Differential effects of R5 and X4 human immunodeficiency virus type 1 infection on CD4+ cell proliferation and activation

Locher, Christopher P.; Witt, Stephanie A.; Kassel, Rachel; Dowell, Noah; Fujimura, Sue H.; Levy, Jay A.

doi:10.1099/vir.0.80674-0

Cited by 23 publications

(16 citation statements)

References 48 publications

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“…Second, we have found that in HIV + individuals the level of CCR5 expression is highly correlated with the degree of T cell activation (our unpublished data), which is consistent with the preferential expression of CCR5 in activated CD4 + T cells from these patients (88). Finally, the fact that HIV R5 but not X4 strains induce increased T cell activation favoring HIV survival and spread (89) further supports a role for CCR5-mediated T cell costimulation in HIV pathogenesis.…”

Section: Discussionmentioning

confidence: 92%

CCR5 Expression Levels Influence NFAT Translocation, IL-2 Production, and Subsequent Signaling Events during T Lymphocyte Activation

Camargo

Quinones

Mummidi

et al. 2009

The Journal of Immunology

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Ligands of CCR5, the major coreceptor of HIV-1, costimulate T lymphocyte activation. However, the full impact of CCR5 expression on T cell responses remains unknown. Here, we show that compared with CCR5 ؉/؉ , T cells from CCR5 ؊/؊ mice secrete lower amounts of IL-2, and a similar phenotype is observed in humans who lack CCR5 expression (CCR5-⌬32/⌬32 homozygotes) as well as after Ab-mediated blockade of CCR5 in human T cells genetically intact for CCR5 expression. Conversely, overexpression of CCR5 in human T cells results in enhanced IL-2 production. CCR5 surface levels correlate positively with IL-2 protein and mRNA abundance, suggesting that CCR5 affects IL-2 gene regulation. Signaling via CCR5 resulted in NFAT transactivation in T cells that was blocked by Abs against CCR5 agonists, suggesting a link between CCR5 and downstream pathways that influence IL-2 expression. Furthermore, murine T cells lacking CCR5 had reduced levels of intranuclear NFAT following activation. Accordingly, CCR5 expression also promoted IL-2-dependent events, including CD25 expression, STAT5 phosphorylation, and T cell proliferation. We therefore suggest that by influencing a NFAT-mediated pathway that regulates IL-2 production and IL-2-dependent events, CCR5 may play a critical role in T cell responses. In accord with our prior inferences from geneticepidemiologic studies, such CCR5-dependent responses might constitute a viral entry-independent mechanism by which CCR5 may influence HIV-AIDS pathogenesis.

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Section: Discussionmentioning

confidence: 92%

CCR5 Expression Levels Influence NFAT Translocation, IL-2 Production, and Subsequent Signaling Events during T Lymphocyte Activation

Camargo

Quinones

Mummidi

et al. 2009

The Journal of Immunology

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“…Experimental evidence suggest several possibilities to account for this observation: (i) chronic expansion of Treg in vivo results in low levels of CD25 expression, retaining their suppressive activity, as previously reported in a murine model [35]; this constant expansion (high Treg frequency) is observed also in GALT from HIV infected patients [5, 30]; (ii) it might reflect internalization of the CD25 molecule after IL-2 binding [36]; in fact, the expansion of CD4 + CD25 lo CD127 lo Foxp3 + Treg is one of the long-term effects of IL-2 therapy in HIV patients [37, 38]; (iii) in vitro assays have shown that HIV induces down regulation of the CD25 molecule in CD4 + infected cells [39]. In addition, HIV viral proteins are involved in this process, inhibiting IL-2R expression; HIV p29 protein induces a two fold increase in the intracellular cyclic adenosine 3’,5’-monophosphate (cAMP) in PBMC which is associated with the decrease of CD25 [40].…”

Section: Discussionmentioning

confidence: 99%

Chronically HIV-1 Infected Patients Exhibit Low Frequencies of CD25+ Regulatory T Cells

Rios

Velilla²,

Rugeles³

2012

TOVJ

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The characterization of regulatory T cells (Treg) during HIV infection has become of particular interest considering their potential role in the pathogenesis of the acquired immunodeficiency syndrome. Different reports on Tregs in HIV-infected patients vary greatly, depending on the state of disease progression, anatomical compartment, and the phenotypic markers used to define this cell subpopulation. To determine the frequency of Tregs we included paired samples from peripheral blood and rectal biopsies from controls and chronic HIV patients with or without detectable viral load. Tregs were determined by flow cytometry using three different protocols: CD4+Foxp3+; CD4+Foxp3+CD127Low/-, and CD4+CD25+CD127Low/-. In addition, and with the purpose to compare the different protocols we also characterized Tregs in peripheral blood of HIV negative individuals with influenza like symptoms. Here, we report that Treg characterization in HIV-infected patients as CD4+Foxp3+ and CD4+Foxp3+CD127Low/- cells was similar, indicating that both protocols represent a suitable method to determine the frequency of Tregs in peripheral blood mononuclear cells (PBMC) and gut associated lymphoid tissue (GALT). In contrast, in HIV but not in flu-like patients, detection of Tregs as CD4+CD25+CD127Low/- cells resulted in a significantly lower percentage of these cells. In both, HIV patients and controls the frequency of Treg was significantly higher in GALT compared to PBMC. The frequency of Tregs in PBMC and GALT using CD4+Foxp3+ and CD4+Foxp3+CD127Low/- was higher in HIV patients than in controls. Similarly, the frequency of Treg using any protocol was higher in flu-like patients compared to controls. The results suggest that relying on the expression of CD25 could be unsuitable to characterize Tregs in PBMC and GALT samples from a chronic infection such as HIV.

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“…For example, the major HIV antigen gp120 [114] and mycobacterial compounds such as glycolipids of the cell wall, particularly LAMs, PIMs, and phenolic glycolipids [115], play a crucial role in modulating immune responses. It is also increasingly apparent that these compounds may differ in biologic activity depending on strain lineages of the two pathogens [53], [115], [116].…”

Section: Summary and Perspectivesmentioning

confidence: 99%

Tuberculosis and HIV Co-Infection

et al. 2012

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Tuberculosis (TB) and HIV co-infections place an immense burden on health care systems and pose particular diagnostic and therapeutic challenges. Infection with HIV is the most powerful known risk factor predisposing for Mycobacterium tuberculosis infection and progression to active disease, which increases the risk of latent TB reactivation 20-fold. TB is also the most common cause of AIDS-related death. Thus, M. tuberculosis and HIV act in synergy, accelerating the decline of immunological functions and leading to subsequent death if untreated. The mechanisms behind the breakdown of the immune defense of the co-infected individual are not well known. The aim of this review is to highlight immunological events that may accelerate the development of one of the two diseases in the presence of the co-infecting organism. We also review possible animal models for studies of the interaction of the two pathogens, and describe gaps in knowledge and needs for future studies to develop preventive measures against the two diseases.

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Differential effects of R5 and X4 human immunodeficiency virus type 1 infection on CD4+ cell proliferation and activation

Cited by 23 publications

References 48 publications

CCR5 Expression Levels Influence NFAT Translocation, IL-2 Production, and Subsequent Signaling Events during T Lymphocyte Activation

CCR5 Expression Levels Influence NFAT Translocation, IL-2 Production, and Subsequent Signaling Events during T Lymphocyte Activation

Chronically HIV-1 Infected Patients Exhibit Low Frequencies of CD25+ Regulatory T Cells

Tuberculosis and HIV Co-Infection

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