HIV-1 Tat reprograms immature dendritic cells to express chemoattractants for activated T cells and macrophages

Abstract

Immature dendritic cells are among the first cells infected by retroviruses after mucosal exposure. We explored the effects of human immunodeficiency virus-1 (HIV-1) and its Tat transactivator on these primary antigen-presenting cells using DNA microarray analysis and functional assays. We found that HIV-1 infection or Tat expression induces interferon (IFN)-responsive gene expression in immature human dendritic cells without inducing maturation. Among the induced gene products are chemokines that recruit activated T cells and macrophages, the ultimate target cells for the virus. Dendritic cells in the lymph nodes of macaques infected with simian immunodeficiency virus (SIV) have elevated levels of monocyte chemoattractant protein 2 (MCP-2), demonstrating that chemokine induction also occurs during retroviral infection in vivo. These results show that HIV-1 Tat reprograms host dendritic cell gene expression to facilitate expansion of HIV-1 infection.

Immunostimulating capacities of stabilized RNA molecules

“…Indeed, although human DC that are generated in vitro do not mature after infection by HIV (this phenomenon might be actually due to some interference of HIV proteins with the DC maturation pathways [40]), plasmacytoid DC, which can be activated by stabilized RNA (B. Scheel, ongoing studies), mature in contact with infectious or heat-inactivated HIV. Activation of plasmacytoid DC by HIV indicates that this virus contains a PAMP and, on the basis of our data, we postulate that this PAMP is the stabilized RNA genome of the retrovirus.…”

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

“…Poluektova et al (21) showed induction of CXCL10 and CXCL9 in MDM, but did not investigate the requirements for chemokine induction. Izmailova et al (19) showed the induction of multiple chemokines in a chip-based screen of gene expression, including CXCL10, CXCL9, and CCL8 by HIV infection of MDDC in vitro, which they attributed to the activity of Tat. Interpretation of these data was complicated, however, by the lack of correspondence in the time courses of accumulation of Tat and chemokines and by the use of an adenovirus vector to express Tat in MDDC, which, based on the data discussed below (44), might have influenced expression of the CXCL10 gene.…”

“…Even the related, third CXCR3 ligand, CXCL9, which was reported recently to be induced by HIV-1 (19,21), is highly dependent for its induction on IFN-␥ both in vitro (52) and in vivo (53), so that induction in the absence of cells producing IFN-␥ would be expected to be minimal. In line with our real-time PCR data, when we used the conditioned medium from infected vs uninfected MDM in a chemotaxis assay with CD4 ϩ T cells, all HIV-1-induced chemotactic activity could be blocked by Ab neutralization of CXCR3, indicating that none of the non-CXCR3 chemokines was contributing.…”

“…2). Some studies, like ours, have addressed potential roles for chemokines in recruiting target cells to infected cells/sites, possibly contributing to the spread of infection (11)(12)(13)(14)(15)(16)(17)(18)(19) and/or to inflammatory damage, particularly in the brain (20 -23). In most of these studies, HIV infection or viral products have been reported to induce CC chemokines (11)(12)(13)(14)(15)(16)20), whose direct effects on infection of T cells by CCR5-using (R5) viruses would be inhibitory.…”

“…In most of these studies, HIV infection or viral products have been reported to induce CC chemokines (11)(12)(13)(14)(15)(16)20), whose direct effects on infection of T cells by CCR5-using (R5) viruses would be inhibitory. Some studies have revealed induction of CC and CXC chemokines as the result of broad screens for changes in gene activity related to infection of cells or monkeys with HIV-1 or SIV, respectively (19,24). We were interested in the induction in HIV-1-infected APCs specifically of ligands for chemokine receptors expressed on CCR5 ϩ CD4 ϩ T cells.…”