Very early antiretroviral therapy permits CD8 T cells to keep HIV reservoirs at bay

Routy, Jean‐Pierre; Mehraj, Vikram

doi:10.21037/atm.2017.08.38

Cited by 6 publications

(6 citation statements)

References 27 publications

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“…In this cross-sectional study, we investigated the contribution of CMV seropositivity on microbial translocation and inflammation in ART-naive and ART-treated PLWH. In line with previous studies, we confirmed that CMV seropositivity was associated with higher CD8 T-cell counts and lower CD4/CD8 ratio in PLWH [ 14 , 29 , 30 ]. Moreover, we expanded upon such observations by showing that CMV seropositivity and anti-CMV IgG levels were associated with higher plasma levels of markers of gut damage (I-FABP), bacterial (LPS) and fungal (BDG) translocation, and proinflammatory cytokines in both ART-naive and ART-treated PLWH as well as uninfected controls.…”

Section: Discussionsupporting

confidence: 92%

Cytomegalovirus Seropositivity Is Associated With Increased Microbial Translocation in People Living With Human Immunodeficiency Virus and Uninfected Controls

Ramendra

Isnard

Lin

et al. 2019

Clinical Infectious Diseases

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Background Cytomegalovirus (CMV) seropositivity and anti-CMV immunoglobulin G (IgG) levels are associated with adverse health outcomes in elderly populations. Among people living with human immunodeficiency virus (PLWH), CMV seropositivity has been associated with persistent CD8 T-cell elevation and increased risk of developing non-AIDS comorbidities despite long-term antiretroviral therapy (ART). Herein, we investigated whether CMV seropositivity and elevation of anti-CMV IgG levels were associated with increased epithelial gut damage, microbial translocation, and systemic inflammation. Methods A total of 150 PLWH (79 ART-naive and 71 ART-treated) were compared to 26 without human immunodeficiency virus (HIV) infection (uninfected controls). Plasma markers of HIV disease progression, epithelial gut damage, microbial translocation, nonspecific B-cell activation, anti-CMV and anti–Epstein-Barr virus (EBV) IgG levels, and proinflammatory cytokines were measured. Results CMV seropositivity and elevated anti-CMV IgG levels were associated with markers of epithelial gut damage, microbial translocation, and inflammation in PLWH and participants without HIV infection. In contrast, total nonspecific IgG, immunoglobulin M, immunoglobulin A, and anti-EBV IgG levels were not associated with these markers. CMV seropositivity was associated with markers of epithelial gut damage, microbial translocation, and inflammation independent of sociodemographic and behavioral characteristics of the study population. Conclusions CMV-seropositive people with and without HIV had increased epithelial gut damage, microbial translocation, and inflammation. Furthermore, anti-CMV IgG levels were independently associated with increased epithelial gut damage and microbial translocation. CMV coinfection may partially explain persistent gut damage, microbial translocation, and inflammation in ART-treated PLWH.

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Section: Discussionsupporting

confidence: 92%

Cytomegalovirus Seropositivity Is Associated With Increased Microbial Translocation in People Living With Human Immunodeficiency Virus and Uninfected Controls

Ramendra

Isnard

Lin

et al. 2019

Clinical Infectious Diseases

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“…However, these individuals on prolonged ART develop signiﬁcant metabolic complications that contribute to an increased risk of inflammatory non-AIDS events 1. Such clinical events are associated with persistent immune activation, and occur more often when ART initiation is delayed 2–4. ART cannot clear latently infected memory CD4+ T cells, which persist to form the viral reservoir, responsible for the rapid viral rebound upon ART interruption 5 6.…”

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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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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“…Type I interferons (IFNs, e in response to infections such a While Type I IFNs are typically facets of adaptive immunity, in been shown to increase both the icity of T cells and NK cells th signaling promotes beneficial in naling. However, excessive Typ tion, worsening HIV disease bu ing chronic HIV infection [24,25 that induce IL-15 production, e uated for the ability to promot fects throughout acute and chro IL-15 shares some features common gamma chain cytokin activate immune cells and prev substantial toxicity, so there is augment immune function wi adaptive immune response, is gamma chain ɣ receptor subu (IL-2Rɣ, CD132) [26][27][28]. In ad subunit of the IL-2 receptor (I formed by the heterodimeric β and IL-15 [29].…”

Section: Discussionmentioning

confidence: 99%

“…It is a critical factor for the development, proliferation, maintena cells and natural killer (NK) cells [18]. Specifically, it has been s and antigen-specific CD8 + T cells, making it attractive for therape cellular immune response against various diseases [19] [24,25]. IL-15 signaling, as well as the fac that induce IL-15 production, expression, and signaling, must the uated for the ability to promote both beneficial and detrimental fects throughout acute and chronic HIV/SIV.…”

Section: Il-15 Is a Cytokine Produced By Mononuclear Phagocytes Dementioning

confidence: 99%

“…In acute infection, Type I IFN signaling promotes beneficial innate and adaptive immune responses, including IL-15 signaling. However, excessive Type I IFN signaling contributes to aberrant immune activation, worsening HIV disease burden, and poor CD4 + T cell reconstitution under ART during chronic HIV infection [ 24 , 25 ]. IL-15 signaling, as well as the factors such as Type I IFNs that induce IL-15 production, expression, and signaling, must therefore be carefully evaluated for the ability to promote both beneficial and detrimental immunomodulatory effects throughout acute and chronic HIV/SIV.…”

Section: Il-15 Signaling Function and Immunotherapeutic Potentialmentioning

confidence: 99%

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Therapeutic Potential of IL-15 and N-803 in HIV/SIV Infection

Harwood

O’Connor

2021

Viruses

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IL-15, a proinflammatory cytokine critical for the generation, maintenance, and homeostasis of T cell responses, is produced naturally in response to HIV/SIV infection, but has also demonstrated therapeutic potential. IL-15 can boost CD4+ and CD8+ T cell and NK cell proliferation, activation, and function. However, IL-15 treatment may cause aberrant immune activation and accelerated disease progression in certain circumstances. Moreover, the relationship between the timing of IL-15 administration and disease progression remains unclear. The IL-15 superagonist N-803 was developed to expand the therapeutic potential of IL-15 by maximizing its tissue distribution and half-life. N-803 has garnered enthusiasm recently as a way to enhance the innate and cellular immune responses to HIV/SIV by improving CD8+ T cell recognition and killing of virus-infected cells and directing immune cells to mucosal sites and lymph nodes, the primary sites of virus replication. N-803 has also been evaluated in “shock and kill” strategies due to its potential to reverse latency (shock) and enhance antiviral immunity (kill). This review examines the current literature about the effects of IL-15 and N-803 on innate and cellular immunity, viral burden, and latency reversal in the context of HIV/SIV, and their therapeutic potential both alone and combined with additional interventions such as antiretroviral therapy (ART) and vaccination.

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Very early antiretroviral therapy permits CD8 T cells to keep HIV reservoirs at bay

Cited by 6 publications

References 27 publications

Cytomegalovirus Seropositivity Is Associated With Increased Microbial Translocation in People Living With Human Immunodeficiency Virus and Uninfected Controls

Cytomegalovirus Seropositivity Is Associated With Increased Microbial Translocation in People Living With Human Immunodeficiency Virus and Uninfected Controls

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

Therapeutic Potential of IL-15 and N-803 in HIV/SIV Infection

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