Productive infection of dendritic cells by HIV-1 and their ability to capture virus are mediated through separate pathways.

We investigated the effect of IL-10 on replication of primary CXCR4-dependent (X4) HIV-1 strains by monocyte-derived dendritic cells (DCs) and macrophages (MΦs). MΦs efficiently replicated CXCR4-dependent HIV-1 (X4 HIV-1) strains NDK and VN44, whereas low levels of p24 were detected in supernatants of infected DCs. IL-10 significantly increased X4 HIV-1 replication by DCs but blocked viral production by MΦs as determined by p24 levels and semiquantitative nested PCR. IL-10 up-regulated CXCR4 mRNA and protein expression on DCs and MΦs, suggesting that IL-10 enhances virus entry in DCs but blocks an entry and/or postentry step in MΦs. The effect of IL-10 on the ability of DCs and MΦs to transmit virus to autologous CD4+ T lymphocytes was investigated in coculture experiments. DCs exhibited a greater ability than did MΦs to transmit a vigorous infection to CD4+ T cells despite their very low replication capacity. IL-10 had no effect on HIV-1 replication in DC:T cell cocultures but markedly decreased viral production in MΦ:T cell cocultures. These results demonstrate that IL-10 has opposite effects on the replication of primary X4 HIV-1 strains by DCs and MΦs. IL-10 increases X4-HIV-1 replication in DCs but does not alter their capacity to transmit virus to CD4+ T lymphocytes. These findings suggest that increased levels of IL-10 observed in HIV-1-infected patients with disease progression may favor the replication of X4 HIV-1 strains in vivo.

Section: Discussionsupporting

confidence: 91%

Opposite Effects of IL-10 on the Ability of Dendritic Cells and Macrophages to Replicate Primary CXCR4-Dependent HIV-1 Strains

Ancuța

Bakri

Chomont

et al. 2001

“…Here, DC-SIGN efficiently transmits the virus to T lymphocytes, resulting in productive HIV infection of T cells (26). The mechanism of protection of the virus by DCs is currently unknown, but several studies have demonstrated intracellular localization of virions in DCs (27). This, together with the fact that the cytoplasmic tail of DC-SIGN contains internalization motifs, prompted us to analyze the intracellular routing of DC-SIGN upon binding of soluble ligand.…”

Section: The Dendritic Cell-specific Adhesion Receptor Dc-sign Internmentioning

confidence: 99%

The Dendritic Cell-Specific Adhesion Receptor DC-SIGN Internalizes Antigen for Presentation to T Cells

Engering¹,

Geijtenbeek²,

Vliet³

et al. 2002

569

500

Dendritic cells (DCs) capture Ags or viruses in peripheral tissue to transport them to lymphoid organs to induce cellular T cell responses. Recently, a DC-specific C-type lectin was identified, DC-specific ICAM-grabbing non-integrin (DC-SIGN), that functions as cell adhesion receptor mediating both DC migration and T cell activation. DC-SIGN also functions as an HIV-1R that captures HIVgp120 and facilitates DC-induced HIV transmission of T cells. Internalization motifs in the cytoplasmic tail of DC-SIGN hint to a function of DC-SIGN as endocytic receptor. In this study we demonstrate that on DCs DC-SIGN is rapidly internalized upon binding of soluble ligand. Mutating a putative internalization motif in the cytoplasmic tail reduces ligand-induced internalization. Detailed analysis using ratio fluorescence imaging and electron microscopy showed that DC-SIGN-ligand complexes are targeted to late endosomes/lysosomes. Moreover, ligands internalized by DC-SIGN are efficiently processed and presented to CD4+ T cells. The distinct pattern of expression of C-type lectins on DCs in situ and their nonoverlapping Ag recognition profile hint to selective functions of these receptors to allow a DC to recognize a wide variety of Ags and to process these to induce T cell activation. These data point to a novel function of the adhesion receptor DC-SIGN as an efficient DC-specific Ag receptor that can be used as a target to induce viral and antitumor immunity.

“…Another important issue in the field of DC-HIV biology is that data derived from studies using particular subtypes of DC (e.g., Langerhans cells vs monocyte-derived DC, immature vs mature DC, myeloid vs plasmacytoid DC) have clearly demonstrated disparate results. Regarding the immunologic function of HIV-infected DC or of DC isolated from HIV-infected individuals, existing literature on this topic is also varied (7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21). Some have claimed significant APC defects and others none.…”

Section: Endritic Cells (Dc)mentioning

confidence: 99%

“…As previously described (15,17,26), plastic-adherent PBMC from healthy adults were cultured for 1 wk in RPMI-based complete medium containing 10% heat-inactivated FBS (Biofluids, Rockville, MD), 1000 U/ml recombinant human GM-CSF (Immunex), and 1000 U/ml recombinant human IL-4 (R&D Systems, Minneapolis, MN). At day 7, DC were harvested, washed, and resuspended in a mixture containing the following mouse anti-human mAbs (each at 5 g/ml): anti-CD3, anti-CD14, anti-CD16, and anti-CD19.…”

Section: Preparation Of Cellsmentioning

confidence: 99%

Decreased Stimulation of CD4+ T Cell Proliferation and IL-2 Production by Highly Enriched Populations of HIV-Infected Dendritic Cells

Kawamura

Gatanaga

Borris³

et al. 2003

APC infection and dysfunction may contribute to the immunopathogenesis of HIV disease. In this study, we examined immunologic function of highly enriched populations of HIV-infected monocyte-derived dendritic cells (DC). Compared with uninfected DC, HIV-infected DC markedly down-regulated surface expression of CD4. HIV p24+ DC were then enriched by negative selection of CD4+HIV p24− DC and assessed for cytokine secretion and immunologic function. Although enriched populations of HIV-infected DC secreted increased IL-12p70 and decreased IL-10, these cells were poor stimulators of allogeneic CD4+ T cell proliferation and IL-2 production. Interestingly, HIV-infected DC secreted HIV gp120 and the addition of soluble (s) CD4 (a known ligand for HIV gp120) to DC-CD4+ T cell cocultures restored T cell proliferation in a dose-dependent manner. By contrast, addition of antiretroviral drugs did not affect CD4+ T cell proliferation. Furthermore, recombinant HIV gp120 inhibited proliferation in uninfected cocultures of allogeneic DC and CD4+ T cells, an effect that was also reversed by addition of sCD4. In summary, we show that HIV gp120 produced by DC infected by HIV in vitro impairs normal CD4+ T cell function and that sCD4 completely reverses HIV gp120-mediated immunosuppression. We hypothesize that HIV-infected DC may contribute to impaired CD4+ T cell-mediated immune responses in vivo and that agents that block this particular immunosuppression may be potential immune adjuvants in HIV-infected individuals.