Impact of intensified antiretroviral therapy during early HIV infection on gut immunology and inflammatory blood biomarkers

Kim, Connie J.; Rousseau, Rodney; Huibner, Sanja; Kovacs, Colin; Benko, Erika; Shahabi, Kamnoosh; Kandel, Gabor; Ostrowski, Mario; Kaul, Rupert

doi:10.1097/qad.0000000000001515

Cited by 24 publications

(27 citation statements)

References 28 publications

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“…Although unexpected, mechanistically, our results could be explained by the paradoxical increases in mucosal CD8 ϩ T-cell activation that we (22) and others (8) have observed under maraviroc intensification, given the strong correlation between the CD4/CD8 ratio and CD8 ϩ T-cell activation in the gut and blood (5,22). It should be noted, however, that other studies have failed to demonstrate the putative beneficial effects of maraviroc on immunoactivation and inflammation (23)(24)(25), T-cell recovery (15,26), or the development of immune reconstitution inflammatory syndrome (26).…”

mentioning

confidence: 52%

Effects of Maraviroc versus Efavirenz in Combination with Zidovudine-Lamivudine on the CD4/CD8 Ratio in Treatment-Naive HIV-Infected Individuals

Serrano‐Villar

Caruana

Zlotnik

et al. 2017

Antimicrob Agents Chemother

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A low CD4/CD8 ratio during treated HIV infection reflects heightened immune activation and predicts death. The effects of different antiretroviral therapy regimens on CD4/CD8 ratio recovery remains unclear. We performed a analysis of the MERIT study, a randomized, double-blind trial of maraviroc versus efavirenz in combination with zidovudine-lamivudine in treatment-naive HIV-infected individuals. We found higher rates of CD4/CD8 ratio normalization with efavirenz, which was driven by a greater CD8 T-cell decline.

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mentioning

confidence: 52%

Effects of Maraviroc versus Efavirenz in Combination with Zidovudine-Lamivudine on the CD4/CD8 Ratio in Treatment-Naive HIV-Infected Individuals

Serrano‐Villar

Caruana

Zlotnik

et al. 2017

Antimicrob Agents Chemother

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“…HIV-1-infected patients have elevated circulating levels of LPS, which can serve to increase transcriptional activation of proinflammatory cytokines (11,50). Elevated levels of IL-1␤ are associated with many of the AANCCs seen in HIV-1-infected patients (91)(92)(93)(94). Currently, there are multiple clinical trials assessing the safety and efficacy of anti-IL-1␤ antibodies in cardiovascular disease (95,96).…”

Section: Discussionmentioning

confidence: 99%

P2X Antagonists Inhibit HIV-1 Productive Infection and Inflammatory Cytokines Interleukin-10 (IL-10) and IL-1β in a Human Tonsil Explant Model

Soare

Durham

Gopal

et al. 2019

J Virol

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HIV-1 causes a persistent infection of the immune system that is associated with chronic comorbidities. The mechanisms that underlie this inflammation are poorly understood. Emerging literature has implicated proinflammatory purinergic receptors and downstream signaling mediators in HIV-1 infection. This study probed whether inhibitors of purinergic receptors would reduce HIV-1 infection and HIV-1-stimulated inflammation. Anex vivohuman tonsil histoculture infection model was developed to support HIV-1 productive infection and stimulated the inflammatory cytokine interleukin-1 beta (IL-1β) and the immunosuppressive cytokine interleukin-10 (IL-10). This study tests whether inhibitors of purinergic receptors would reduce HIV-1 infection and HIV-1-stimulated inflammation. The purinergic P2X1 receptor antagonist NF449, the purinergic P2X7 receptor antagonist A438079, and azidothymidine (AZT) were tested in HIV-1-infected human tonsil explants to compare levels of inhibition of HIV-1 infection and HIV-stimulated inflammatory cytokine production. All drugs limited HIV-1 productive infection, but P2X-selective antagonists (NF449 and A438079) significantly lowered HIV-stimulated IL-10 and IL-1β. We further observed that P2X1- and P2X7-selective antagonists can act differentially as inhibitors of both HIV-1 infection and HIV-1-stimulated inflammation. Our findings highlight the differential effects of HIV-1 on inflammation in peripheral blood compared to those in lymphoid tissue. For the first time, we demonstrate that P2X-selective antagonists act differentially as inhibitors of both HIV-1 infection and HIV-1-stimulated inflammation. Drugs that block these pathways can have independent inhibitory activities against HIV-1 infection and HIV-induced inflammation.IMPORTANCEPatients who are chronically infected with HIV-1 experience sequelae related to chronic inflammation. The mechanisms of this inflammation have not been elucidated. Here, we describe a class of drugs that target the P2X proinflammatory signaling receptors in a human tonsil explant model. This model highlights differences in HIV-1 stimulation of lymphoid tissue inflammation and peripheral blood. These drugs serve to block both HIV-1 infection and production of IL-10 and IL-1β in lymphoid tissue, suggesting a novel approach to HIV-1 therapeutics in which both HIV-1 replication and inflammatory signaling are simultaneously targeted.

