We have recently shown that HIV-1 Pr55gag virus-like particles (HIV-VLPs), produced in a baculovirus expression system and presenting a gp120 molecule from a Ugandan HIV-1 isolate of clade A (HIV-VLPAs), induce maturation and activation of antigen-presenting cells (APCs) in fresh peripheral blood mononuclear cells (PBMCs) from seronegative as well as seropositive, with either low or high viremia, HIV-1 subjects. A Th2 polarization has been observed in both HIV seropositive groups, which is efficiently boosted by HIV-VLP induction and does not switch into a Th1 pattern. Here we show that the production of the known immune-suppressive IL-10 is induced in both HIV-seropositive groups at a significantly lower level by HIV-VLPs compared to LPS. These levels, however, appear to still negatively interfere with the innate as well as adaptive Th1-polarized response observed in HIV-seropositive groups. These results indicate that vaccines and novel adjuvants (i.e., TLR agonists, such as LPS) must be evaluated not only for their immunogenicity but also for their potential immune-suppressive effects. In this perspective, fresh ex vivo PBMCs can be of high value for screening the responses as well as eventual failures of vaccinees enrolled in clinical trials.
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References
1.
GheysenD, JacobsE, de ForestaFet al.Assembly and release of HIV-1 precursor Pr55gag virus-like particles from recombinant baculovirus-infected insect cells. Cell, 1989; 59:103–112.
2.
DelchambreM, GheysenD, ThinesDet al.The GAG precursor of simian immunodeficiency virus assembles into virus-like particles. EMBO J, 1989; 8,9:2653–2660.
3.
MiyanoharaA, ImamuraT, ArakiMet al.Expression of hepatitis B virus core antigen gene in Saccharomyces cerevisiae: Synthesis of two polypeptides translated from different initiation codons. J Virol, 1986; 59:176–180.
4.
KirnbauerR, BooyF, ChengN, LowyDR, SchillerJT. Papillomavirus L1 major capsid protein self-assembles into virus-like particles that are highly immunogenic. Proc Natl Acad Sci USA, 1992; 89:12180–12184.
5.
BachmannMF, LutzMB, LaytonGTet al.Dendritic cells process exogenous viral proteins and virus-like particles for class I presentation to CD8+ cytotoxic T lymphocytes. Eur J Immunol, 1996; 26,11:2595–2600.
6.
RuedlC, SchwarzK, JegerlehnerAet al.Virus-like particles as carriers for T-cell epitopes: Limited inhibition of T-cell priming by carrier-specific antibodies. J Virol, 2005; 79,2:717–724.
7.
RuedlC, StorniT, LechnerF, BachiT, BachmannMF. Cross-presentation of virus-like particles by skin-derived CD8(−) dendritic cells: A dispensable role for TAP. Eur J Immunol, 2002; 32,3:818–825.
8.
BuonaguroL, Del GaudioE, MonacoMet al.Heteroduplex mobility assay and phylogenetic analysis of V3 region sequences of HIV 1 isolates from Gulu–Northern Uganda. J Virol, 1995; 69:7971–7981.
9.
BuonaguroL, BuonaguroFM, RussoFet al.A novel gp120 sequence from an HIV-1 isolate of the A clade identified in North Uganda. AIDS Res Hum Retroviruses, 1998; 14:1287–1289.
10.
BuonaguroL, BuonaguroFM, TorneselloMLet al.High efficient production of Pr55gag virus-like particles expressing multiple HIV-1 epitopes, including a gp120 protein derived from an Ugandan HIV-1 isolate of subtype A. Antiviral Res, 2001; 49:35–47.
11.
BuonaguroL, RacioppiL, TorneselloMLet al.Induction of neutralizing antibodies and CTLs in Balb/c mice immunized with virus-like particles presenting a gp120 molecule from a HIV-1 isolate of clade A (HIV-VLPAs)Antiviral Res, 2002; 54:189–201.
12.
BuonaguroL, ViscianoML, TorneselloMLet al.Induction of systemic and mucosal cross-clade neutralizing antibodies in BALB/c mice immunized with human immunodeficiency virus type 1 clade A virus-like particles administered by different routes of inoculation. J Virol, 2005; 79:7059–7067.
13.
BuonaguroL, DevitoC, TorneselloMLet al.DNA-VLP prime-boost intra-nasal immunization induces cellular and humoral anti-HIV-1 systemic and mucosal immunity with cross-clade neutralizing activity. Vaccine, 2007; 25,32:5968–5977.
14.
BuonaguroL, TorneselloML, TagliamonteMet al.Baculovirus-derived human immunodeficiency virus type 1 virus-like particles activate dendritic cells and induce ex vivo T-cell responses. J Virol, 2006; 80:9134–9143.
BuonaguroL, MonacoA, AricoEet al.Gene expression profile of peripheral blood mononuclear cells in response to HIV-VLPs stimulation. BMC Bionform, 2008; 9,Suppl. 2:S5.
17.
BuonaguroL, TorneselloML, GalloRCet al.Th2 Polarization in peripheral blood mononuclear cells from human immunodeficiency virus (HIV)-infected subjects, as activated by HIV virus-like particles. J Virol, 2009; 83,1:304–313.
18.
MooreKW, de WaalMR, CoffmanRL, O'GarraA. Interleukin-10 and the interleukin-10 receptor. Annu Rev Immunol, 2001; 19:683–765.
19.
FiorentinoDF, BondMW, MosmannTR. Two types of mouse T helper cell. IV. Th2 clones secrete a factor that inhibits cytokine production by Th1 clones. J Exp Med, 1989; 170,6:2081–2095.
20.
DemangelC, BertolinoP, BrittonWJ. Autocrine IL-10 impairs dendritic cell (DC)-derived immune responses to mycobacterial infection by suppressing DC trafficking to draining lymph nodes and local IL-12 production. Eur J Immunol, 2002; 32,4:994–1002.
21.
SchandeneL, Onso-VegaC, WillemsFet al.B7/CD28-dependent IL-5 production by human resting T cells is inhibited by IL-10. J Immunol, 1994; 152,9:4368–4374.
22.
JossA, AkdisM, FaithA, BlaserK, AkdisCA. IL-10 directly acts on T cells by specifically altering the CD28 co-stimulation pathway. Eur J Immunol, 2000; 30,6:1683–1690.
JangS, UematsuS, AkiraS, SalgameP. IL-6 and IL-10 induction from dendritic cells in response to Mycobacterium tuberculosis is predominantly dependent on TLR2-mediated recognition. J Immunol, 2004; 173,5:3392–3397.
25.
CouperKN, BlountDG, RileyEM. IL-10: the master regulator of immunity to infection. J Immunol, 2008; 180,9:5771–5777.
26.
den HaanJM, KraalG, BevanMJ. Cutting edge: Lipopolysaccharide induces IL-10-producing regulatory CD4+ T cells that suppress the CD8+ T cell response. J Immunol, 2007; 178,9:5429–5433.
27.
GarconN, ChomezP, VanMM. GlaxoSmithKline Adjuvant Systems in vaccines: Concepts, achievements and perspectives. Expert Rev Vaccines, 2007; 6,5:723–739.
28.
DalyLM, JohnsonPA, DonnellyGet al.Innate IL-10 promotes the induction of Th2 responses with plasmid DNA expressing HIV gp120. Vaccine, 2005; 23,7:963–974.
