Roles for CXC Chemokine Ligands 10 and 11 in Recruiting CD4+ T Cells to HIV-1-Infected Monocyte-Derived Macrophages, Dendritic Cells, and Lymph Nodes

Abstract

We investigated roles for chemoattractants in dissemination of HIV-1 by examining the induction of T cell-active chemokines in HIV-1-infected human monocyte-derived macrophages and dendritic cells. Of the 12 chemokines analyzed, mRNAs for two, CXCL10 and CXCL11, ligands for the chemokine receptor CXCR3, were up-regulated in both cell types upon infection by HIV-1. Induction of these chemokine genes in infected cultures was dependent on both viral entry and reverse transcriptase activity, but not on the HIV-1 envelope glycoprotein. Conditioned medium from infected cells was chemotactic for freshly isolated human CD4+ T cells, and chemotaxis was abolished by pretreatment with an Ab against CXCR3. A lymph node from an HIV-1-infected individual expressed CXCL10 and CXCL11 mRNAs in the paracortex, including venules, as detected by in situ hybridization, whereas neither mRNA was detected after highly active antiretroviral therapy. Because CCR5 on CD4+ T cells is found predominantly on cells that also express CXCR3, these data implicate CXCL10 and CXCL11 in the recruitment of susceptible T cells to HIV-1-infected lymph nodes, macrophages, and dendritic cells. This recruitment might enhance the sequestration of T cells in infected lymphoid organs and the spread of infection between cells, contributing to the immunopathology of AIDS.

Interferon Alpha Subtype-Specific Suppression of HIV-1 InfectionIn Vivo

“…CXCL10 has been reported to be inducible by IFN-␣ (74,75) and is produced by HIV-1-infected macrophages and dendritic cells as a chemoattractant to recruit activated T cells to sites of infection (76). As CD4 ϩ T cells are major targets for HIV-1, such recruitment accelerates their infection and loss (76). Thus, CXCL10 levels are predictive of both HIV-1 loads (77) and disease progression (78).…”

“…Thus, it was important to determine whether IFN-␣ therapy elevated levels of plasma CXCL10, a hallmark of HIV-1-induced immune dysregulation (55,56). CXCL10 has been reported to be inducible by IFN-␣ (74,75) and is produced by HIV-1-infected macrophages and dendritic cells as a chemoattractant to recruit activated T cells to sites of infection (76). As CD4 ϩ T cells are major targets for HIV-1, such recruitment accelerates their infection and loss (76).…”

HIV Exposure to the Epithelia in Ectocervical and Colon Tissues Induces Inflammatory Cytokines Without Tight Junction Disruption

“…10 Thus, results from our study suggest that the epithelial cells might be one of the primary sources of chemokines postexposure to HIV. Since CXCL10 and CXCL11 have been reported to contribute to the recruitment of susceptible T cell, macrophages, and DCs to HIV-infected lymph nodes, 41 the observed HIV-mediated upregulation of chemokines may be responsible for recruitment of target cells toward the epithelial region, resulting in enhanced HIV transmission.…”

Regulation of Lentivirus Neurovirulence by Lipopolysaccharide Conditioning: Suppression of CXCL10 in the Brain by IL-10

“…However, CXCL10 has multiple actions, including chemotaxis as well as neurotoxicity, regulated through its cognate receptor, CXCR3 (60). CXCR3 is also expressed by neurons; therefore, an autocrine neurotoxic pathway is plausible, although its chemotactic effects are more widely recognized and understood (61).…”