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“…The ability of ART in restoring the gut and peripheral Th17 cell counts remains controversial. Kim et al reported that short-term ART restores the numbers of sigmoid colon Th17 cells but not their function during chronic infection [ 188 ], even with ART intensification [ 278 ]. Furthermore, studies by Ciccone et al as well as Chege et al reported similar frequencies of gut and/or peripheral blood Th17 cells between ART-treated HIV-infected and uninfected individuals [ 189 , 238 ].…”

Section: Role Of Th17 Cells In Hiv-1/siv Pathogenesismentioning

confidence: 99%

“…Increased frequency of total CD4+ T-cells in the gastrointestinal tract following treatment was correlated with the partial restoration of Th17 cells [ 186 ]. Considering the fact that ART initiated during chronic infection fails to completely restore Th17 cells [ 186 ], even when ART is intensified with raltegravir (integrase inhibitor) and maraviroc (CCR5-mediated entry inhibitor) [ 278 ], the search for additional strategies to restore Th17 cells in chronically-infected individuals is ongoing. Indeed, treatment with probiotics along with ART in SIV-infected pigtail macaques was reported to increase the levels of IL-23, which was accompanied with the enhancement of Th17 cells when compared to animals that were only treated with ART [ 235 ].…”

Section: Role Of Th17 Cells In Hiv-1/siv Pathogenesismentioning

confidence: 99%

The Th17 Lineage: From Barrier Surfaces Homeostasis to Autoimmunity, Cancer, and HIV-1 Pathogenesis

Wacleche

Landay

Routy

et al. 2017

Viruses

144

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The T helper 17 (Th17) cells represent a subset of CD4+ T-cells with unique effector functions, developmental plasticity, and stem-cell features. Th17 cells bridge innate and adaptive immunity against fungal and bacterial infections at skin and mucosal barrier surfaces. Although Th17 cells have been extensively studied in the context of autoimmunity, their role in various other pathologies is underexplored and remains an area of open investigation. This review summarizes the history of Th17 cell discovery and the current knowledge relative to the beneficial role of Th17 cells in maintaining mucosal immunity homeostasis. We further discuss the concept of Th17 pathogenicity in the context of autoimmunity, cancer, and HIV infection, and we review the most recent discoveries on molecular mechanisms regulating HIV replication/persistence in pathogenic Th17 cells. Finally, we stress the need for novel fundamental research discovery-based Th17-specific therapeutic interventions to treat pathogenic conditions associated with Th17 abnormalities, including HIV infection.

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Impact of intensified antiretroviral therapy during early HIV infection on gut immunology and inflammatory blood biomarkers

Abstract: Early HIV infection causes substantial mucosal and systemic immune activation, and gut CD4 T-cell dysfunction. One year of ART improved but did not normalize most parameters, regardless of intensification with raltegravir and maraviroc, and did not restore mucosal Th17 function.

Cited by 24 publications

References 28 publications

Effects of Maraviroc versus Efavirenz in Combination with Zidovudine-Lamivudine on the CD4/CD8 Ratio in Treatment-Naive HIV-Infected Individuals

Effects of Maraviroc versus Efavirenz in Combination with Zidovudine-Lamivudine on the CD4/CD8 Ratio in Treatment-Naive HIV-Infected Individuals

P2X Antagonists Inhibit HIV-1 Productive Infection and Inflammatory Cytokines Interleukin-10 (IL-10) and IL-1β in a Human Tonsil Explant Model

The Th17 Lineage: From Barrier Surfaces Homeostasis to Autoimmunity, Cancer, and HIV-1 Pathogenesis

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