Suppression of HIV-specific T cell activity by lymph node CD25(+) regulatory T cells from HIV-infected individuals

Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, 9000 Rockville Pike, Bethesda, MD 20892, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 03/2007; 104(9):3390-5. DOI: 10.1073/pnas.0611423104
Source: PubMed


CD25(+) CD4(+) FoxP3(+) regulatory T (Treg) cells isolated from the peripheral blood of asymptomatic HIV-infected individuals have been demonstrated to significantly suppress HIV-specific immune responses in vitro. CD25(+) Treg cell suppressor activity in the peripheral blood seems to diminish with progression of HIV disease, and it has been suggested that loss of Treg cells contributes to aberrant immune activation and disease progression. However, phenotypic studies suggest that Treg cells may migrate to, and be maintained or even expanded in, tissue sites of HIV replication. Currently, it is not known whether tissue-associated Treg cells maintain suppressive activity in the context of HIV infection, particularly in individuals with advanced disease. The present study demonstrates that CD25(+) Treg cells isolated from lymph nodes and peripheral blood of HIV(+) subjects, even those with high viral loads and/or low CD4(+) T cell counts, maintain potent suppressive activity against HIV-specific cytolytic T cell function. This activity was better in lymph node as compared with peripheral blood, particularly in patients with high levels of plasma viremia. In addition, the expression of certain CD25(+) Treg-associated markers on CD4(+) T cells isolated from lymph nodes differed significantly from those on CD4(+) T cell subsets isolated from the peripheral blood. These data suggest that CD25(+) Treg cell-mediated suppression of HIV-specific responses continues throughout the course of HIV disease and, because of their particularly potent suppression of HIV-specific CTL activity in lymphoid tissue, may considerably impact the ability to control HIV replication in vivo.


