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Article ; Online: The build-up of stock of stable integrated proviruses overtime explains the difficulty in reducing HIV-1 DNA levels when treatment is initiated at the chronic stage of the infection

Gilbert Mchantaf / Antoine Cheret / Adeline Melard / Asma Essat / Elise Gardiennet / Rebecca Bauer / Caroline Charre / Vincent Meiffredy / Lionel Piroth / Cécile Goujard / Laurence Meyer / Véronique Avettand-Fenoel

Journal of Virus Eradication, Vol 9, Iss 4, Pp 100357- (2023)

2023

Abstract: Background: Understanding factors affecting the size and the evolution of the HIV reservoir is essential for the development of curative strategies. This study aimed to assess the impact of antiretroviral therapy (ART) initiated during primary infection ( ...

Abstract	Background: Understanding factors affecting the size and the evolution of the HIV reservoir is essential for the development of curative strategies. This study aimed to assess the impact of antiretroviral therapy (ART) initiated during primary infection (PHI) vs chronic infection (CHI) on the levels and dynamics of integrated HIV-1 DNA, a biomarker of viral persistence. Methods: Integrated and total HIV-1-DNA were measured in the blood of 92 patients treated during PHI (early group) and 41 during CHI (deferred group), at diagnosis, ART initiation, and 12–24 months on treatment. Results: On ART, detectable (>1.78 log10 copies/106 PBMCs) integrated HIV-1 DNA levels were significantly lower in the early vs deferred group (2.99 log10 vs 3.29 log10, p = 0.005). The proportion of undetectable integrated HIV-1 DNA tended to be higher in the early group vs deferred group (61 % vs 46 %; p = 0.133). Conclusion: Treatment initiated at PHI limits the levels of integrated HIV-1 DNA in blood. However, initiating treatment at CHI does not allow reaching such low levels in most patients, probably because the stable proviruses at that stage are present in the less prone to elimination long-lived cells. Thus, early ART could provide an opportunity to preparing for functional cure and eradication strategies.
Keywords	Integrated HIV-1 DNA ; Total HIV-1 DNA ; Early ART ; Deferred treatment ; Reservoir decay ; Microbiology ; QR1-502 ; Public aspects of medicine ; RA1-1270
Subject code	610
Language	English
Publishing date	2023-12-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Antiretroviral therapy for HIV controllers

Léo Plaçais / Faroudy Boufassa / Camille Lécuroux / Elise Gardiennet / Véronique Avettand-Fenoel / Asier Saez-Cirion / Olivier Lambotte / Nicolas Noël

EClinicalMedicine, Vol 37, Iss , Pp 100963- (2021)

Reasons for initiation and outcomes in the French ANRS-CO21 CODEX cohort

2021

Abstract: Background: Less than 1% of Human Immunodeficiency Virus (HIV)-infected individuals are able to achieve spontaneous viral control without requiring antiretroviral therapy (ART). Whether these HIV controllers (HIC) are at risk of HIV-associated ... ...

Abstract	Background: Less than 1% of Human Immunodeficiency Virus (HIV)-infected individuals are able to achieve spontaneous viral control without requiring antiretroviral therapy (ART). Whether these HIV controllers (HIC) are at risk of HIV-associated comorbidities and could benefit from ART is debated, but recent studies reported decreased T-cell activation upon ART initiation. We report the frequency of ART initiation, reasons to treat, treatment outcome on immunovirological parameters, and rate of side-effects and treatment discontinuation in the French cohort of HIC. Methods: Participants included in the French multicenter Agence Nationale de Recherche sur le SIDA et les Hépatites (ANRS) Cohorte des extremes (CODEX) cohort of HIC between July 6, 2007 and January 3, 2018 were prospectively followed. ART initiation, indication, discontinuation, non-Acquired ImmunoDeficiency Syndrome (AIDS)-defining events, side-effects, and immunovirological parameters were recorded. Undetectable HIC (u-HIC) were defined as participants with strictly undetectable viral loads based on routinely used assays throughout the follow-up and blipper HIC (b-HIC) as participants with possible detectable viral loads above the detection threshold during follow-up. Findings: Among 302 HIC followed for a median of 14.8 years [10.3–20.2], 90 (30%) received ART (7 u-HIC and 83 b-HIC). The main reasons for ART initiation were decreased CD4 T-cell counts (n = 36, 40%), loss of virological control (n = 13, 14%), and non-AIDS-defining events (n = 12, 13%). Sixteen (18%) participants experienced 17 grade 1–2 adverse events. In b-HIC, ART slightly increased the CD4/CD8 ratio (median +0.19, p < 0.0001) and decreased the frequency of circulating CD38+ HLA-DR.+ CD4 and CD8 lymphocytes (median -0.75%, p = 0.003, and -2%, p < 0.0001, respectively), but these changes were not observed for treated u-HIC. Thirteen (14%) participants discontinued ART (5 (38%) because of side-effects, and 10 remained HIC after treatment cessation (median follow-up: 305 days ...
Keywords	HIV controllers ; Elite controllers ; Antiretroviral therapy ; Immune activation ; Non-aids-defining events ; Medicine (General) ; R5-920
Subject code	700
Language	English
Publishing date	2021-07-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Early antiretroviral therapy favors post-treatment SIV control associated with the expansion of enhanced memory CD8+ T-cells

