Brief Report: A High Rate of β7+ Gut-Homing Lymphocytes in HIV-Infected Immunological Nonresponders is Associated With Poor CD4 T-Cell Recovery During Suppressive HAART

Girard, Alexandre; Vergnon-Miszczycha, Delphine; Berger, Anne‐Emmanuelle; Roblin, Xavier; Lutch, Frederic; Lambert, Claude; Rochereau, Nicolas; Bourlet, Thomas; Genin, Christian; Paul, Stéphane

doi:10.1097/qai.0000000000000943

Cited by 24 publications

(17 citation statements)

References 36 publications

(41 reference statements)

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“…Interestingly, α4β7-integrins favor the HIV colonization of GALT and the establishment of mucosal HIV reservoir ( 31 ). In this line, the higher expression of α4β7 in CD4 T-cells recently reported in a different cohort of immunodiscordant subjects under suppressive cART, was correlated with a higher proviral HIV load ( 24 ). Additionally, the expression of OX40 on CD4 T-cells has been associated with a high metabolic activity which is ultimately associated with a higher permissibility to HIV infection ( 32 ), and HP process itself has been also associated with higher amounts of HIV provirus ( 33 ).…”

Section: Discussionmentioning

confidence: 55%

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HIV-Infected Subjects With Poor CD4 T-Cell Recovery Despite Effective Therapy Express High Levels of OX40 and α4β7 on CD4 T-Cells Prior Therapy Initiation

et al. 2018

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BackgroundHIV-infected subjects with suboptimal CD4 restoration despite suppressive combined antiretroviral treatment (cART) (immunodiscordant subjects) have been classically characterized after a variable period of time under cART. Recently, we have reported that an increased frequency of proliferating CD4 T-cells in these subjects is already present before the cART onset. The potential contribution of peripheral compensatory homeostatic proliferation (HP) is yet unknown. We aimed to analyze the expression of HP-related cellular markers on CD4 T-cells of immunodiscordant subjects before cART.MethodsWe analyzed the expression of OX40 and α4β7 on peripheral CD4 T-cells from immunodiscordant and control subjects (n = 21 each group) before cART initiation, and also on available follow-up samples (after 24 month of suppressive cART). Additionally, we tested the expression of these markers in an in vitro system for the study of human HP processes.ResultsImmunodiscordant subjects showed increased levels of OX40 and α4β7 on CD4 T-cells before cART initiation. While the cART tended to reduce these levels, immunodiscordant subjects still maintained comparatively higher levels of OX40 and α4β7 after 24 months under suppressive cART. These HP-related markers were upregulated in vitro during the human HP, especially during the fast HP.ConclusionOur results are compatible with exacerbated HP processes in immunodiscordant subjects, already before the cART onset.

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Section: Discussionmentioning

confidence: 55%

“…It is well-known that immunodiscordant subjects present higher frequencies of Treg ( 21 , 22 ) and Th17 ( 23 , 24 ) after cART initiation. Additionally, we have recently reported that increased frequencies of both Treg and Th17 are already present before cART initiation ( 5 , 6 ) in these subjects.…”

Section: Discussionmentioning

confidence: 99%

HIV-Infected Subjects With Poor CD4 T-Cell Recovery Despite Effective Therapy Express High Levels of OX40 and α4β7 on CD4 T-Cells Prior Therapy Initiation

et al. 2018

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“…Ϫ cells in vitro (9). This is also supported by studies that demonstrate preferential infection of ␣ 4 ␤ 7 high cells in vivo (10)(11)(12). Because these cells are present at high density in the gut (13) and are highly susceptible to HIV-1 infection, they may facilitate HIV-1 propagation throughout GALT.…”

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confidence: 75%

Extracellular Matrix Proteins Mediate HIV-1 gp120 Interactions with α₄β₇

Plotnik

Guo

Cleveland

et al. 2017

J Virol

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Gut-homing αβ CD4 T lymphocytes have been shown to be preferentially targeted by human immunodeficiency virus type 1 (HIV-1) and are implicated in HIV-1 pathogenesis. Previous studies demonstrated that HIV-1 envelope protein gp120 binds and signals through αβ and that this likely contributes to the infection of αβ T cells and promotes cell-to-cell virus transmission. Structures within the second variable loop (V2) of gp120, including the tripeptide motif LDV/I, are thought to mediate gp120-αβ binding. However, lack of αβ binding has been reported in gp120 proteins containing LDV/I, and the precise determinants of gp120-αβ binding are not fully defined. In this work, we report the novel finding that fibronectins mediate indirect gp120-αβ interactions. We show that Chinese hamster ovary (CHO) cells used to express recombinant gp120 produced fibronectins and other extracellular matrix proteins that copurified with gp120. CHO cell fibronectins were able to mediate the binding of a diverse panel of gp120 proteins to αβ in an cell binding assay. The V2 loop was not required for fibronectin-mediated binding of gp120 to αβ, nor did V2-specific antibodies block this interaction. Removal of fibronectin through anion-exchange chromatography abrogated V2-independent gp120-αβ binding. Additionally, we showed a recombinant human fibronectin fragment mediated gp120-αβ interactions similarly to CHO cell fibronectin. These findings provide an explanation for the apparently contradictory observations regarding the gp120-αβ interaction and offer new insights into the potential role of fibronectin and other extracellular matrix proteins in HIV-1 biology. Immune tissues within the gut are severely damaged by HIV-1, and this plays an important role in the development of AIDS. Integrin αβ plays a major role in the trafficking of lymphocytes, including CD4 T cells, into gut lymphoid tissues. Previous reports indicate that some HIV-1 gp120 envelope proteins bind to and signal through αβ, which may help explain the preferential infection of gut CD4 T cells. In this study, we demonstrate that extracellular matrix proteins can mediate interactions between gp120 and αβ This suggests that the extracellular matrix may be an important mediator of HIV-1 interaction with αβ-expressing cells. These findings provide new insight into the nature of HIV-1-αβ interactions and how these interactions may represent targets for therapeutic intervention.