Available from: Gregg Roby
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    • "In this context, Treg activity could have a beneficial effect through suppression of generalized chronic immune activation, but also through inhibition of activated CD4+ T cells and subsequent control of viral replication, as demonstrated by Moreno-Fernandez et al. [8]. In contrast, Tregs may play a detrimental role through inhibition of anti-HIV-1 immune responses [9], [10], [11], [12], thus promoting HIV-1 persistence at the host's expense. HIV-1 infection appears to directly and indirectly modulate Tregs in vivo, as suggested by data demonstrating that individuals with chronic HIV-1 infection have higher Treg frequencies than individuals who control HIV-1 infection and healthy control subjects [13], [14]. "
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    ABSTRACT: While modulation of regulatory T cell (Treg) function and adoptive Treg transfer are being explored as therapeutic modalities in the context of autoimmune diseases, transplantation and cancer, their role in HIV-1 pathogenesis remains less well defined. Controversy persists regarding their beneficial or detrimental effects in HIV-1 disease, which warrants further detailed exploration. Our objectives were to investigate if functional CD4(+) Tregs can be isolated and expanded from HIV-1-infected individuals for experimental or potential future therapeutic use and to determine phenotype and suppressive capacity of expanded Tregs from HIV-1 positive blood and tissue. Tregs and conventional T cell controls were isolated from blood and gut-associated lymphoid tissue of individuals with HIV-1 infection and healthy donors using flow-based cell-sorting. The phenotype of expanded Tregs was assessed by flow-cytometry and quantitative PCR. T-cell receptor ß-chain (TCR-β) repertoire diversity was investigated by deep sequencing. Flow-based T-cell proliferation and chromium release cytotoxicity assays were used to determine Treg suppressive function. Tregs from HIV-1 positive individuals, including infants, were successfully expanded from PBMC and GALT. Expanded Tregs expressed high levels of FOXP3, CTLA4, CD39 and HELIOS and exhibited a highly demethylated TSDR (Treg-specific demethylated region), characteristic of Treg lineage. The TCRß repertoire was maintained following Treg expansion and expanded Tregs remained highly suppressive in vitro. Our data demonstrate that Tregs can be expanded from blood and tissue compartments of HIV-1+ donors with preservation of Treg phenotype, function and TCR repertoire. These results are highly relevant for the investigation of potential future therapeutic use, as currently investigated for other disease states and hold great promise for detailed studies on the role of Tregs in HIV-1 infection.
    PLoS ONE 02/2014; 9(2):e86920. DOI:10.1371/journal.pone.0086920 · 3.23 Impact Factor
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    • "The role of this cell population during HIV infection is controversial. It has been proposed that excessive immune suppression by Treg cells might be responsible for the faster progression on HIV pathogenesis (Kinter et al., 2007). On the other hand, Treg cells might protect individuals from the deleterious effects of chronic immune activation that is typically observed in HIV infection (Belkaid and Rouse, 2005; Fazekas de St Groth and Landay, 2008). "
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    ABSTRACT: The natural course of human immunodeficiency virus (HIV) infection is characterized by high viral load, depletion of immune cells, and immunodeficiency, ultimately leading to acquired immunodeficiency syndrome phase and the occurrence of opportunistic infections and diseases. Since the discovery of HIV in the early 1980s a naturally selected population of infected individuals has been emerged in the last years, characterized by being infected for many years, with viremia constantly below detectable level and poor depletion of immune cells. These individuals are classified as "elite controllers (EC) or suppressors" and do not develop disease in the absence of anti-retroviral therapy. Unveiling host factors and immune responses responsible for the elite status will likely provide clues for the design of therapeutic vaccines and functional cures. Scope of this review was to examine and discuss differences of the cell-mediated immune responses between HIV+ individuals with disease progression and EC.
    Frontiers in Immunology 04/2013; 4:86. DOI:10.3389/fimmu.2013.00086
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    • "For example , protectiv e immunity to TB depends on both CD4 + and CD8 + Tcells which rarely eradicate the infection but rather this process promotes granuloma formation (Rahman et al., 2009 ). Not only do the granulomas favor mycobacteri al survival and mutation strategies , but also lead to chronicity which buys the pathogen time (Iwashiro et al., 2001; Rushbroo k et al., 2005; Kinter et al., 2007; Rahman et al., 2009 ).This would explain the bacteria's ability to adapt thus become protected in the absence of timely treatment and the association of this phenomeno n with HIV/TB co-infection (García de Viedma et al., 2005; Cohen et al., 2012 ). Currently, reports of mixed M. tuberculosis infections are accumulating for various geographic settings. "
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    ABSTRACT: Abstract Multiple strain tuberculosis (TB) infections are now an acceptable facet of tuberculosis epidemiology. Identification of patients infected with more than one strain gives an insight in disease dynamics at individual and population level. This study therefore aimed at identifying multiple strain infections among TB infected patients. Furthermore, to determine factors associated with multiple strain infections in Mubende district of Uganda. A total of 72 M. tuberculosis isolates from patients at Mubende regional referral hospital were characterized using 15 loci MIRU-VNTR, Spoligotyping and deletion analysis. Genotypic and epidemiological data were analyzed using MIRU-VNTR plus, Bionumerics software version 6.1 and an exact logistic regression model respectively. Eight (11.1%) of the 72 patients had mixed TB infections. Five were exclusively pulmonary mixed infections while three had both pulmonary and extra-pulmonary infections (Compartmentalized TB infections). Unlike previous studies that have linked this phenomenon to Beijing strains, multiple strains in this study belonged to T2-Uganda, X2 and T1 lineages. Two of the pulmonary mixed infections were resistant to rifampicin or isoniazid. All except one were HIV positive, newly diagnosed cases and urban residents of Mubende district. The study revealed that one in nine urban dwelling, HIV/TB co- infected patient were infected with more than one M. tuberculosis strains. The molecular findings give indications of a vital component of the disease dynamics that is most likely under looked at clinical level
    Infection Genetics and Evolution 03/2013; DOI:10.1016/j.meegid.2013.03.039 · 3.02 Impact Factor
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