Different Plasma Markers of Inflammation Are Influenced by Immune Recovery and cART Composition or Intensification in Treated HIV Infected Individuals

BACKGROUND: HIV-1 infection increases plasma levels of inflammatory markers. Combination antiretroviral therapy (cART) does not restore inflammatory markers to normal levels. Since intensification of cART with raltegravir reduced CD8 T-cell activation in the Discor-Ral and IntegRal studies, we have evaluated the effect of raltegravir intensification on several soluble inflammation markers in these studies. METHODS: Longitudinal plasma samples (0-48 weeks) from the IntegRal (n = 67, 22 control and 45 intensified individuals) and the Discor-Ral studies (44 individuals with CD4 T-cell counts<350 cells/µl, 14 control and 30 intensified) were assayed for 25 markers. Mann-Whitney, Wilcoxon, Spearman test and linear mixed models were used for analysis. RESULTS: At baseline, different inflammatory markers were strongly associated with HCV co-infection, lower CD4 counts and with cART regimens (being higher in PI-treated individuals), but poorly correlated with detection of markers of residual viral replication. Although raltegravir intensification reduced inflammation in individuals with lower CD4 T-cell counts, no effect of intensification was observed on plasma markers of inflammation in a global analysis. An association was found, however, between reductions in immune activation and plasma levels of the coagulation marker D-dimer, which exclusively decreased in intensified patients on protease inhibitor (PI)-based cART regimens (P = 0.040). CONCLUSIONS: The inflammatory profile in treated HIV-infected individuals showed a complex association with HCV co-infection, the levels of CD4 T cells and the cART regimen. Raltegravir intensification specifically reduced D-dimer levels in PI-treated patients, highlighting the link between cART composition and residual viral replication; however, raltegravir had little effect on other inflammatory markers

Identification of interleukin-27 (IL-27)/IL-27 receptor subunit alpha as a critical immune axis for in vivo hiv control

Intact and broad immune cell effector functions and specific individual cytokines have been linked to HIV disease outcome, but their relative contribution to HIV control remains unclear. We asked whether the proteome of secreted cytokines and signaling factors in peripheral blood can be used to discover specific pathways critical for host viral control. A custom glass-based microarray, able to measure >600 plasma proteins involved in cell-to-cell communication, was used to measure plasma protein profiles in 96 HIV-infected, treatment-naive individuals with high (> 50,000) or low (<10,000 HIV RNA copies/ml) viral loads. Univariate and regression model analysis demonstrate that plasma levels of soluble interleukin-27 (IL-27) are significantly elevated in individuals with high plasma viremia (P < 0.0001) and are positively correlated with proviral HIV-DNA copy numbers in peripheral blood mononuclear cells (PBMC) (Rho = 0.4011; P = 0.0027). Moreover, soluble IL-27 plasma levels are negatively associated with the breadth and magnitude of the total virus-specific T-cell responses and directly with plasma levels of molecules involved in Wnt/beta-catenin signaling. In addition to IL-27, gene expression levels of the specific IL-27 receptor (IL27RA) in PBMC correlated directly with both plasma viral load (Rho = 0.3531; P = 0.0218) and the proviral copy number in the peripheral blood as an indirect measure of partial viral reservoir (Rho = 0.4580; P = 0.0030). These results were validated in unrelated cohorts of early infected subjects as well as subjects before and after initiation of antiretroviral treatment, and they identify IL-27 and its specific receptor as a critical immune axis for the antiviral immune response and as robust correlates of viral load and proviral reservoir size in PBMC. IMPORTANCE The detailed knowledge of immune mechanisms that contribute to HIV control is a prerequisite for the design of effective treatment strategies to achieve HIV cure. Cells communicate with each other by secreting signaling proteins, and the blood is a key conduit for transporting such factors. Investigating the communication factors promoting effective immune responses and having potentially antiviral functions against HIV using a novel focused omics approach (Peer ReviewedPostprint (published version

