Cohort study of diabetes in HIV-infected adult patients: Evaluating the effect of diabetes mellitus on immune reconstitution

Moyo, Daniel; Tanthuma, G; Cary, Mark; Mushisha, O.; Kwadiba, G; Chikuse, Fancis F.; Steenhoff, Andrew P.; Reid, Michael

doi:10.1016/j.diabres.2013.12.042

Cited by 20 publications

(22 citation statements)

References 7 publications

(7 reference statements)

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“…We further propose that immunometabolism, which has been shown to affect the ability of T-cells to proliferate, would regulate optimal cytotoxic responses and influence the size of the HIV reservoir 23. Given metformin’s immunomodulatory properties,28–34 43 45 and its ability to improve CD4+ T-cell counts in one study of participants initiating ART,31 we propose that this antidiabetic medication may enhance T-cell effector function to control the HIV reservoir.…”

Section: Discussionmentioning

confidence: 99%

“…Metformin promotes autophagy and modulates T-cell glycolysis by inhibiting mTOR, improving CD4+ T cell counts in diabetic PLWH initiating ART 31. The effects of metformin in PLWH may be due to: (1) its ability to overcome the inhibition AMPK by viral transactivator of transcription (Tat) protein32; (2) an anti-inflammatory effect on the intestine by suppressing nuclear factor κB activation33; (3) an indirect anti-inflammatory effect caused by the reduced production of cytokines such as tumour necrosis factor-alpha (TNF-α) and interleukin-1 (IL-1)34 and/or (4) changes in the composition of the gut microbiota which have been observed in mice and in humans 35–38.…”

Section: Introductionmentioning

confidence: 99%

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Effect of metformin on the size of the HIV reservoir in non-diabetic ART-treated individuals: single-arm non-randomised Lilac pilot study protocol

et al. 2019

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IntroductionPeople living with HIV (PLWH) on antiretroviral therapy (ART) do not progress to AIDS. However, they still suffer from an increased risk of inflammation-associated complications. HIV persists in long-lived CD4+ T cells, which form the major viral reservoir. The persistence of this reservoir despite long-term ART is the major hurdle to curing HIV. Importantly, the size of the HIV reservoir is larger in individuals who start ART late in the course of infection and have a low CD4+/CD8+ ratio. HIV reservoir size is also linked to the levels of persistent inflammation on ART. Thus, novel strategies to reduce immune inflammation and improve the host response to control the HIV reservoir would be a valuable addition to current ART. Among the different strategies under investigation is metformin, a widely used antidiabetic drug that was recently shown to modulate T-cell activation and inflammation. Treatment of non-diabetic individuals with metformin controls inflammation by improving glucose metabolism and by regulating intracellular immunometabolic checkpoints such as the adenosin 5 monophosphate activated protein kinase and mammalian target of rapamycin, in association with microbiota modification.Methods and analysis22 PLWH on ART for more than 3 years, at high risk of inflammation or the development of non-AIDS events (low CD4+/CD8+ ratio) will be recruited in a clinical single-arm pilot study. We will test whether supplementing ART with metformin in non-diabetic HIV-infected individuals can reduce the size of the HIV reservoir as determined by various virological assays. The expected outcome of this study is a reduction in both the size of the HIV reservoir and inflammation following the addition of metformin to ART, thus paving the way towards HIV eradication.Ethics and disseminationEthical approval: McGill university Health Centre committee number MP-37-2016-2456. Canadian Canadian Institutes of Health Research/Canadian HIV Trials Network (CTN) protocol CTNPT027. Results will be made available through publication in peer-reviewed journals and through the CTN website.Trial registration numberNCT02659306

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Effect of metformin on the size of the HIV reservoir in non-diabetic ART-treated individuals: single-arm non-randomised Lilac pilot study protocol

et al. 2019

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“… 14 A small case–control study from Botswana suggested an association between efavirenz use and diabetes. 35 Randomized controlled trials showed significantly higher serum glucose concentrations in participants in the efavirenz arms than the following comparator antiretroviral drugs: nevirapine, 13 abacavir, 13 atazanavir, 11 atazanavir–ritonavir, 9 and raltegravir. 12 …”

Section: Discussionmentioning

confidence: 99%

Risk Factors for Incident Diabetes in a Cohort Taking First-Line Nonnucleoside Reverse Transcriptase Inhibitor-Based Antiretroviral Therapy

et al. 2016

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“…To reduce systemic and local inflammation, pravastatin is already being used to treat HIV-infected patients (Toribio et al, 2017). Another possible treatment option is metformin, an antidiabetic, senolytic drug that might promote metabolic function in the AT, decrease inflammation, and modulate T cell activation (Moyo et al, 2014). Metformin's effects have been studied in HIV-infected people with diabetes, and the drug is currently being tested clinically in non-diabetic HIV-infected patients (Routy et al, 2019).…”

Section: Therapeutic Strategies Based On Metabolic Pathwaysmentioning

confidence: 99%

Specific Biological Features of Adipose Tissue, and Their Impact on HIV Persistence

et al. 2019

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Although white AT can contribute to anti-infectious immune responses, it can also be targeted and perturbed by pathogens. The AT's immune involvement is primarily due to strong pro-inflammatory responses (with both local and paracrine effects), and the large number of fat-resident macrophages. Adipocytes also exert direct antimicrobial responses. In recent years, it has been found that memory T cells accumulate in AT, where they provide efficient secondary responses against viral pathogens. These observations have prompted researchers to re-evaluate the links between obesity and susceptibility to infections. In contrast, AT serves as a reservoir for several persistence pathogens, such as human adenovirus Ad-36, Trypanosoma gondii, Mycobacterium tuberculosis, influenza A virus, and cytomegalovirus (CMV). The presence and persistence of bacterial DNA in AT has led to the concept of a tissuespecific microbiota. The unexpected coexistence of immune cells and pathogens within the specific AT environment is intriguing, and its impact on anti-infectious immune responses requires further evaluation. AT has been recently identified as a site of HIV persistence. In the context of HIV infection, AT is targeted by both the virus and the antiretroviral drugs. AT's intrinsic metabolic features, large overall mass, and wide distribution make it a major tissue reservoir, and one that may contribute to the pathophysiology of chronic HIV infections. Here, we review the immune, metabolic, viral, and pharmacological aspects that contribute to HIV persistence in AT. We also evaluate the respective impacts of both intrinsic and HIV-induced factors on AT's involvement as a viral reservoir. Lastly, we examine the potential consequences of HIV persistence on the metabolic and immune activities of AT.

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Cohort study of diabetes in HIV-infected adult patients: Evaluating the effect of diabetes mellitus on immune reconstitution

Cited by 20 publications

References 7 publications

Effect of metformin on the size of the HIV reservoir in non-diabetic ART-treated individuals: single-arm non-randomised Lilac pilot study protocol

Effect of metformin on the size of the HIV reservoir in non-diabetic ART-treated individuals: single-arm non-randomised Lilac pilot study protocol

Risk Factors for Incident Diabetes in a Cohort Taking First-Line Nonnucleoside Reverse Transcriptase Inhibitor-Based Antiretroviral Therapy

Specific Biological Features of Adipose Tissue, and Their Impact on HIV Persistence

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