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Introduction – objectifs L’essai randomisé multicentrique OPTIPRIM avait pour objectif d’évaluer l’impact sur les niveaux d’ADN-VIH dans les lymphocytes circulants du sang périphérique (PBMC), d’un traitement initié en primo-infection VIH (PHI) de 24 mois par raltegravir, maraviroc, darunavir/r, emtricitabine/tenofovir (bras 1) en comparaison avec un traitement par darunavir/r, emtricitabine/tenofovir (bras 2). Matériels et méthodes Patients en PHI : western blot (WB) incomplet ≤ 4 anticorps (Ac) et ARN-VIH positive (VL). Interruption de traitement à M24 si VL < 50 copies (cp)/mL et CD4 ≥ 500/mm 3 or ≥ 3 0 % et reprise si VL ≥ 50 000 cp/mL et CD4 < 500/mm 3 et < 30 %. Résultats 90 patients, à 36 jours en médiane de la contamination, 43 % avec un WB ≤ 1 Ac. Les traitements ont été bien tolérés. À M24, en intention de traiter, bras 1 et 2 : décroissance similaire de l’ADN-VIH en médiane à – 1,43 et – 1,44 log 10 cp/10 6 PBMC (p = 0,8), gain de CD4 équivalent, proportion similaire de patients avec VL < 50 cp/mL, 91 % et 93 % respectivement. Dans le bras 1, cinétique paradoxale de VL < 50cp/ml 60 % à M3 vs 31 % (p = 0,01), puis moins bon contrôle virologique de M6 à M18 (p < 0,04). Un sujet (bras2) maintient un statut contrôleur post traitement (PTC) avec VL < 20 cp/mL > 18 mois après l’interruption. Conclusion Emtricitabine/tenofovir + darunavir/r en PHI permet une diminution intense du réservoir VIH, sans bénéfice additionnel de la pentathérapie. L’effet immuno-modulateur du maraviroc pourrait expliquer la faible charge virale persistante paradoxale. Preuve du concept, dans une étude randomisée, que l’interruption d’un traitement initié précocement en PHI peut conduire à l’état de PTC. [ABSTRACT FROM AUTHOR]

The investigation of the methanol extract of the flowers of Jacaranda mimosifolia led to the isolation and characterisation of fourteen secondary metabolites (1-14) by the means of chromatographic and spectroscopic analysis. These compounds include eight flavonoids sorted as two flavonols (1-2), three flavones (3, 7-8), and three isoflavones (4, 9-10), two glucoiridoids (5-6), and four triterpenoids sorted as one oleanane (11), one hopane (12), and two lupane (13-14). The in vitro antioxidant potential of all the isolated compounds was evaluated using the ABTS- and FRAP- methods, which demonstrated concentration-dependent activity. Chloroflavonin A (1) and 4',5,7-trihydroxyflavone (2) demonstrated exceptional antioxidant activity, with scavenging rates of 98.63 % and 97.89 %, respectively, at a concentration of 300 μg/mL, and also showed strong ferric-reducing antioxidant power. Chloroflavonin A (1) demonstrated the most potent dual inhibitory effects on Cyclooxigenase-2 (COX-2) and NADPH-Oxidase-5 (NOX-5) enzymes, with binding affinities of -9.7 and -8.2 kcal/mol, respectively, indicating its potential as a strong anti-inflammatory compound. The molecular dynamics simulation, conducted with the Desmond v3.6, demonstrated the stability of the various complexes within the biological system. The findings indicate that compounds derived from Jacaranda mimosifolia may serve as potential therapeutic agents for the management of inflammation and oxidative stress., Competing Interests: Declaration of Competing Interest None., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Background: Therapeutic control of HIV replication reduces the size of the viral reservoir, particularly among central memory CD4+ T cells, and this effect might be accentuated by early treatment., Methods: We examined the effect of ART initiated at the time of the primary HIV infection (early ART), lasting 2 and 6 years in 11 and 10 patients, respectively, on the HIV reservoir in peripheral resting CD4+ T cells, sorted into naive (TN), central memory (TCM), transitional memory (TTM) and effector memory (TEM) cells, by comparison with 11 post-treatment controllers (PTCs)., Results: Between baseline and 2 years, CD4+ T cell subset numbers increased markedly (P < 0.004) and HIV DNA levels decreased in all subsets (P < 0.009). TTM cells represented the majority of reservoir