Chemokine CXCL8 Promotes HIV-1 Replication in Human Monocyte-Derived Macrophages and Primary Microglia via Nuclear Factor-κB Pathway

Abstract

BackgroundChemokine CXCL8 is an important neutrophil chemoattractant implicated in various neurodegenerative disorders. Cytokine/chemokine imbalance, with an increase in proinflammatory cytokines like interleukin-1β and tumor necrosis factor-α within the central nervous system, is a hallmark of human immunodeficiency virus (HIV)-1 infection. We previously reported that HIV-1 infection is linked to upregulation of CXCL8 in brain tissues and human astrocytes. Chemokines play crucial roles in trafficking of leukocytes and trafficking of HIV-1-infected across the blood-brain barrier play an important role in HIV-1 central nervous system disease. In the post-antiretroviral therapy era, low level of productive replication of HIV-1 in brain is a critical component of neuropathogenesis regulation. The present study investigated the effect of CXCL8 on productive infection of HIV-1 in human monocytes-derived macrophages (MDM) and primary human microglia.ResultsHuman MDM and microglia were infected with the blood or brain derived HIV-1 isolates, HIV-1ADA or HIV-1JRFL. Treatment with CXCL8 significantly upregulated HIV-1p24 levels in supernatants of both HIV-1-infected MDM as well as microglia. In addition, the formation of 2-long terminal repeat (LTR) circles, a measure of viral genome integration, was significantly higher in CXCL8-treated, HIV-1-infected MDM and microglia. Transient transfection of U937 cells with HIV-1 LTR luciferase reporter construct resulted in increased promoter activity when treated with CXCL8. Moreover, increased nuclear translocation of nuclear factor-κB was seen in HIV-1-infected MDM following CXCL8 treatment. Blocking CXCL8 receptors CXCR1 and CXCR2 abrogated the CXCL8-mediated enhanced HIV-1 replication.ConclusionOur results show that CXCL8 mediates productive infection of HIV-1 in MDM and microglia via receptors CXCR1 and CXCR2. These results demonstrate that CXCL8 exerts its downstream effects by increasing translocation of nuclear factor-κB into the nucleus, thereby promoting HIV-1 LTR activity.

Mycobacterium tuberculosis Reactivates HIV-1 via Exosome-Mediated Resetting of Cellular Redox Potential and Bioenergetics

“…5C). All of these factors are well known to facilitate HIV-1 infection and promote replication in macrophages (51). In fact, higher levels of CCL2 were detected in the bronchoalveolar lavage (BAL) fluid of pulmonary TB patients and pleural fluid of HIV-1-infected patients, indicating the importance of this proinflammatory cytokine in HIV-M. tuberculosis coinfection (52).…”

Statin modulation of monocyte phenotype and function: implications for HIV-1-associated neurocognitive disorders

“…4b & 4c) (MCP-1 stimulation did not induce MIP-1α production, and IL-8 induction was minimal; data not shown). Both MIP-1α and IL-8 are markers of inflammation in HIV infection and IL-8 has specifically been associated with ongoing inflammation in HIV+ individuals on HAART (Pierdominici, Giovannetti et al 2002; Letendre, Zheng et al 2011; Bastard, Soulie et al 2012; Mamik and Ghorpade 2014; Wada, Jacobson et al 2015). Additionally, CSF IL-8 correlates with HIV-associated neurocognitive disorders (Kamat, Lyons et al 2012; Yuan, Qiao et al 2013; Yuan, Liu et al 2015).…”

Mycobacterium tuberculosis reactivates HIV via exosomes mediated resetting of cellular redox potential and bioenergetics

“…5C). All of these factors are well known to facilitate HIV-1 infection and promote replication in macrophages [51]. In facts, higher levels of CCL2 were detected in the bronchoalveolar lavage (BAL) fluid of pulmonary TB patients and pleural fluid of HIV-1 infected patients, indicating the importance of this proinflammatory cytokine in HIV-TB co-infection [52].…”