Abnormal activation and cytokine spectra in lymph nodes of people chronically infected with HIV-1

Biancotto, Angélique; Grivel, Jean‐Charles; Iglehart, Sarah J.; Vanpouille, Christophe; Lisco, Andrea; Sieg, Scott F.; Debernardo, Robert; Garate, Kristen; Rodrı́guez, Benigno; Margolis, Leonid; Lederman, Michael M.

doi:10.1182/blood-2006-11-055764

Cited by 173 publications

(169 citation statements)

References 54 publications

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“…We observed that CD8 + T cells are more susceptible to cytokine stimulation, since CD8 + T cells, in contrast to CD4 + T cells, were strongly activated (assessed by coexpression of CD38 and HLA-DR and proliferation) by cytokines present during untreated HIV-1 infection, such as IL-15 and IL-12 (11). A different susceptibility toward cytokine activation was also apparent between different T cell subsets, with memory CD8 + T cells being activated more efficiently than naive CD8 + T cells by in vitro cytokine stimulation.…”

Section: Ontinuous Loss Of Cd4 + T Cells and Hyperactivation Of T Cmentioning

confidence: 82%

“…Although such cross-reactivity might contribute, it would not readily explain the observation that adenovirus-specific CD8 + T cell responses are similarly affected and that overall levels of CD8 + T cell activation and proliferation correlate with HIV-1 viral load (42,43 T cells much faster than that of CD4 + T cells. So far the relevance of TCR-independent T cell activation, involving cytokine stimulation or engagement of pattern recognition receptors, in chronic HIV-1 infection is not known, but it is possible that the inflammatory environment present during untreated HIV-1 infection has a significant effect on the induction of T cell hyperactivation and consequently contributes to disease progression (8,11,27 + T cells and not CD4 + T cells, both with respect to upregulation of the activation markers CD38 and HLA-DR, which are commonly used to characterize activated T cells in HIV-1-infected patients and with respect to proliferation. Notably, IL-15 activated memory CD8 + T cells more efficiently than naive CD8 + T cells, which is consistent with the notion that activated and memory CD8 + T cells show increased turnover rates in HIV-1-infected patients compared with naive CD8 + T cells (54).…”

Section: Discussionmentioning

confidence: 99%

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CD8+ T Cells Are Activated in an Antigen-Independent Manner in HIV-Infected Individuals

Bastidas

Graw

Smith

et al. 2014

The Journal of Immunology

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Hyperactivation of T cells, particularly of CD8+ T cells, is a hallmark of chronic HIV 1 (HIV-1) infection. Little is known about the antigenic specificities and the mechanisms by which HIV-1 causes activation of CD8+ T cells during chronic infection. We report that CD8+ T cells were activated during in vivo HIV-1 replication irrespective of their Ag specificity. Cytokines present during untreated HIV-1 infection, most prominently IL-15, triggered proliferation and expression of activation markers in CD8+ T cells, but not CD4+ T cells, in the absence of TCR stimulation. Moreover, LPS or HIV-1–activated dendritic cells (DCs) stimulated CD8+ T cells in an IL-15–dependent but Ag-independent manner, and IL-15 expression was highly increased in DCs isolated from viremic HIV-1 patients, suggesting that CD8+ T cells are activated by inflammatory cytokines in untreated HIV-1 patients independent of Ag specificity. This finding contrasts with CD4+ T cells whose in vivo activation seems biased toward specificities for persistent Ags. These observations explain the higher abundance of activated CD8+ T cells compared with CD4+ T cells in untreated HIV-1 infection.

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Section: Ontinuous Loss Of Cd4 + T Cells and Hyperactivation Of T Cmentioning

confidence: 82%

Section: Discussionmentioning

confidence: 99%

CD8+ T Cells Are Activated in an Antigen-Independent Manner in HIV-Infected Individuals

Bastidas

Graw

Smith

et al. 2014

The Journal of Immunology

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“…However, the possibility that different cell types account for the observed differences in transporter expression cannot be completely excluded. Evidence exists that HIV infection leads to a hyperplasia of the lymphoid tissue and a perturbation of cytokine expression, redistribution, and sequestration of lymphocyte subpopulations in the LNs (Orenstein et al, 1999;Biancotto et al, 2007). Nevertheless, the higher mRNA levels of the OCTs in the LNs of HIV-infected persons indicate a strongly increased potential for the accumulation of OCT substrates in the LNs.…”

Section: Discussionmentioning

confidence: 95%

Relevance of the Organic Cation Transporters 1 and 2 for Antiretroviral Drug Therapy in Human Immunodeficiency Virus Infection

