Inflammatory Cytokines Drive CD4+ T-Cell Cycling and Impaired Responsiveness to Interleukin 7: Implications for Immune Failure in HIV Disease

Shive, Carey L.; Mudd, Joseph C.; Funderburg, Nicholas T.; Sieg, Scott F.; Kyi, Benjamin; Bazdar, Doug A.; Mangioni, Davide; Gori, Andrea; Jacobson, Jeffrey M.; Brooks, Ari D.; Hardacre, Jeffrey M.; Ammori, John B.; Estes, Jacob D.; Schacker, Timothy W.; Rodrı́guez, Benigno; Lederman, Michael M.

doi:10.1093/infdis/jiu125

Cited by 78 publications

(91 citation statements)

References 50 publications

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“…In earlier work, we showed that a variety of microbial TLR agonists, including bacterial LPS and single-stranded RNAs that, like HIV, can bind and signal through TLR7 and TLR8, could indirectly activate memory CD4 ϩ T cells to enter the cell cycle (20). In more recent work, we found that the inflammatory cytokines IL-6 and IL-1␤, which are inducible by these microbial products, can also drive the cycling of CD4 ϩ T cells in vitro and can block IL-7 responsiveness (34). The significance of the negative correlation between memory CD4 ϩ T cell cycling and plasma LPS levels in healthy controls is less clear.…”

Section: Discussionmentioning

confidence: 95%

Cycling Memory CD4⁺T Cells in HIV Disease Have a Diverse T Cell Receptor Repertoire and a Phenotype Consistent with Bystander Activation

Jiang

Younes

Funderburg

et al. 2014

J Virol

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The mechanisms of increased memory CD4؉ T cell cycling in HIV disease are incompletely understood but have been linked to antigen stimulation, homeostatic signals, or exposure to microbial products and the inflammatory cytokines that they induce. We examined the phenotype and V␤ family distribution in cycling memory CD4 ؉ T cells among 52 healthy and 59 HIV-positive (HIV ؉ ) donors. Cycling memory CD4 ؉ T cells were proportionally more frequent in subjects with HIV infection than in controls, more often expressed CD38 and PD-1, and less frequently expressed OX40 and intracellular CD40L. OX40 expression on memory CD4؉ T cells was induced in vitro by anti-CD3, interleukin-2 (IL-2), IL-7, or IL-15 but not by Toll-like receptor ligands. In HIV ؉ donors, memory CD4 ؉ T cell cycling was directly related to plasma lipopolysaccharide (LPS) levels, to plasma HIV RNA levels, and to memory CD8 ؉ T cell cycling and was inversely related to peripheral blood CD4 ؉ T cell counts but not to the levels of IL-2, IL-7, or IL-15, while in HIV-negative donors, memory CD4 ؉ T cell cycling was related to IL-7 levels and negatively related to the plasma levels of LPS. In both controls and HIV ؉ donors, cycling memory CD4 ؉ T cells had a broad distribution of V␤ families comparable to that of noncycling cells. Increased memory CD4؉ T cell cycling in HIV disease is reflective of generalized immune activation and not driven primarily by cognate peptide stimulation or exposure to common gamma-chain cytokines. This cycling may be a consequence of exposure to microbial products, to plasma viremia, or, otherwise, to proinflammatory cytokines. IMPORTANCE This work provides evidence that the increased memory CD4؉ T cell cycling in HIV infection is not a result of cognate peptide recognition but, rather, is more likely related to the inflammatory environment of HIV infection.

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Section: Discussionmentioning

confidence: 95%

Cycling Memory CD4⁺T Cells in HIV Disease Have a Diverse T Cell Receptor Repertoire and a Phenotype Consistent with Bystander Activation

Jiang

Younes

Funderburg

et al. 2014

J Virol

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“…Therefore, we analyzed the levels of 16 inflammatory cytokines, chemokines, and markers of gut damage and microbial translocation at or before seroconversion to assess the effect of vRC on the early inflammatory milieu [n = 33; previously dichotomized into lowand high-vRC phenotypes (15)]. We found that vRC was positively correlated with a number of inflammatory cytokines (Table 2), most notably IL-6 and IL-1β, two proinflammatory cytokines previously implicated in driving aberrant CD4 + T-cell turnover and impairing homeostatic proliferation (21). Of note, vRC was also strongly correlated with elevated levels of IL-10, an important antiinflammatory cytokine linked to T-cell dysfunction in HIV infection (22,23).…”

Section: Viral Replicative Capacity Alters Early Inflammatory Cytokinmentioning

confidence: 87%

Replicative fitness of transmitted HIV-1 drives acute immune activation, proviral load in memory CD4 ⁺ T cells, and disease progression

