Immunogenic and tolerogenic signatures in human immunodeficiency virus (HIV)-infected controllers compared with progressors and a conversion strategy of virus control - PubMed (original) (raw)

Immunogenic and tolerogenic signatures in human immunodeficiency virus (HIV)-infected controllers compared with progressors and a conversion strategy of virus control

T Whittall et al. Clin Exp Immunol. 2011 Nov.

Abstract

Epidemiological studies have identified a small cohort of controllers of human immunodeficiency virus (HIV)-1 infection, who without treatment have no detectable virus, and others who progress at a variable rate. The objective of this study was to distinguish immune signatures in HIV controllers and progressors, by evaluating tolerogenic and immunogenic factors in untreated HIV-1 infected individuals. The recruited population was divided into putative elite controllers (PEC), long-term non-progressors (LTNP), normal progressors (NP) and fast progressors (FP). The proportion of regulatory T cells [T(regs) , CD4+ CD25+ forkhead box P3 (FoxP3+)], programmed death (PD)-1 and cytotoxic T lymphocyte antigen (CTLA)-inhibitory molecules and CD40L, CD69 and Ki67 activation markers were evaluated in peripheral blood mononuclear cells (PBMC) by flow cytometry. Significant differences were found between HIV controllers and HIV progressors, with up-regulation of T(regs) , PD-1 and CTLA-4 and decrease of CD40L expression in progressors compared with controllers. Expression of CD40L and concentrations of interleukin (IL)-6, CCL-3, and CCL-4 were significantly higher in PEC and LTNP than in NP and FP. In an attempt to convert immune signatures of progressors to those of controllers, seven agents were used to stimulate PBMC from the four cohorts. Treatment with CD40L and IL-4 or PD-1 antibodies in vitro were most effective in converting the immune signatures of progressors to those observed in controllers by down-regulating T(regs) and up-regulating CD40L expression in CD4+ T cells. The conversion concept merits translation to in vivo immune control of HIV infection.

© 2011 The Authors. Clinical and Experimental Immunology © 2011 British Society for Immunology.

PubMed Disclaimer

Figures

Fig. 1

Fig. 1

Analysis of CD25+forkhead box P3 (FoxP3)+, programmed death (PD)-1 and cytotoxic T lymphocyte antigen (CTLA)-4 CD4+ T cells. The proportion of CD4 T cells expressing these molecules in putative elite controllers (PEC) (n = 6), long-term non-progressors (LTNP) (n = 18), normal progressors (NP) (n = 9) and fast progressors (FP) (n = 8), except for CTLA-4 (n = 5, 17, 7 and 8, respectively) of untreated individuals. Analysis of variance (

anova

), followed by the _t_-test for two means, was used for comparative analyses; *P < 0·05; **P < 0·01; ***P < 0·001.

Fig. 2

Fig. 2

Correlation between CD25+forkhead box P3 (FoxP3)+ T regulatory cells and programmed death (PD)-1 or CD40L expression in CD4+ T cells (a,c) in putative elite controllers (PEC) and long-term non-progressors (LTNP) (b,d) in normal progressors (NP) and fast progressors (FP), respectively. ▴ P elite controllers (n = 6), o LTNP (n = 18), ▵ normal progressors (n = 8) and • fast progressors (n = 9).

Fig. 3

Fig. 3

Conversion of CD25+forkhead box P3 (FoxP3)+CD4+ T regulatory cells. Changes in (a) fast progressors (FP) (n = 6–9), (b) normal progressors (NP) (n = 3), (c) long-term non-progressors (LTNP) (n = 6) and (d) selected putative elite controllers (PEC) (n = 5), all after treatment with seven potential converting agents. Corresponding flow cytometry illustrations are presented for CD40L+interleukin (IL)-4 and programmed death (PD)-1 antibodies; the bold line shows conversion of FoxP3+CD4+ T cells. (e) Gating of viable CD4 T cells and representative CD25 versus FoxP3 expression. *P < 0·05; **P < 0·01; ***P < 0·001.

Fig. 4

Fig. 4

Expression and up-regulation of CD40L. (a) Activation molecule CD40L expressed by CD4+ T cells in the four cohorts, and (b) up-regulation of CD40L on CD4+ T cells of peripheral blood mononuclear cells (PBMC) from fast progressors (FP) stimulated with five potential converting agents demonstrated by immunofluorescence using anti-CD40L-antibodies. All data are expressed as mean [± standard error of the mean (s.e.m.)]; *P = 0·05; **P = 0·02; ***P ≤ 0·01.

References

    1. Kornfeld C, Ploquin MJ, Pandrea I, et al. Antiinflammatory profiles during primary SIV infection in African green monkeys are associated with protection against AIDS. J Clin Invest. 2005;115:1082–91. - PMC - PubMed
    1. Sharp PM, Shaw GM, Hahn BH. Immunodeficiency virus infection of chimpanzee. J Virol. 2005;79:3891–902. - PMC - PubMed
    1. Madec Y, Boufassa F, Porter K, Meyer L. Spontaneous control of viral load and CD4 cell count progression among HIV-1 seroconverters. AIDS. 2005;19:2001–7. - PubMed
    1. Lambotte O, Boufassa F, Madec Y, Venet A, Delfraissy JF. HIV controllers: a homogeneous group of HIV-1 infected patients with spontaneous control of viral replication. Clin Invest Dis. 2005;41:1053–6. - PubMed
    1. Cao Y, Qin L, Zhang L, Safrit J, Ho DD. Virologic and immunologic characterization of long-term survivors of human immunodeficiency virus type 1 infection. N Engl J Med. 1995;332:201–8. - PubMed

Publication types

MeSH terms

Substances

LinkOut - more resources