Jung

Lehmann²,

Rubbert³

et al. 2008

Drug Metab Dispos

131

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ABSTRACT:Carrier-mediated transport across cell membranes is an important determinant of activity, resistance, and toxicity of chemotherapeutic agents including antiretroviral (ARV) drugs (ARDs). The organic cation transporters (OCTs) 1 and 2 have been implicated in the translocation of different cationic drugs but so far were insufficiently tested for interactions with ARDs. Here, we assessed among cationic drugs commonly used in human immunodeficiency virus (HIV) therapy inhibitors and substrates of OCTs, and analyzed the tissue distribution of OCTs and their expression in lymph nodes (LNs), the primary intracellular target of HIV and ARDs. Inhibitors were identified by measuring the attenuated uptake of the radiolabeled model substrate 1-methyl-4-phenylpyridinium into OCTtransfected human embryonic kidney-293 cells in the presence of ARDs. Substrates were identified by measuring OCT-specific intracellular accumulation using liquid chromatography/tandem mass spectrometry. Inhibitory drugs were (in order of increasing potency): nelfinavir < ritonavir < saquinavir < indinavir < trimethoprim < pentamidine, with consistently lower IC 50 values determined for OCT1. Substrates with highest transport efficacy (V max /K m ) were lamivudine (OCT1, 8 l/mg protein/min; OCT2, 4.4 l/mg protein/min) and zalcitabine (OCT1, 4.1 l/mg protein/min; OCT2, 2.6 l/mg protein/min). Using quantitative real-time polymerase chain reaction, a marked expression level of OCT1 was detected in human samples of liver, ovary, prostate, and testis, and of OCT2 in kidney, colon, heart, skeletal muscle, and testis. Expression of OCTs in LNs was low in HIV-negative control individuals but dramatically increased in HIV-infected persons. These data suggest that drug interactions about the OCTs may be relevant for the ARV therapy, in particular by influencing drug accession to infected tissues and hepatic or renal elimination.

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“…Significant depletion and functional impairment of both NK and DC compartments have been documented in HIV infection (17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27) but the mechanisms underlying innate immune dysfunction remain to be elucidated. A loss in circulating CD123…”

Section: H Uman Immunodeficiency Virus Infection Is Associatedmentioning

confidence: 99%

Baseline Viral Load and Immune Activation Determine the Extent of Reconstitution of Innate Immune Effectors in HIV-1-Infected Subjects Undergoing Antiretroviral Treatment

Chehimi

Azzoni

Farabaugh

et al. 2007

The Journal of Immunology

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We analyzed dendritic cell (DC) and NK cell compartments in relation to CD4 recovery in 21 HIV-infected subjects followed to <50 copies/ml once starting antiretroviral therapy (ART) and observed for 52 wk of sustained suppression. Although CD4 counts increased in all subjects in response to ART, we observed a restoration of functional plasmacytoid DC (PDC) after 52 wk of sustained suppression under ART (from 1850 cells/ml to 4550 cells/ml) to levels comparable to controls (5120 cells/ml) only in subjects with a low baseline viral load, which also rapidly suppressed to <50 copies/ml upon ≤60 days from ART initiation. Recovery of PDC at week 52 correlates with level of CD95 expression on CD8 T cells and PDC frequency following first ART suppression. NK cytotoxic activity increased rapidly upon viral suppression (VS) and correlated with PDC function at week 52. However, restoration of total NK cells was incomplete even after 52 wk on ART (73 cells/μl vs 122 cells/μl in controls). Direct reconstitution experiments indicate that NK cytotoxic activity against virally infected target cells requires DC/NK cooperation, and can be recovered upon sustained VS and recovery of functional PDC (but not myeloid DC) from ART-suppressed subjects. Our data indicate that viremic HIV-infected subjects may have different levels of reconstitution of DC and NK-mediated function following ART, with subjects with lower initial viremia and the greatest reduction of baseline immune activation at VS achieving the greatest level of innate effector cell reconstitution.

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Abnormal activation and cytokine spectra in lymph nodes of people chronically infected with HIV-1

Cited by 173 publications

References 54 publications

CD8+ T Cells Are Activated in an Antigen-Independent Manner in HIV-Infected Individuals

CD8+ T Cells Are Activated in an Antigen-Independent Manner in HIV-Infected Individuals

Relevance of the Organic Cation Transporters 1 and 2 for Antiretroviral Drug Therapy in Human Immunodeficiency Virus Infection

Baseline Viral Load and Immune Activation Determine the Extent of Reconstitution of Innate Immune Effectors in HIV-1-Infected Subjects Undergoing Antiretroviral Treatment

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