cells at both timepoints, T cell activation status normalized and viral diversity remained stable over time. The HIV reservoir was smaller after 6 years of early ART than after 2 years (P < 0.019), and did not differ between PTCs and patients treated for 6 years. One patient, who had low reservoir levels in all T cell subsets after 2 years of treatment similar to the levels in PTCs, spontaneously controlled viral replication during 18 months off treatment., Conclusions: Early prolonged ART thus limits the size of the HIV reservoir, protects long-lived cells from persistent infection and may enhance post-treatment control., (© The Author 2015. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Background: Early combination antiretroviral therapy (cART) initiation at the time of primary HIV-1 infection could restrict the establishment of HIV reservoirs. We aimed to assess the effect of a cART regimen intensified with raltegravir and maraviroc, compared with standard triple-drug cART, on HIV-DNA load., Methods: In this randomised, open-label, phase 3 trial, we recruited patients from hospitals across France. Inclusion criteria were primary HIV-1 infection (an incomplete HIV-1 western blot and detectable plasma HIV-RNA), with either symptoms or a CD4+ cell count below 500 cells per μL. Patients were randomly assigned (1:1) to an intensive, five-drug cART regimen (raltegravir 400 mg and maraviroc 150 mg twice daily, and a fixed-dose combination of tenofovir disoproxil fumarate 300 g plus emtricitabine 200 g, darunavir 800 g, and ritonavir 100 g once daily) or a standard triple-drug cART regimen (tenofovir disoproxil fumarate 300 g plus emtricitabine 200 g, darunavir 800 g, and ritonavir 100 g once daily) using a predefined randomised list generated by randomly selected variable block sizes. The primary endpoint was the median number of HIV-DNA copies per 10(6) peripheral blood mononuclear cells (PBMC) at month 24, analysed in the modified intention-to-treat population, defined as all patients who started their assigned treatment. This study is registered with ClinicalTrials.gov, number NCT01033760., Findings: Between April 26, 2010, and July 13, 2011, 110 patients were enrolled, of whom 92 were randomly assigned and 90 started treatment (45 in each treatment group). Six (13%) patients in the intensive cART group and two (4%) in the standard cART group discontinued before month 24. At month 24, HIV-DNA loads were similar between groups (2·35 [IQR 2·05-2·50] log₁₀ per 10(6) PBMC in the intensive cART group vs 2·25 [1·71-2·55] in the standard cART group; p=0·21). Eight grade 3-4 clinical adverse events were reported in seven patients in the intensive cART group and seven grade 3-4 clinical adverse events were reported in seven patients in the standard cART group. Three serious clinical adverse events occurred: two (pancreatitis and lipodystrophy) in the standard cART group, which were regarded as treatment related, and one event (suicide attempt) in the intensive cART group that was unrelated to treatment., Interpretation: After 24 months, cART intensified with raltegravir and maraviroc did not have a greater effect on HIV blood reservoirs than did standard cART. These results should help to design future trials of treatments aiming to decrease the HIV reservoir in patients with primary HIV-1 infection., Funding: Inserm-ANRS, Gilead Sciences, Janssen Pharmaceuticals, Merck, and ViiV Laboratories., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Optimizing therapeutic strategies for an HIV cure requires better understanding the characteristics of early HIV-1 spread among resting CD4+ cells within the first month of primary HIV-1 infection (PHI). We studied the immune distribution, diversity, and inducibility of total HIV-DNA among the following cell subsets: monocytes, peripheral blood activated and resting CD4 T cells, long-lived (naive [TN] and central-memory [TCM]) and short-lived (transitional-memory [TTM] and effector-memory cells [TEM]) resting CD4+T cells from 12 acutely-infected individuals recruited at a median 36 days from infection. Cells were sorted for total HIV-DNA quantification, phylogenetic