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“…The frequency of CD4+CCR9+α4β7+ cells featuring a gut-homing phenotype was also significantly impaired in untreated HIV infection and correlated with the HIV RNA load and CD4+ activation. Upon cART introduction, we observed a further contraction of this subset which may be either due to their migration from the peripheral blood to the gut in the course of cART [26] or apoptosis. Although we do not have evidence to prove these hypotheses, given that CD4+CCR9+α4β7+ serve as viral targets [32], our results may point to ongoing infection and damage at mucosal sites even in the course of effective treatment, thus highlighting the role of this population in the pathogenesis of HIV disease within the gastrointestinal tract.…”

Section: Discussionmentioning

confidence: 99%

“…On the other hand, the absence of correlation between CD4+CCR9+α4β7+ cells and markers of T-cell activation after the introduction of treatment allow for the speculation that the repopulation of this gut-homing population at mucosal sites may be linked to decreased inflammation as well as the containment of the HIV reservoir [26]. Studies aimed at investigating the precise migration patterns of gut-homing populations and their effects on the structure of the gut barrier are warranted in humans to shed light on their contribution to HIV pathogenesis.…”

Section: Discussionmentioning

confidence: 99%

Mucosal cell populations may contribute to peripheral immune abnormalities in HIV-infected subjects introducing cART with moderate immune-suppression

Basilissi¹,

Tincati²,

Merlini³

et al. 2019

PLoS ONE

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HIV infection causes the progressive depletion of CD4+ T-lymphocytes and profound modifications of T-cell homeostasis, which persist despite virologically-suppressive treatment and have been linked to a worse clinical outcome. Enduring alterations of the gastrointestinal tract may represent the underlying pathogenic mechanisms of these phenomena. Twenty-six HIV-infected subjects were assessed over a 12-month period following the introduction of antiretroviral therapy. 18 uninfected individuals were enrolled as controls. Parameters of peripheral T-cell homeostasis (activation, maturation), gastrointestinal function (microbial translocation, gut inflammation, fecal microbiota composition) and mucosal immunity (CD4+CCR6+CD161+, CD4+CCR9+α4β7+, stem cell memory CD4+/CD8+ T-cells) were assessed. CD4+CCR6+CD161+ cells were depleted in HIV-infected untreated subjects and maintained significantly lower levels compared to controls, despite the introduction of effective antiviral treatment. The frequency of gut-homing CD4+CCR9+α4β7+ cells was also impaired in untreated infection and correlated with the HIV RNA load and CD4+HLADR+CD38+; during therapy, we observed a contraction of this pool in the peripheral blood and the loss of its correlation with antigenic exposure/immune activation. A partial correction of the balance between stem cell memory pools and T-cell homeostasis was registered following treatment. In HIV-infected subjects with moderate immune-suppression, antiretroviral therapy has a marginal impact on mucosal immune populations which feature distinctive kinetics in the periphery, possibly reflecting their diverse recruitment from the blood to the mucosa. The persistent defects in mucosal immunity may fuel peripheral T-cell abnormalities through diverse mechanisms, including the production of IL-17/IL-22, cellular permissiveness to infection and regulation of T-lymphocyte maturation.

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Brief Report: A High Rate of β7+ Gut-Homing Lymphocytes in HIV-Infected Immunological Nonresponders is Associated With Poor CD4 T-Cell Recovery During Suppressive HAART

Abstract: Supplemental Digital Content is Available in the Text.

Cited by 24 publications

References 36 publications

HIV-Infected Subjects With Poor CD4 T-Cell Recovery Despite Effective Therapy Express High Levels of OX40 and α4β7 on CD4 T-Cells Prior Therapy Initiation

HIV-Infected Subjects With Poor CD4 T-Cell Recovery Despite Effective Therapy Express High Levels of OX40 and α4β7 on CD4 T-Cells Prior Therapy Initiation

Extracellular Matrix Proteins Mediate HIV-1 gp120 Interactions with α₄β₇

Mucosal cell populations may contribute to peripheral immune abnormalities in HIV-infected subjects introducing cART with moderate immune-suppression

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Brief Report: A High Rate of β7+ Gut-Homing Lymphocytes in HIV-Infected Immunological Nonresponders is Associated With Poor CD4 T-Cell Recovery During Suppressive HAART

Abstract: Supplemental Digital Content is Available in the Text.

Cited by 24 publications

References 36 publications

HIV-Infected Subjects With Poor CD4 T-Cell Recovery Despite Effective Therapy Express High Levels of OX40 and α4β7 on CD4 T-Cells Prior Therapy Initiation

HIV-Infected Subjects With Poor CD4 T-Cell Recovery Despite Effective Therapy Express High Levels of OX40 and α4β7 on CD4 T-Cells Prior Therapy Initiation

Extracellular Matrix Proteins Mediate HIV-1 gp120 Interactions with α4β7

Mucosal cell populations may contribute to peripheral immune abnormalities in HIV-infected subjects introducing cART with moderate immune-suppression

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Extracellular Matrix Proteins Mediate HIV-1 gp120 Interactions with α₄β₇