Transcriptional Regulation of CXCL5 in HIV-1-Infected Macrophages and Its Functional Consequences on CNS Pathology

Address correspondence to: Dr. Velpandi Ayyavoo, Department of Infectious Diseases and Microbiology, Graduate School of Public Health, University of Pittsburgh, 404 Parran Hall, 130 DeSoto St. Pittsburgh, PA 15261, E-mail: [email protected]

Introduction

Human immunodeficiency virus-1 (HIV-1) infection triggers host immune responses by increasing the expression of a number of proinflammatory cytokines and chemokines both in the periphery as well as in tissue compartments, including the central nervous system (CNS) (Fontaine and others 2011; Letendre and others 2011; Pitha 2011; Nakayama and others 2012). Chemokines, the chemoattractive cytokines, are one of the major coordinators that regulate the immune response during HIV-1 pathogenesis. These chemokines have dual roles during HIV-1 infection, where they either participate in host defense or contribute toward disease progression. For instance, chemokine receptors CCR5 and CXCR4 function as coreceptors for viral entry (Cocchi and others 1995; Bleul and others 1996), whereas chemokines, including CXCL12, CCL3, CCL4, and CCL5 restrict the virus entry by binding and blocking viral coreceptors. Although HIV-1 infection disrupts the balance of cytokine/chemokine networks, during the acute phase of infection, chemokines play a crucial role in host defense by modulating other immune cells (Zlotnik and Yoshie 2000). For example, ELR+ chemokines, including CXCL1, CXCL2, and CXCL5 contribute to host defense through their involvement in leukocyte migration and activation to tissue compartments. They infiltrate neutrophils, monocytes, and lymphocytes to the site of infection as part of the defense mechanism. Presence of ELR+ chemokines is reported in several diseases caused by both viral and nonviral origin. ELR+ chemokines have both inflammatory injury and protective effects through their recruitment of neutrophils (Hosking and others 2009; Ichikawa and others 2013). These chemokines are also known to play a role in breakdown of the blood brain barrier (BBB) (Hosking and others 2009; Marro and others 2012) that would lead to infiltration...