analysis and inducibility, all studied in relation to activation status and cell signaling. One month post-infection, a single CCR5-restricted viral cluster was massively distributed in all resting CD4+ subsets from 88% subjects, while one subject showed a slight diversity. High levels of total HIV-DNA were measured among TN (median 3.4 log copies/million cells), although 10-fold less (p = 0.0005) than in equally infected TCM (4.5), TTM (4.7) and TEM (4.6) cells. CD3-CD4+ monocytes harbored a low viral burden (median 2.3 log copies/million cells), unlike equally infected resting and activated CD4+ T cells (4.5 log copies/million cells). The skewed repartition of resting CD4 subsets influenced their contribution to the pool of resting infected CD4+T cells, two thirds of which consisted of short-lived TTM and TEM subsets, whereas long-lived TN and TCM subsets contributed the balance. Each resting CD4 subset produced HIV in vitro after stimulation with anti-CD3/anti-CD28+IL-2 with kinetics and magnitude varying according to subset differentiation, while IL-7 preferentially induced virus production from long-lived resting TN cells. In conclusion, within a month of infection, a clonal HIV-1 cluster is massively distributed among resting CD4 T-cell subsets with a flexible inducibility, suggesting that subset activation and skewed immune homeostasis determine the conditions of viral dissemination and early establishment of the HIV reservoir.

The adherence profile of HIV-infected patients predicts the therapeutic outcome, in particular during the early phase of antiretroviral therapy (ART). We conducted a prospective observational multicenter trial monitoring adherence and virological and immunological parameters over the initial 6 months of treatment. Thirty-five subjects were starting a treatment regimen including atazanavir, ritonavir, and emtricitabine-tenofovir. Adherence was assessed using self-completed questionnaires, announced pill counts, and the medication event monitoring system (MEMS) for each drug. Three MEMS measures were defined: the percentages of doses taken, days with the correct dosing, and doses taken on time (± 3 h). Dynamic virological suppression (DVS) was defined as a reduction in the plasma HIV-RNA level of >1 log10 per month or <40 copies/ml. The cumulative treatment time was 5,526 days. A high level of adherence was observed. The MEMS-defined adherence for correct dosing (-0.68% per 4-week period, P < 0.03) and timing compliance (-1.60% per 4-week period, P < 0.003) decreased significantly over time. The MEMS-defined adherence data were concordant with the pill counts during the trial but not with the data from the questionnaires. The median [range] percentages of doses taken (100% [50 to 102]), days with the correct dosing (95% [41 to 100]), and doses taken on time (86% [32 to 100]) were significantly associated with DVS in separate models. Among these three measures, the percentage of doses taken on time had the greatest ability to predict DVS. Timing compliance should be supported to optimize DVS during the early phase of treatment by once-daily boosted protease inhibitor-based ART. (This study has been registered at ClinicalTrials.gov under registration no. NCT00528060.).

The strong CD8+ T-cell-mediated HIV-1-suppressive capacity found in a minority of HIV-infected patients in chronic infection is associated with spontaneous control of viremia. However, it is still unclear whether such capacities were also present earlier in the CD8+ T cells from non controller patients and then lost as a consequence of uncontrolled viral replication. We studied 50 patients with primary HIV-1-infection to determine whether strong CD8+ T-cell-mediated HIV suppression is more often observed at that time. Despite high frequencies of polyfunctional HIV-specific CD8+ T-cells and a strong CD4+ T-helper response, CD8+ T-cells from 48 patients lacked strong HIV-suppressive capacities ex vivo. This indicates that the superior HIV-suppressive capacity of CD8+ T-cells from HIV controllers is not a general characteristic of the HIV-specific CD8+ T cell response in primary HIV infection.