HIV-1 gp120 signaling through TLR4 modulates innate immune activation in human macrophages and the biology of hepatic stellate cells

Abstract

Highly active antiretroviral therapy has significantly improved the prognosis of HIV-infected subjects. However, patients treated long term still manifest increased mortality and, even with undetectable plasma viremia, often experience persistent immune activation. Furthermore, liver-related mortality is now the most common cause of non-AIDS-related death in HIV-infected individuals on highly active antiretroviral therapy through accelerated fibrosis progression. TLRs are the first line of the host response to pathogens and play an important role in human host defense against viruses through sensing of viral structural proteins. Growing evidence points to TLR4 as a key player in chronic immune activation, HIV recognition/replication, and liver fibrosis progression, suggesting that HIV triggering of TLR4 may dictate some aspects of the multifaceted AIDS pathogenesis. In this study, we provide evidence for an interplay between host TLR4 and HIV-1 gp120 in human monocyte-derived macrophages and hepatic stellate cells, leading to intracellular pathways and biologic activities that mediate proinflammatory and profibrogenic signals. Finally, we hypothesize that CCR5 and TLR4 are likely part of a common receptor cluster, as the blocking of CCR5 by specific antagonists impairs the macrophage capacity to produce chemokines in response to LPS. Chronic immune activation and liver fibrosis remain important obstacles for highly active antiretroviral therapy success. Thus, the identification of gp120-TLR4 axis as a novel determinant of immune system and hepatic stellate cell biology opens new perspectives to the management of HIV infection and disease.

One of the immune activation profiles observed in HIV-1-infected adults with suppressed viremia is linked to metabolic syndrome: The ACTIVIH study

“…A first cause is the presence of the virus itself, detected by the immune system as a xenoantigen and a danger. For example, gp120 has recently been shown to activate monocytes and macrophages via TLR4 ( Del Corno et al, 2016 ). A second cause is the infection process that triggers a DNA detection system resulting in inflammatory cytokine production ( Doitsh et al, 2014 ).…”

PKC-δ isoform plays a crucial role in Tat-TLR4 signalling pathway to activate NF-κB and CXCL8 production

“…VpR, like HIV-1 Tat protein, has been shown to activate TLR4-Myd88/MAPk/NF-κB/C-EPB-pathways leading to the production of IL-6 in human macrophages 6 . In addition to auxiliary HIV-1 proteins, several structural proteins have also been reported for their capacity to activate TLR pathways, including the matrix p17 and the transmembrane gp41 proteins with TLR2/1, p24 core protein with TLR2/6 and the surface unit glycoprotein gp120 with TLR2 and TLR4 15, 16, 25 . It is interesting to note the dual synergistic role of HIV-1 matrix p17 protein, which in addition to its interaction with TLR2/1, acts as a viral-CXCL8 chemokine to interact directly with CXCR1, the major receptor of CXCL8, leading to monocyte chemotaxis through activation of Rho/ROCK pathways 77 .…”

“…This pro-inflammatory state contributes to the establishment of a chronic hyperactivation of the immune system leading not only to its weakening 8–12 but also to the development of several other disorders including neurological and cardiovascular pathologies 13 . In HIV-1 infection, the persistent activation of the immune system seems to be essentially initiated by HIV-1 infection following the recruitment and activation of various Pattern Recognition Receptors (PRR) by the proteic (gp120 via TLR2 and TLR4 14, 15 , gp41 via TLR2/1, p24 via TLR2/6 16 , Tat via TLR4 17 , VpR via TLR4 6 ) and nucleic acid (the uridine rich ssRNA via TLR7/8, and the double stranded DNA via c-GAS 18 ) viral components 19 . Secreted pro-inflammatory cytokines/chemokines also participate in the stimulation of viral replication, leading to the rapid depletion of activated CD4+ T cells in the gut-associated lymphoid tissue (GALT), within the two first weeks post-infection 20, 21 .…”

Analysis of the collagen fibers on autopsied patients’ uterus with the Acquired Immunodeficiency Syndrome

“…5 Studies demonstrate that HIV can interact by means of gp120 with immune cells which activate local inflammatory responses and repairs. 6 However, sometimes this interaction may occur by producing inappropriate activations 7 and increase the production of collagen and monocyte chemoattractant protein (a macrophage chemoattractant). 8 The cervix is a dense fibrous tissue that is located at the lowest part of the uterus.…”