Human Immunodeficiency Virus Type 1 gp120 Induces Abnormal Maturation and Functional Alterations of Dendritic Cells: a Novel Mechanism for AIDS Pathogenesis

Abstract

Dendritic cells (DCs) play a crucial role in bridging innate and acquired immune responses to pathogens. In human immunodeficiency virus type 1 (HIV-1) infection, immature DCs (iDCs) are also main targets for HIV-1 at the mucosal level. In this study, we evaluated the effects of HIV-1-DC interactions on the maturation and functional activity of these cells. Exposure of human monocyte-derived iDCs to either aldrithiol-2-inactivated HIV-1 or gp120 led to an upmodulation of activation markers indicative of functional maturation. Despite their phenotype, these cells retained antigen uptake capacity and showed an impaired ability to secrete cytokines or chemokines and to induce T-cell proliferation. Although gp120 did not interfere with DC differentiation, the capacity of these cells to produce interleukin-12 (IL-12) upon maturation was markedly reduced. Likewise, iDCs stimulated by classical maturation factors in the presence of gp120 lacked allostimulatory capacity and did not produce IL-12, in spite of their phenotype typical of activated DCs. Exogenous addition of IL-12 restores the allostimulatory capacity of gp120-exposed DCs. The finding that gp120 induces abnormal maturation of DCs linked to profound suppression of their activities unravels a novel mechanism by which HIV can lead to immune dysfunction in AIDS patients.

Efficient inhibition of HIV-1 replication in human immature monocyte-derived dendritic cells by purified anti–HIV-1 IgG without induction of maturation

“…Granelli-Piperno et al have recently found similar results with infectious HIV-1 BaL particles, 16 whereas others have observed an augmentation of CD83 expression in the presence of high concentrations of recombinant gp-120 or inactivated HIV particles. 5,17 In the presence of concentrations of IgG that result in a 90% reduction of HIV-1 infection, no maturation of MDDCs was detected 24 or 64 hours after infection, indicating that the inhibition of HIV replication by these IgGs was not due to MDDC maturation. Nevertheless, at high concentrations of mAb 2F5 (100 g/mL) or polyclonal IgG (650 g/mL), an increased percentage of CD83 ϩ and DC-LAMPpositive MDDCs was measured.…”

“…13,16 Moreover, abnormal maturation induced by LPS has been measured after exposure of iMDDCs to HIV-1 gp-120. 17,18 Recently, it has been shown that LPSinduced maturation could be prevented by addition of recombinant Vpr. 19 Thus, new evidence has shown that HIV-1 could interfere with DC immune responses by impairing their maturation process, their cytokine production, and their allogenic T-cell stimulatory function; this could contribute to immune dysfunction in AIDS patients.…”

Herpes Simplex Virus Type 1 Induces CD83 Degradation in Mature Dendritic Cells with Immediate-Early Kinetics via the Cellular Proteasome

“…Furthermore, some human immunodeficiency virus type 1 proteins influence specific functions of DCs. Vpr prevents expression of the costimulatory molecules CD80, CD83, and CD86 at the transcriptional level without altering normal cellular transcription (40); glycoprotein gp120 induces an impaired ability to secrete cytokines or chemokines, and as a consequence, T-cell stimulation is reduced (24).…”

HIV-1 gp120 Activates the STAT3/Interleukin-6 Axis in Primary Human Monocyte-Derived Dendritic Cells

“…Both cytokines were kindly provided by Schering-Plough (Dardilly, France). On day 6, MDDCs were stimulated with lipopolysaccharide (LPS; 10 ng/ml), gp120 (5 g/ml, unless otherwise indicated), AT-2-inactivated HIV-1 BaL (46.783 ng/ml p24) (22), or CCL4 (100 nM). Monocyte-derived macrophages (MDMs) were obtained after 6 days of in vitro culture in endotoxin-free Iscove's medium containing 10% FBS as previously described (23).…”

“…The HIV-1 BaL virus preparation were purchased from ABI (Columbia, MD) and inactivated as previously described (22).…”