Caroline Passaes / Delphine Desjardins / Anaïs Chapel / Valérie Monceaux / Julien Lemaitre / Adeline Mélard / Federico Perdomo-Celis / Cyril Planchais / Maël Gourvès / Nastasia Dimant / Annie David / Nathalie Dereuddre-Bosquet / Aurélie Barrail-Tran / Hélène Gouget / Céline Guillaume / Francis Relouzat / Olivier Lambotte / Jérémie Guedj / Michaela Müller-Trutwin /

Hugo Mouquet / Christine Rouzioux / Véronique Avettand-Fenoël / Roger Le Grand / Asier Sáez-Cirión

Nature Communications, Vol 15, Iss 1, Pp 1-

2024 Volume 19

Abstract: Abstract HIV remission can be achieved in some people, called post-treatment HIV controllers, after antiretroviral treatment discontinuation. Treatment initiation close to the time of infection was suggested to favor post-treatment control, but the ... ...

Abstract	Abstract HIV remission can be achieved in some people, called post-treatment HIV controllers, after antiretroviral treatment discontinuation. Treatment initiation close to the time of infection was suggested to favor post-treatment control, but the circumstances and mechanisms leading to this outcome remain unclear. Here we evaluate the impact of early (week 4) vs. late (week 24 post-infection) treatment initiation in SIVmac251-infected male cynomolgus macaques receiving 2 years of therapy before analytical treatment interruption. We show that early treatment strongly promotes post-treatment control, which is not related to a lower frequency of infected cells at treatment interruption. Rather, early treatment favors the development of long-term memory CD8+ T cells with enhanced proliferative and SIV suppressive capacity that are able to mediate a robust secondary-like response upon viral rebound. Our model allows us to formally demonstrate a link between treatment initiation during primary infection and the promotion of post-treatment control and provides results that may guide the development of new immunotherapies for HIV remission.
Keywords	Science ; Q
Subject code	616
Language	English
Publishing date	2024-01-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Persistence of monocyte activation under treatment in people followed since acute HIV-1 infection relative to participants at high or low risk of HIV infection

Sophie Novelli / Camille Lécuroux / Cécile Goujard / Jacques Reynes / Agnès Villemant / Laurent Blum / Asma Essat / Véronique Avettand-Fenoël / Odile Launay / Jean-Michel Molina / Christine Bourgeois / Laurence Meyer

EBioMedicine, Vol 62, Iss , Pp 103129- (2020)

2020

Abstract: Background: Interpretation of the increase in certain inflammatory markers in virally suppressed HIV-infected individuals must rely on an appropriate uninfected control group well characterized for non-HIV-related factors that contribute to chronic ... ...