Claiborne

Prince

Scully

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

111

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HIV-1 infection is characterized by varying degrees of chronic immune activation and disruption of T-cell homeostasis, which impact the rate of disease progression. A deeper understanding of the factors that influence HIV-1–induced immunopathology and subsequent CD4+ T-cell decline is critical to strategies aimed at controlling or eliminating the virus. In an analysis of 127 acutely infected Zambians, we demonstrate a dramatic and early impact of viral replicative capacity (vRC) on HIV-1 immunopathogenesis that is independent of viral load (VL). Individuals infected with high-RC viruses exhibit a distinct inflammatory cytokine profile as well as significantly elevated T-cell activation, proliferation, and CD8+ T-cell exhaustion, during the earliest months of infection. Moreover, the vRC of the transmitted virus is positively correlated with the magnitude of viral burden in naive and central memory CD4+ T-cell populations, raising the possibility that transmitted viral phenotypes may influence the size of the initial latent viral reservoir. Taken together, these findings support an unprecedented role for the replicative fitness of the founder virus, independent of host protective genes and VL, in influencing multiple facets of HIV-1–related immunopathology, and that a greater focus on this parameter could provide novel approaches to clinical interventions.

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“…Recently, we and others have reported increased levels of IL-1β in the lymphoid tissues of untreated and ART-treated HIV infected patients and have found that IL-1β can promote the expansion of memory CD4 and CD8 T cells in vitro without addition of exogenous antigen (70, 71). It is plausible that sustained expression of inflammatory cytokines such as IFN-a IL-1 β and IL-15 play a role in the profound and persistent memory CD8 T cell expansion that characterizes HIV infection.…”

Section: What Are the Determinants Of Cd8 T Cell Persistence In Treatmentioning

confidence: 94%

CD8 T cell persistence in treated HIV infection

Mudd

Lederman

2014

Current Opinion in HIV and AIDS

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Purpose of review Many treated HIV infected persons maintain persistently high circulating CD8 T cell numbers, even after many years of therapy. Recent reports suggest that persistent CD8 T cell expansion is associated with higher risk of morbid non-AIDS events. Thus, assessing the mechanisms of CD8 T cell expansion and persistence may give insights into a feature of HIV disease that is clinically important. Recent findings Acute HIV infection is associated with activation and expansion of the CD8 T cell compartment. Expanded CD8 T cells persist throughout disease course and, in contrast to the plasticity that typically characterizes immune responses to most other pathogens, circulating CD8 T cell numbers do not normalize in many patients despite pharmacological suppression of HIV replication. We suspect that residual inflammation in treated HIV infection contributes to antigen-independent CD8 T cell expansion and persistence as most of these cells are not HIV-reactive. Summary Circulating CD8 T cell numbers remain abnormally elevated in many treated HIV-infected patients and this elevation is associated with adverse clinical events. Future studies will need to assess the mechanisms of CD8 T cell expansion and to define the role of CD8 lymphocytosis in the clinical course of treated HIV disease.

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Inflammatory Cytokines Drive CD4+ T-Cell Cycling and Impaired Responsiveness to Interleukin 7: Implications for Immune Failure in HIV Disease

Abstract: Induction of CD4(+) T-cell turnover and diminished T-cell responsiveness to IL-7 by IL-1β and IL-6 exposure may contribute to the lack of CD4(+) T-cell reconstitution in treated HIV-infected subjects.

Cited by 78 publications

References 50 publications

Cycling Memory CD4⁺T Cells in HIV Disease Have a Diverse T Cell Receptor Repertoire and a Phenotype Consistent with Bystander Activation

Cycling Memory CD4⁺T Cells in HIV Disease Have a Diverse T Cell Receptor Repertoire and a Phenotype Consistent with Bystander Activation

Replicative fitness of transmitted HIV-1 drives acute immune activation, proviral load in memory CD4 ⁺ T cells, and disease progression

CD8 T cell persistence in treated HIV infection

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Inflammatory Cytokines Drive CD4+ T-Cell Cycling and Impaired Responsiveness to Interleukin 7: Implications for Immune Failure in HIV Disease

Abstract: Induction of CD4(+) T-cell turnover and diminished T-cell responsiveness to IL-7 by IL-1β and IL-6 exposure may contribute to the lack of CD4(+) T-cell reconstitution in treated HIV-infected subjects.

Cited by 78 publications

References 50 publications

Cycling Memory CD4+T Cells in HIV Disease Have a Diverse T Cell Receptor Repertoire and a Phenotype Consistent with Bystander Activation

Cycling Memory CD4+T Cells in HIV Disease Have a Diverse T Cell Receptor Repertoire and a Phenotype Consistent with Bystander Activation

Replicative fitness of transmitted HIV-1 drives acute immune activation, proviral load in memory CD4 + T cells, and disease progression

CD8 T cell persistence in treated HIV infection

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Cycling Memory CD4⁺T Cells in HIV Disease Have a Diverse T Cell Receptor Repertoire and a Phenotype Consistent with Bystander Activation

Cycling Memory CD4⁺T Cells in HIV Disease Have a Diverse T Cell Receptor Repertoire and a Phenotype Consistent with Bystander Activation

Replicative fitness of transmitted HIV-1 drives acute immune activation, proviral load in memory CD4 ⁺ T cells, and disease progression