronic immune activation, thus inducing cell‐exhaustion and immune‐senescence . Increasing evidence support the idea that alterations in cell recruitment to the gut are a major obstacle for intestinal T‐cell reconstitution in HIV‐1 infected individuals, also in those under successful ART treatment . Mavigner and colleagues in 2012 demonstrated that T‐helper cells expressing the gut homing receptor CCR9 accumulate in the bloodstream of HIV‐infected individuals under ART, and proposed that the reduced expression of CCR9 agonist, CCL25, in the intestine prevents a proper recruitment of these cells into the tissues .…”

“…Mavigner and colleagues in 2012 demonstrated that T‐helper cells expressing the gut homing receptor CCR9 accumulate in the bloodstream of HIV‐infected individuals under ART, and proposed that the reduced expression of CCR9 agonist, CCL25, in the intestine prevents a proper recruitment of these cells into the tissues . On the contrary, is still debated if expression of CCL20 and CXCL10 is maintained or reduced in the intestine during the infection, probably due to the fact that the intestinal mucosa of different anatomical sites have been analyzed by the different groups. Recently, we have shown that T‐helper cells expressing the chemokine receptor CCR6 and CXCR3 accumulate in the blood of ART treated HIV‐1 infected patients and that their frequency correlates with markers of chronic immune activation .…”

“…On the contrary, is still debated if expression of CCL20 and CXCL10 is maintained or reduced in the intestine during the infection, probably due to the fact that the intestinal mucosa of different anatomical sites have been analyzed by the different groups. Recently, we have shown that T‐helper cells expressing the chemokine receptor CCR6 and CXCR3 accumulate in the blood of ART treated HIV‐1 infected patients and that their frequency correlates with markers of chronic immune activation . Noteworthy, these cells express normal levels of chemokine receptors, but are not able to migrate in response to chemokines.…”

“…In these cells, the cytoskeleton machinery is altered, and can thus be a potential target for pharmacological intervention. Indeed, as a proof of principle, okadaic acid treatment of lymphocytes from HIV‐1 infected individuals, able to modulate the activity of cofilin, can rescue both optimal levels of intracellular F‐actin and efficient cell migration following chemokine receptor triggering …”

“…In particular, it is becoming evident how persistent infections can alter lymphocyte responses, [63][64][65] and reduce their ability to respond to chemotactic cues when chemokine receptor expression is preserved. 66…”