HIV-Related Metabolic Comorbidities in the Current ART Era

Warriner, Amy H.; Burkholder, Greer A.; Overton, Edgar Turner

doi:10.1016/j.idc.2014.05.003

Cited by 47 publications

(37 citation statements)

References 178 publications

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“…Treg depletion may also be a strategy to boost the efficacy of potential HIV vaccine candidates. Exploring such immunotherapies are particularly important for HIV infected children, as the long-term consequences of persistent inflammation beginning at a young age may include impaired neurocognitive development, early cardiovascular disease, metabolic complications, and premature aging 4,5,18 .…”

Section: Discussionmentioning

confidence: 99%

“…Very few reports examine Tregs in HIV infected children, in whom a disruption may have the added consequence of altering responses to essential childhood vaccines. Moreover, persistent inflammation in children may have long-term health and developmental consequences 4,5,18 . In this study, we examined regulatory T cells in a perinatally infected HIV+ pediatric cohort from Mombasa, Kenya by FOXP3 coexpressed with Helios or CD25 and their correlation with HIV disease progression.…”

Section: Introductionmentioning

confidence: 99%

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FOXP3+Helios+ Regulatory T Cells, Immune Activation, and Advancing Disease in HIV-Infected Children

Khaitan

Kravietz

Mwamzuka

et al. 2016

JAIDS Journal of Acquired Immune Deficiency Syndromes

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Regulatory T cells (Tregs) are functionally suppressive CD4 T cells, critical for establishing peripheral tolerance and controlling inflammatory responses. Previous reports of Tregs during chronic HIV disease have conflicting results with higher or lower levels compared to controls. Identifying true Tregs with suppressive activity proves challenging during HIV infection, as traditional Treg markers, CD25 and FOXP3, may transiently up-regulate expression as a result of immune activation. Helios is an Ikaros family transcription factor that marks natural Tregs with suppressive activity and does not up-regulate expression after activation. Coexpression of FOXP3 and Helios has been suggested as a highly specific marker of “bona fide” Tregs. We evaluated Treg subsets by FOXP3 co-expressed with either CD25 or Helios and their association with HIV disease progression in perinatally-infected HIV positive children. Identifying Tregs by FOXP3 coexpression with Helios rather than CD25 revealed markedly higher Treg frequencies, particularly in HIV+ children. Regardless of ART, HIV infected children had a selective expansion of memory FOXP3+Helios+ Tregs. The rise in memory Tregs correlated with declining HIV clinical status, indicated by falling CD4 percentages and CD4:CD8 ratios and increasing HIV plasma viremia and immune activation. In addition, untreated HIV+ children exhibited an imbalance between the levels of Tregs and activated T cells. Finally, memory Tregs expressed immune activation markers CD38 and Ki67 and exhaustion marker, PD-1, that tightly correlated with a similar phenotype in memory CD4 T cells. Overall, HIV infected children had significant disruptions of memory Tregs that associated with advancing HIV disease.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

FOXP3+Helios+ Regulatory T Cells, Immune Activation, and Advancing Disease in HIV-Infected Children

Khaitan

Kravietz

Mwamzuka

et al. 2016

JAIDS Journal of Acquired Immune Deficiency Syndromes

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“…However, even with ART HIV-1 infected adults remain at higher risk of cardiovascular disease, dyslipidemia, insulin resistance, liver, kidney and bone dysfunction, neurocognitive disorders, accelerated biological aging, and cancer [1, 2]. Although the precise pathophysiology of many of these disorders is poorly understood, a syndrome of chronic immune activation and inflammation is a common feature [3, 4].…”

Section: Introductionmentioning

confidence: 99%

Intracellular HIV-1 RNA and CD4+ T-cell activation in patients starting antiretrovirals

El-Diwany

Breitwieser

Soliman

et al. 2017

Aids

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Objective To assess if the reduction in HIV-1 RNA in CD4+ T cells is correlated with the persistence of immune activation following early antiretroviral therapy (ART) Design Clinical trial (NCT01285050). Methods Next-generation sequencing was used to study total RNA from activated CD4+ T cells (CD38 and HLA-DR expressing) collected from 19 treatment-naïve HIV-1/HCV infected patients before and early after ART initiation (≥12 weeks after plasma HIV RNA < 50 c/ml). To validate comparisons, pre- and post-ART measures were adjusted for input RNA and overall read number. Results As expected, ART use was associated with a median (IQR) 4.3 (2.2–8.3) reduction in the proportion of activated CD4+ T cells (P=0.0008). Whereas in those activated CD4+ T cells no consistent differences in overall gene expression were detected, interferon stimulated gene expression declined (P<2×10−16). Pre-ART, sorted activated CD4+ T cells contained a median (IQR) of 959 (252–1614) HIV-1 reads/107 reads compared to 72 (55–152) HIV-1 reads/107 reads after ≥12 weeks of suppressive ART (P=8×10−5). The decrease in HIV-1 reads in activated CD4+ T cells was associated with the change in plasma HIV-1 RNA levels (r=0.77, P=2×10−4) and the change in the proportion of activated CD4+ T cells (r=0.70, P=0.0016). Conclusions Months of ART led to a marked decrease in cell-associated HIV-1 RNA and ISG expression in activated CD4+ T cells that were strongly associated with the reduction in the proportion of activated CD4+ T cells.

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“…However, HIV persists in patients despite long-term ART therapy such that, once ART is withdrawn, virus invariably rebounds. Lifetime ART treatment is associated with toxicity (1), residual chronic inflammation, and the accelerated onset of diseases associated with aging (2, 3). …”

mentioning

confidence: 99%

Sustained virologic control in SIV ⁺ macaques after antiretroviral and α ₄ β ₇ antibody therapy

Byrareddy

Arthos

Cicala

et al. 2016

Science

183

245

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Antiretroviral drug therapy (ART) effectively suppresses replication of both the immunodeficiency viruses, human (HIV) and simian (SIV); however, virus rebounds soon after ART is withdrawn. SIV-infected monkeys were treated with a 90-day course of ART initiated at 5 weeks post infection followed at 9 weeks post infection by infusions of a primatized monoclonal antibody against the α4β7 integrin administered every 3 weeks until week 32. These animals subsequently maintained low to undetectable viral loads and normal CD4+ T cell counts in plasma and gastrointestinal tissues for more than 9 months, even after all treatment was withdrawn. This combination therapy allows macaques to effectively control viremia and reconstitute their immune systems without a need for further therapy.

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HIV-Related Metabolic Comorbidities in the Current ART Era

Cited by 47 publications

References 178 publications

FOXP3+Helios+ Regulatory T Cells, Immune Activation, and Advancing Disease in HIV-Infected Children

FOXP3+Helios+ Regulatory T Cells, Immune Activation, and Advancing Disease in HIV-Infected Children

Intracellular HIV-1 RNA and CD4+ T-cell activation in patients starting antiretrovirals

Sustained virologic control in SIV ⁺ macaques after antiretroviral and α ₄ β ₇ antibody therapy

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HIV-Related Metabolic Comorbidities in the Current ART Era

Cited by 47 publications

References 178 publications

FOXP3+Helios+ Regulatory T Cells, Immune Activation, and Advancing Disease in HIV-Infected Children

FOXP3+Helios+ Regulatory T Cells, Immune Activation, and Advancing Disease in HIV-Infected Children

Intracellular HIV-1 RNA and CD4+ T-cell activation in patients starting antiretrovirals

Sustained virologic control in SIV + macaques after antiretroviral and α 4 β 7 antibody therapy

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Sustained virologic control in SIV ⁺ macaques after antiretroviral and α ₄ β ₇ antibody therapy