Normal T-cell activation in elite controllers with preserved CD4+ T-cell counts

Bansal, Anju; Erdmann, Nathan; Westfall, Andrew O.; Dionne-Odom, Jodie; Overton, Edgar Turner; Goepfert, Paul

doi:10.1097/qad.0000000000000860

Cited by 26 publications

(28 citation statements)

References 56 publications

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“…There is a strong association between PD-1 and the immune activation marker Ki67 in CD4 + T cells from cART-treated individuals ( 29 , 42 ). Consistent with these data, reduced PD-1 expression correlates with lower immune activation in HIV-elite controllers, the HIV + infected individuals with immune control of viral loads ( 46 , 47 ). Transcriptomic analyses of PD-1 + cells isolated from blood also suggest a significant increase in IFN-γ response genes and IL-6 response genes in INR with higher immune activation, compared to IR with lower immune activation (Figure 1 ).…”

Section: Immune Activation Correlates To Increased Hiv Reservoir Sizesupporting

confidence: 75%

“…While it is unclear, how increased proliferation and HIV reservoir size are linked, these data suggest that increased T-cell proliferation might also provide a mechanism for the maintenance of the HIV reservoir. Increased cycling and higher Ki67 protein expression further correlate with higher expression of PD-1, a marker that can be up-regulated as a result of homeostatic or antigen-induced proliferation, and T-cell exhaustion ( 43 – 46 ). There is a strong association between PD-1 and the immune activation marker Ki67 in CD4 + T cells from cART-treated individuals ( 29 , 42 ).…”

Section: Immune Activation Correlates To Increased Hiv Reservoir Sizementioning

confidence: 96%

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Mucosal Regulatory T Cells and T Helper 17 Cells in HIV-Associated Immune Activation

et al. 2016

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Residual mucosal inflammation along with chronic systemic immune activation is an important feature in individuals infected with human immunodeficiency virus (HIV), and has been linked to a wide range of co-morbidities, including malignancy, opportunistic infections, immunopathology, and cardiovascular complications. Although combined antiretroviral therapy (cART) can reduce plasma viral loads to undetectable levels, reservoirs of virus persist, and increased mortality is associated with immune dysbiosis in mucosal lymphoid tissues. Immune-based therapies are pursued with the goal of improving CD4+ T-cell restoration, as well as reducing chronic immune activation in cART-treated patients. However, the majority of research on immune activation has been derived from analysis of circulating T cells. How immune cell alterations in mucosal tissues contribute to HIV immune dysregulation and the associated risk of non-infectious chronic complications is less studied. Given the significant differences between mucosal T cells and circulating T cells, and the immediate interactions of mucosal T cells with the microbiome, more attention should be devoted to mucosal immune cells and their contribution to systemic immune activation in HIV-infected individuals. Here, we will focus on mucosal immune cells with a specific emphasis on CD4+ T lymphocytes, such as T helper 17 cells and CD4+Foxp3+ regulatory T cells (Tregs), which play crucial roles in maintaining mucosal barrier integrity and preventing inflammation, respectively. We hypothesize that pro-inflammatory milieu in cART-treated patients with immune activation significantly contributes to enhanced loss of Th17 cells and increased frequency of dysregulated Tregs in the mucosa, which in turn may exacerbate immune dysfunction in HIV-infected patients. We also present initial evidence to support this hypothesis. A better comprehension of how pro-inflammatory milieu impacts these two types of cells in the mucosa will shed light on mucosal immune dysfunction and HIV reservoirs, and lead to novel ways to restore immune functions in HIV+ patients.

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Section: Immune Activation Correlates To Increased Hiv Reservoir Sizesupporting

confidence: 75%

Section: Immune Activation Correlates To Increased Hiv Reservoir Sizementioning

confidence: 96%

Mucosal Regulatory T Cells and T Helper 17 Cells in HIV-Associated Immune Activation

et al. 2016

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“…The factors involved in the immunological progression observed in some ECs that maintain virological control are largely unknown and studies addressing this issue are scarce, with only a few investigating potential associated immunological factors [ 10 , 15 , 36 , 37 ]. In some of these studies, T-cell activation was shown to be associated with disease progression in ECs using a cross-sectional design [ 15 , 36 ]. The other two studies addressing the association of T-cell activation with CD4 evolution in EC patients and using a longitudinal follow-up period similar to our study [ 10 , 37 ] found discordant results.…”

Section: Discussionmentioning

confidence: 99%

Class-modeling analysis reveals T-cell homeostasis disturbances involved in loss of immune control in elite controllers

