Macrophage-tropic HIV and SIV envelope proteins induce a signal through the CCR5 chemokine receptor

Abstract

Human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) enter target cells by forming a complex between the viral envelope protein and two cell-surface membrane receptors: CD4 and a 7-span transmembrane chemokine receptor. Isolates of HIV that differ in cellular tropism use different subsets of chemokine receptors as entry cofactors: macrophage-tropic HIVs primarily use CCR5, whereas T-cell-tropic and dual-tropic isolates use CXCR4 receptors. HIV-mediated signal transduction through CCR5 is not required for efficient fusion and entry of HIV in vitro. Here we show that recombinant envelope proteins from macrophage-tropic HIV and SIV induce a signal through CCR5 on CD4+ T cells and that envelope-mediated signal transduction through CCR5 induces chemotaxis of T cells. This chemotactic response may contribute to the pathogenesis of HIV in vivo by chemo-attracting activated CD4+ cells to sites of viral replication. HIV-mediated signalling through CCR5 may also enhance viral replication in vivo by increasing the activation state of target cells. Alternatively, envelope-mediated CCR5 signal transduction may influence viral-associated cytopathicity or apoptosis.

Distinct Mechanisms of Agonist-induced Endocytosis for Human Chemokine Receptors CCR5 and CXCR4

“…In contrast, T-tropic infection of monocytes or macrophages requires high threshold levels of CXCR4 on the target cells (Tokunaga et al, 2001). M-and T-tropic HIV gp120s function as agonists for CCR5 and CXCR4, respectively (Davis et al, 1997;Weissman et al, 1997). It is possible that M-tropic HIV gp41-mediated membrane fusion occurs efficiently during the long residence time of occupied CCR5 at the plasma membrane.…”

HIV‐1 infection of primary effusion lymphoma cell line triggers Kaposi's sarcoma‐associated herpesvirus (KSHV) reactivation

“…Since the binding of the HIV-1 envelope (through its surface subunit, gp120) was shown to modulate cellular activation, in particular through its interaction with CD4 or its coreceptors 13,14 and to stimulate human cytomegalovirus (HCMV; another herpesvirus) replication in monocytes, 15 the effect of recombinant gp120 was assessed on BC-3 cells. Cells were treated with different concentrations of recombinant HIV-1 gp120 (the T-tropic HIV-1 IIIB strain), and 48 hr after treatment, 10 g of total RNA were analyzed by Northern blot using GAPDH hybridization as a control.…”

CXCR4-Tropic HIV-1 Envelope Glycoprotein Functions as a Viral Chemokine in Unstimulated Primary CD4+ T Lymphocytes

“…Chemoattractant gradients induce the polarization of the phosphoinositide signal transduction machinery, resulting in reorganization of the actin cytoskeleton and ultimately in directed cell migration (16). Triggering of chemoreceptors by HIV-1 envelope glycoprotein was shown to induce some, though often not all, of these responses, depending on the chemoreceptor used and of the nature of target cells (17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29). Previous studies showed that binding of gp120 from CXCR4-tropic (X4) HIV-1 strains to activated CD4 ϩ T cells induced the phosphorylation of kinases involved in cell adhesion and directed migration, such as Pyk-2 and PI3K (17,18).…”