Dendritic cells (DCs) perform a basic role in the immune system by allowing the initiation of the primary T-cell-dependent immune response. Given previous indirect evidence that DC maturation and function are impaired by HIV, we have developed an in vitro culture system in order to verify the effect of HIV infection on DC function during the development from hematopoietic progenitors. Considering that monocytic (Mo) differentiating cells efficiently replicate monocytotropic HIV, we examined whether HIV-infected monocytic precursors (MoP) were able to generate functional DCs. CD34+ hematopoietic progenitor cells (HPCs) were induced along Mo differentiative pathway in liquid cultures and at an early stage of culture, MoP were infected with M-tropic BaL HIV strain, and after 2 days they were switched to DC differentiation with GM-CSF and IL-4. Derived DCs were actively infected, as detected by HIV-p24 production. HIV did not significantly affect cell viability, but induced a reduction in cell proliferation and an inefficient functional activity in terms of uptake capability and stimulation of allogenic T cells. These results indicate that HIV-infected MoP lost the capacity to generate functional DCs, and this may represent one of the many mechanisms of immunosuppression exploited by HIV.
HengelHKoszinowskiUH. Interference with antigen processing by viruses. Curr Opin Immunol1997; 9:470–76.
2.
WiertzEJMukherjeeSPloeghHL. Viruses use stealth technology to escape from the host immune system. Mol Med Today1997; 3:116–23.
3.
CarlierJMartinHMariameB. Paracrine inhibition of GM-CSF signaling by human cytomegalovirus in monocytes differentiating to dendritic cells. Blood2011; 118:6783–92.
4.
KruseMRosoriusOKratzerFStelzGKuhntCSchulerGHauberJSteinkassererA. Mature dendritic cells infected with herpes simplex virus type 1 exhibit inhibited T-cell stimulatory capacity. J Virol2000; 74:7127–36.
5.
SmithAPPaolucciCDiLGBurasteroSESantoroFLussoP. Viral replication-independent blockade of dendritic cell maturation and interleukin-12 production by human herpesvirus 6. J Virol2005; 79:2807–13.
6.
LiuKNussenzweigMC. Origin and development of dendritic cells. Immunol Rev2010; 234:45–54.
7.
BanchereauJSteinmanRM. Dendritic cells and the control of immunity. Nature1998; 392:245–52.
8.
KushwahRHuJ. Complexity of dendritic cell subsets and their function in the host immune system. Immunology2011; 133:409–19.
9.
DonaghyHGazzardBGotchFPattersonS. Dysfunction and infection of freshly isolated blood myeloid and plasmacytoid dendritic cells in patients infected with HIV-1. Blood2003; 101:4505–11.
10.
HarmanANLaiJTurvilleS. HIV infection of dendritic cells subverts the IFN induction pathway via IRF-1 and inhibits type 1 IFN production. Blood2011; 118:298–308.
11.
HsiehSMPanSCHungCCChenMYChangSC. Differential impact of late-stage HIV-1 infection on in vitro and in vivo maturation of myeloid dendritic cells. J Acquir Immune Defic Syndr2003; 33:413–9.
12.
KnightSCMacatoniaSEPattersonS. HIV I infection of dendritic cells. Int Rev Immunol1990; 6:163–75.
13.
FinkeJSShodellMShahKSiegalFPSteinmanRM. Dendritic cell numbers in the blood of HIV-1 infected patients before and after changes in antiretroviral therapy. J Clin Immunol2004; 24:647–52.
14.
KamgaIKahiSDeveliogluL. Type I interferon production is profoundly and transiently impaired in primary HIV-1 infection. J Infect Dis2005; 192:303–10.
15.
ChambersKAParatoKGAngelJB. Active cellular infection of myeloid cells is required for HIV-1-mediated suppression of interleukin-12 p40 expression. Cell Immunol2002; 215:120–32.
16.
ChehimiJStarrSEFrankID'AndreaAMaXMacGregorRRSennelierJTrinchieriG. Impaired interleukin 12 production in human immunodeficiency virus-infected patients. J Exp Med1994; 179:1361–6.
17.
SabadoRLO'BrienMSubediA. Evidence of dysregulation of dendritic cells in primary HIV infection. Blood2010; 116:3839–52.
18.