Abstract	Background: Interpretation of the increase in certain inflammatory markers in virally suppressed HIV-infected individuals must rely on an appropriate uninfected control group well characterized for non-HIV-related factors that contribute to chronic inflammation, e.g. smoking, alcohol consumption, or being overweight. We compared the inflammatory profiles of HIV-infected participants under long-term antiretroviral therapy (ART) with those of two HIV-uninfected groups with contrasting health behaviours. Methods: We studied 150 HIV-infected participants (42 women, 108 men) under long-term ART (median, 6 years) followed in the ANRS PRIMO cohort since acute/early HIV-1 infection (AHI) diagnosis. Sex and age-matched controls were sampled from i) the ANRS IPERGAY pre-exposure prophylaxis trial among men at high risk for HIV infection and with high frequencies of non-HIV factors of inflammation ii) the ANRS COHVAC cohort of volunteers in vaccine trials with a low-risk profile for HIV infection. We measured the plasma levels of ten inflammatory markers. Findings: After adjusting for smoking, alcohol use and body mass index, both HIV-infected men and women had higher levels of sCD14, sCD163, sTNFRII and I-FABP than their high-risk IPERGAY and low-risk COHVAC counterparts. Hierarchical clustering showed a subset of 15 PRIMO participants to have an inflammatory profile similar to that of most HIV-negative participants. These participants already had favourable markers at AHI diagnosis. Interpretation: Long-term ART, even when initiated at a low level of immunodeficiency, fails to normalize monocyte/macrophage activation and gut epithelial dysfunction. Persistent inflammation under treatment may be related to an increased inflammatory profile since AHI. Funding: ANRS and Paris-Saclay University.
Keywords	HIV infection ; Inflammation ; Immune activation ; Long-term ART ; Medicine ; R ; Medicine (General) ; R5-920
Language	English
Publishing date	2020-12-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Low CCR5 expression protects HIV-specific CD4+ T cells of elite controllers from viral entry

Mathieu Claireaux / Rémy Robinot / Jérôme Kervevan / Mandar Patgaonkar / Isabelle Staropoli / Anne Brelot / Alexandre Nouël / Stacy Gellenoncourt / Xian Tang / Mélanie Héry / Stevenn Volant / Emeline Perthame / Véronique Avettand-Fenoël / Julian Buchrieser / Thomas Cokelaer / Christiane Bouchier / Laurence Ma / Faroudy Boufassa / Samia Hendou /

Valentina Libri / Milena Hasan / David Zucman / Pierre de Truchis / Olivier Schwartz / Olivier Lambotte / Lisa A. Chakrabarti

Nature Communications, Vol 13, Iss 1, Pp 1-

2022 Volume 19

Abstract: Here, Claireaux et al. show that people who naturally control HIV infection express lower levels of the viral co-receptor CCR5 in specific CD4+ T cells, and that this results from mutations or receptor internalization by CD4+ T cell-produced chemokines. ...

Abstract	Here, Claireaux et al. show that people who naturally control HIV infection express lower levels of the viral co-receptor CCR5 in specific CD4+ T cells, and that this results from mutations or receptor internalization by CD4+ T cell-produced chemokines.
Keywords	Science ; Q
Language	English
Publishing date	2022-01-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Increasing contribution of integrated forms to total HIV DNA in blood during HIV disease progression from primary infectionResearch in context

Pauline Trémeaux / Tiphaine Lenfant / Faroudy Boufassa / Asma Essat / Adeline Mélard / Marine Gousset / Olivier Delelis / Jean-Paul Viard / Marc Bary / Cécile Goujard / Christine Rouzioux / Laurence Meyer / Véronique Avettand-Fenoel

EBioMedicine, Vol 41, Iss , Pp 455-

2019 Volume 464

Abstract: Background: In the current context of research on HIV reservoirs, offering new insights into the persistence of HIV DNA in infected cells, which prevents viral eradication, may aid in identifying cure strategies. This study aimed to describe the ... ...

Abstract	Background: In the current context of research on HIV reservoirs, offering new insights into the persistence of HIV DNA in infected cells, which prevents viral eradication, may aid in identifying cure strategies. This study aimed to describe the establishment of stable integrated forms among total HIV DNA during primary infection (PHI) and their dynamics during the natural history of infection. Methods: Total and integrated HIV DNA were quantified in blood from 74 PHI patients and 97 recent seroconverters (<12 months following infection, “progression cohort”). The evolution of both markers over six years was modelled (mixed-effect linear models). Their predictive values for disease progression were studied (Cox models). Findings: For most patients during PHI, stable integrated forms were a minority among total HIV DNA (median: 12%) and became predominant thereafter (median at AIDS stage: 100%). Both total and integrated HIV DNA increased over a six-year period. Patients from the progression cohort who reached clinical AIDS during follow-up (n = 34) exhibited higher total and integrated HIV DNA levels at seroconversion and a higher percentage of integrated forms than did slower progressors (n = 63) (median: 100% vs 44%). The integrated HIV DNA load was strongly associated with the risk of developing AIDS (aRR = 2.63, p = 0.002). Interpretation: The profile of “rapid” or “slower” progression in the natural history of HIV infection appears to be determined early in the course of HIV infection. The strong predominance of unstable unintegrated forms in PHI may explain the great benefit of this early treatment, which induces a sharp decrease in total HIV DNA. Fund: French National Agency for Research on AIDS and Viral Hepatitis. Keywords: Total HIV DNA, Integrated HIV DNA, Reservoirs, Natural history, Primary HIV infection, Acquired immunodeficiency syndrome, Kinetics
Keywords	Medicine ; R ; Medicine (General) ; R5-920
Subject code	310
Language	English
Publishing date	2019-03-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Novel role of UHRF1 in the epigenetic repression of the latent HIV-1