Benito

Ortiz

León

et al. 2018

BMC Med

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BackgroundDespite long-lasting HIV replication control, a significant proportion of elite controller (EC) patients may experience CD4 T-cell loss. Discovering perturbations in immunological parameters could help our understanding of the mechanisms that may be operating in those patients experiencing loss of immunological control.MethodsA case–control study was performed to evaluate if alterations in different T-cell homeostatic parameters can predict CD4 T-cell loss in ECs by comparing data from EC patients showing significant CD4 decline (cases) and EC patients showing stable CD4 counts (controls). The partial least-squares–class modeling (PLS-CM) statistical methodology was employed to discriminate between the two groups of patients, and as a predictive model.ResultsHerein, we show that among T-cell homeostatic alterations, lower levels of naïve and recent thymic emigrant subsets of CD8 cells and higher levels of effector and senescent subsets of CD8 cells as well as higher levels of exhaustion of CD4 cells, measured prior to CD4 T-cell loss, predict the loss of immunological control.ConclusionsThese data indicate that the parameters of T-cell homeostasis may identify those EC patients with a higher proclivity to CD4 T-cell loss. Our results may open new avenues for understanding the mechanisms underlying immunological progression despite HIV replication control, and eventually, for finding a functional cure through immune-based clinical trials.Electronic supplementary materialThe online version of this article (10.1186/s12916-018-1026-6) contains supplementary material, which is available to authorized users.

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“…Consistent with this evidence, some studies suggest that the cART might lead to a marked decrease in immune activation and increased CD4 + T cell counts in ECs, reducing the risk of non-AIDS-related events ( 6 – 8 ). Conversely, other studies describe that elevated levels of T cell activation and soluble inflammation markers are not associated with a faster rate of CD4 + T cell decline in ECs ( 9 , 10 ) or that ECs maintain absolute CD4 + T cell counts and T cell activation levels within the normal range over time ( 10 – 12 ), thus concluding that these individuals may not have benefited from early cART initiation.…”

Section: Introductionmentioning

confidence: 96%

Plasmatic Levels of IL-18, IP-10, and Activated CD8+ T Cells Are Potential Biomarkers to Identify HIV-1 Elite Controllers With a True Functional Cure Profile

et al. 2018

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Elite controllers (ECs) are rare individuals able to naturally control HIV-1 replication below the detection limit of viral load (VL) commercial assays. It is unclear, however, whether ECs might be considered a natural model of a functional cure because some studies have noted CD4+ T cell depletion and disease progression associated with abnormally high levels of immune activation and/or inflammation in this group. Here, we propose the use of immunological parameters to identify HIV-1 ECs that could represent the best model of a functional cure. We compared plasma levels of six inflammatory biomarkers (IP-10, IL-18, sCD163, sCD14, CRP, and IL-6) and percentages of activated CD8+ T cells (CD38+HLA-DR+) between 15 ECs [8 with persistent undetectable viremia (persistent elite controllers) and 7 with occasional viral blips (ebbing elite controllers)], 13 viremic controllers (VCs—plasma VL between 51 and 2,000 RNA copies/mL), and 18 HIV-1 infected patients in combined antiretroviral therapy, with suppressed viremia, and 18 HIV-uninfected controls (HIV-neg). The two groups of ECs presented inflammation and activation profiles similar to HIV-neg individuals, and there was no evidence of CD4+ T cell decline over time. VCs, by contrast, had higher levels of IL-18, IP-10, and CRP and a lower CD4/CD8 ratio than that of HIV-neg (P < 0.05). Plasma levels of IL-18 and IP-10 correlated positively with CD8+ T cell activation and negatively with both CD4/CD8 and CD4% in HIV-1 controllers. These results suggest that most ECs, defined using stringent criteria in relation to the cutoff level of viremia (≤50 copies/mL) and a minimum follow-up time of >5 years, show no evidence of persistent inflammation or immune activation. This study further suggests that plasmatic levels of IL-18/IP-10 combined with the frequency of CD8+CD38+HLA-DR+ T cells can be important biomarkers to identify models of a functional cure among HIV-1 ECs.

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Normal T-cell activation in elite controllers with preserved CD4+ T-cell counts

Cited by 26 publications

References 56 publications

Mucosal Regulatory T Cells and T Helper 17 Cells in HIV-Associated Immune Activation

Mucosal Regulatory T Cells and T Helper 17 Cells in HIV-Associated Immune Activation

Class-modeling analysis reveals T-cell homeostasis disturbances involved in loss of immune control in elite controllers

Plasmatic Levels of IL-18, IP-10, and Activated CD8+ T Cells Are Potential Biomarkers to Identify HIV-1 Elite Controllers With a True Functional Cure Profile

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