AyehunieSGarcia-ZepedaEAHoxieJAHorukRKupperTSLusterADRuprechtRM. Human immunodeficiency virus-1 entry into purified blood dendritic cells through CC and CXC chemokine coreceptors. Blood1997; 90:1379–86.
19.
CameronPUForsumUTepplerHGranelli-PipernoASteinmanRM. During HIV-1 infection most blood dendritic cells are not productively infected and can induce allogeneic CD4+ T cells clonal expansion. Clin Exp Immunol1992; 88:226–36.
20.
KnightSCPattersonS. Bone marrow-derived dendritic cells, infection with human immunodeficiency virus, and immunopathology. Annu Rev Immunol1997; 15:593–615.
21.
McIlroyDAutranBCheynierRWain-HobsonSClauvelJPOksenhendlerEDebrePHosmalinA. Infection frequency of dendritic cells and CD4+ T lymphocytes in spleens of human immunodeficiency virus-positive patients. J Virol1995; 69:4737–45.
22.
WeissmanDLiYOrensteinJMFauciAS. Both a precursor and a mature population of dendritic cells can bind HIV. However, only the mature population that expresses CD80 can pass infection to unstimulated CD4+ T cells. J Immunol1995; 155:4111–7.
23.
CanqueBRosenzwajgMCamusSYagelloMBonnetMLGuigonMGluckmanJC. The effect of in vitro human immunodeficiency virus infection on dendritic-cell differentiation and function. Blood1996; 88:4215–28.
24.
CanqueBBakriYCamusSYagelloMBenjouadAGluckmanJC. The susceptibility to X4 and R5 human immunodeficiency virus-1 strains of dendritic cells derived in vitro from CD34(+) hematopoietic progenitor cells is primarily determined by their maturation stage. Blood1999; 93:3866–75.
25.
KnightSCElsleyWWangH. Mechanisms of loss of functional dendritic cells in HIV-1 infection. J Leukoc Biol1997; 62:78–81.
26.
MontesoroECastelliGMorsilliONisiniRStafsnesMHCareAPeschleCChelucciC. Unilineage monocytopoiesis in hematopoietic progenitor culture: switching cytokine treatment at all Mo developmental stages induces differentiation into dendritic cells. Cell Death Differ2006; 13:250–9.
27.
ChelucciCCasellaIFedericoM. Lineage-specific expression of human immunodeficiency virus (HIV) receptor/coreceptors in differentiating hematopoietic precursors: correlation with susceptibility to T- and M-tropic HIV and chemokine-mediated HIV resistance. Blood1999; 94:1590–600.
28.
WarrenMKRoseWLConeJLRiceWGTurpinJA. Differential infection of CD34+ cell-derived dendritic cells and monocytes with lymphocyte-tropic and monocyte-tropic HIV-1 strains. J Immunol1997; 158:5035–42.
29.
GartnerSMarkovitsPMarkovitzDMKaplanMHGalloRCPopovicM. The role of mononuclear phagocytes in HTLV-III/LAV infection. Science1986; 233:215–9.
30.
MeeraSMadhuriTManishaGRameshP. Irreversible loss of pDCs by apoptosis during early HIV infection may be a critical determinant of immune dysfunction. Viral Immunol2010; 23:241–9.
31.
MeyersJHJustementJSHallahanCW. Impact of HIV on cell survival and antiviral activity of plasmacytoid dendritic cells. PLoS One2007; 2:e458.
32.
BlauveltAClericiMLuceyDRSteinbergSMYarchoanRWalkerRShearerGMKatzSI. Functional studies of epidermal Langerhans cells and blood monocytes in HIV-infected persons. J Immunol1995; 154:3506–15.
33.
MacatoniaSEGompelsMPinchingAJPattersonSKnightSC. Antigen-presentation by macrophages but not by dendritic cells in human immunodeficiency virus (HIV) infection. Immunology1992; 75:576–81.
34.
GuoYXuWWSongJDengWLiuDQZhangHT. Intracellular overexpression of HIV-1 Nef impairs differentiation and maturation of monocytic precursors towards dendritic cells. PLoS One2012; 7:e40179.
35.
KodamaATanakaRZhangLFAdachiTSaitoMAnsariAATanakaY. Impairment of in vitro generation of monocyte-derived human dendritic cells by inactivated human immunodeficiency virus-1: Involvement of type I interferon produced from plasmacytoid dendritc cells. Hum Immunol2010; 71:541–50.