Roxane Verdikt / Maryam Bendoumou / Sophie Bouchat / Lorena Nestola / Alexander O. Pasternak / Gilles Darcis / Véronique Avettand-Fenoel / Caroline Vanhulle / Amina Aït-Ammar / Marion Santangelo / Estelle Plant / Valentin Le Douce / Nadège Delacourt / Aurelija Cicilionytė / Coca Necsoi / Francis Corazza / Caroline Pereira Bittencourt Passaes / Christian Schwartz / Martin Bizet /

François Fuks / Asier Sáez-Cirión / Christine Rouzioux / Stéphane De Wit / Ben Berkhout / Virginie Gautier / Olivier Rohr / Carine Van Lint

EBioMedicine, Vol 79, Iss , Pp 103985- (2022)

2022

Abstract: Summary: Background: The multiplicity, heterogeneity, and dynamic nature of human immunodeficiency virus type-1 (HIV-1) latency mechanisms are reflected in the current lack of functional cure for HIV-1. Accordingly, all classes of latency-reversing ... ...

Abstract	Summary: Background: The multiplicity, heterogeneity, and dynamic nature of human immunodeficiency virus type-1 (HIV-1) latency mechanisms are reflected in the current lack of functional cure for HIV-1. Accordingly, all classes of latency-reversing agents (LRAs) have been reported to present variable ex vivo potencies. Here, we investigated the molecular mechanisms underlying the potency variability of one LRA: the DNA methylation inhibitor 5-aza-2’-deoxycytidine (5-AzadC). Methods: We employed epigenetic interrogation methods (electrophoretic mobility shift assays, chromatin immunoprecipitation, Infinium array) in complementary HIV-1 infection models (latently-infected T-cell line models, primary CD4+ T-cell models and ex vivo cultures of PBMCs from HIV+ individuals). Extracellular staining of cell surface receptors and intracellular metabolic activity were measured in drug-treated cells. HIV-1 expression in reactivation studies was explored by combining the measures of capsid p24Gag protein, green fluorescence protein signal, intracellular and extracellular viral RNA and viral DNA. Findings: We uncovered specific demethylation CpG signatures induced by 5-AzadC in the HIV-1 promoter. By analyzing the binding modalities to these CpG, we revealed the recruitment of the epigenetic integrator Ubiquitin-like with PHD and RING finger domain 1 (UHRF1) to the HIV-1 promoter. We showed that UHRF1 redundantly binds to the HIV-1 promoter with different binding modalities where DNA methylation was either non-essential, essential or enhancing UHRF1 binding. We further demonstrated the role of UHRF1 in the epigenetic repression of the latent viral promoter by a concerted control of DNA and histone methylations. Interpretation: A better understanding of the molecular mechanisms of HIV-1 latency allows for the development of innovative antiviral strategies. As a proof-of-concept, we showed that pharmacological inhibition of UHRF1 in ex vivo HIV+ patient cell cultures resulted in potent viral reactivation from latency. ...
Keywords	HIV-1 latency ; Reactivation ; UHRF1 ; Epigenetics ; EGCG ; Medicine ; R ; Medicine (General) ; R5-920
Subject code	570
Language	English
Publishing date	2022-05-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Optimal Maturation of the SIV-Specific CD8+ T Cell Response after Primary Infection Is Associated with Natural Control of SIV

Cell Reports, Vol 32, Iss 12, Pp 108174- (2020)

ANRS SIC Study

2020

Abstract: Summary: Highly efficient CD8+ T cells are associated with natural HIV control, but it has remained unclear how these cells are generated and maintained. We have used a macaque model of spontaneous SIVmac251 control to monitor the development of ... ...

Abstract	Summary: Highly efficient CD8+ T cells are associated with natural HIV control, but it has remained unclear how these cells are generated and maintained. We have used a macaque model of spontaneous SIVmac251 control to monitor the development of efficient CD8+ T cell responses. Our results show that SIV-specific CD8+ T cells emerge during primary infection in all animals. The ability of CD8+ T cells to suppress SIV is suboptimal in the acute phase but increases progressively in controller macaques before the establishment of sustained low-level viremia. Controller macaques develop optimal memory-like SIV-specific CD8+ T cells early after infection. In contrast, a persistently skewed differentiation phenotype characterizes memory SIV-specific CD8+ T cells in non-controller macaques. Accordingly, the phenotype of SIV-specific CD8+ T cells defined early after infection appears to favor the development of protective immunity in controllers, whereas SIV-specific CD8+ T cells in non-controllers fail to gain antiviral potency, feasibly as a consequence of early defects imprinted in the memory pool.
Keywords	HIV ; SIV ; natural control ; elite controllers ; T cell memory ; CD8+ T cells ; Biology (General) ; QH301-705.5
Language	English
Publishing date	2020-09-01T00:00:00Z
Publisher	Elsevier
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Article ; Online: Cis-perturbation of cancer drivers by the HTLV-1/BLV proviruses is an early determinant of leukemogenesis

Nicolas Rosewick / Keith Durkin / Maria Artesi / Ambroise Marçais / Vincent Hahaut / Philip Griebel / Natasa Arsic / Véronique Avettand-Fenoel / Arsène Burny / Carole Charlier / Olivier Hermine / Michel Georges / Anne Van den Broeke

Nature Communications, Vol 8, Iss 1, Pp 1-

2017 Volume 15

Abstract: Human T-cell leukaemia virus type-1 and bovine leukaemia virus infect T and B lymphocytes and lead to aggressive leukaemia. Here, the authors show these proviruses integrate near cancer drivers perturbing transcription termination or antisense RNA- ... ...

Abstract	Human T-cell leukaemia virus type-1 and bovine leukaemia virus infect T and B lymphocytes and lead to aggressive leukaemia. Here, the authors show these proviruses integrate near cancer drivers perturbing transcription termination or antisense RNA-dependent interaction, suggesting post-transcriptional mechanisms in some cases.
Keywords	Science ; Q
Language	English
Publishing date	2017-05-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Impact of early cART on HIV blood and semen compartments at the time of primary infection.

Antoine Chéret / Christine Durier / Adeline Mélard / Mickaël Ploquin / Julia Heitzmann / Camille Lécuroux / Véronique Avettand-Fenoël / Ludivine David / Gilles Pialoux / Jean-Marie Chennebault / Michaela Müller-Trutwin / Cécile Goujard / Christine Rouzioux / Laurence Meyer / ANRS OPTIPRIM study group

PLoS ONE, Vol 12, Iss 7, p e

2017 Volume 0180191

Abstract: HIV-infected cells in semen facilitate viral transmission. We studied the establishment of HIV reservoirs in semen and blood during PHI, along with systemic immune activation and the impact of early cART.Patients in the ANRS-147-OPTIPRIM trial received ... ...

Abstract	HIV-infected cells in semen facilitate viral transmission. We studied the establishment of HIV reservoirs in semen and blood during PHI, along with systemic immune activation and the impact of early cART.Patients in the ANRS-147-OPTIPRIM trial received two years of early cART. Nineteen patients of the trial were analyzed, out of which 8 had acute PHI (WB ≤1 Ab). We quantified total cell-associated (ca) HIV-DNA in blood and semen and HIV-RNA in blood and semen plasma samples, collected during PHI and at 24 months of treatment.At enrollment, HIV-RNA load was higher in blood than in semen (median 5.66 vs 4.22 log10 cp/mL, p<0.0001). Semen HIV-RNA load correlated strongly with blood HIV-RNA load (r = 0.81, p = 0.02, the CD4 cell count (r = -0.98, p<0.0001), and the CD4/CD8 ratio (r = -0.85, p<0.01) in acute infection but not in later stages of PHI. Median blood and seminal cellular HIV-DNA levels were 3.59 and 0.31 log10cp/106 cells, respectively. HIV-DNA load peaked in semen later than in blood and then correlated with blood IP10 level (r = 0.62, p = 0.04). HIV-RNA was undetectable in blood and semen after two years of effective cART. Semen HIV-DNA load declined similarly, except in one patient who had persistently high IP-10 and IL-6 levels and used recreational drugs.HIV reservoir cells are found in semen during PHI, with gradual compartmentalization. Its size was linked to the plasma IP-10 level. Early treatment purges both the virus and infected cells, reducing the high risk of transmission during PHI.NCT01033760.
Keywords	Medicine ; R ; Science ; Q
Subject code	630 ; 610
Language	English
Publishing date	2017-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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