Methylation regulation of Antiviral host factors, Interferon Stimulated Genes (ISGs) and T-cell responses associated with natural HIV control

GWAS, immune analyses and biomarker screenings have identified host factors associated with in vivo HIV-1 control. However, there is a gap in the knowledge about the mechanisms that regulate the expression of such host factors. Here, we aimed to assess DNA methylation impact on host genome in natural HIV-1 control. To this end, whole DNA methylome in 70 untreated HIV-1 infected individuals with either high (>50,000 HIV-1-RNA copies/ml, n = 29) or low (<10,000 HIV-1-RNA copies/ml, n = 41) plasma viral load (pVL) levels were compared and identified 2,649 differentially methylated positions (DMPs). Of these, a classification random forest model selected 55 DMPs that correlated with virologic (pVL and proviral levels) and HIV-1 specific adaptive immunity parameters (IFNg-T cell responses and neutralizing antibodies capacity). Then, cluster and functional analyses identified two DMP clusters: cluster 1 contained hypo-methylated genes involved in antiviral and interferon response (e.g. PARP9, MX1, and USP18) in individuals with high viral loads while in cluster 2, genes related to T follicular helper cell (Tfh) commitment (e.g. CXCR5 and TCF7) were hyper-methylated in the same group of individuals with uncontrolled infection. For selected genes, mRNA levels negatively correlated with DNA methylation, confirming an epigenetic regulation of gene expression. Further, these gene expression signatures were also confirmed in early and chronic stages of infection, including untreated, cART treated and elite controllers HIV-1 infected individuals (n = 37). These data provide the first evidence that host genes critically involved in immune control of the virus are under methylation regulation in HIV-1 infection. These insights may offer new opportunities to identify novel mechanisms of in vivo virus control and may prove crucial for the development of future therapeutic interventions aimed at HIV-1 cure

Evidence for HIV-1 cure after CCR5 Δ32/Δ32 allogeneic haemopoietic stem-cell transplantation 30 months post analytical treatment interruption : a case report

The London patient (participant 36 in the IciStem cohort) underwent allogeneic stem-cell transplantation with cells that did not express CCR5 (CCR5 Δ32/Δ32); remission was reported at 18 months after analytical treatment interruption (ATI). Here, we present longer term data for this patient (up to 30 months after ATI), including sampling from diverse HIV-1 reservoir sites. We used ultrasensitive viral load assays of plasma, semen, and cerebrospinal fluid (CSF) samples to detect HIV-1 RNA. In gut biopsy samples and lymph-node tissue, cell-copy number and total HIV-1 DNA levels were quantified in multiple replicates, using droplet digital PCR (ddPCR) and quantitative real-time PCR. We also analysed the presence of intact proviral DNA using multiplex ddPCR targeting the packaging signal (ψ) and envelope (env). We did intracellular cytokine staining to measure HIV-1-specific T-cell responses. We used low-sensitive and low-avidity antibody assays to measure the humoral response to HIV-1. We predicted the probability of rebound using a mathematical model and inference approach. HIV-1 viral load in plasma remained undetectable in the London patient up to 30 months (last tested on March 4, 2020), using an assay with a detection limit of 1 copy per mL. The patient's CD4 count was 430 cells per μL (23·5% of total T cells) at 28 months. A very low-level positive signal for HIV-1 DNA was recorded in peripheral CD4 memory cells at 28 months. The viral load in semen was undetectable in both plasma (lower limit of detection [LLD] <12 copies per mL) and cells (LLD 10 copies per 10 6 cells) at 21 months. CSF was within normal parameters at 25 months, with HIV-1 RNA below the detection limit (LLD 1 copy per mL). HIV-1 DNA by ddPCR was negative in rectum, caecum, and sigmoid colon and terminal ileum tissue samples at 22 months. Lymph-node tissue from axilla was positive for the long-terminal repeat (33 copies per 10 6 cells) and env (26·1 copies per 10 6 cells), negative for ψ and integrase, and negative by the intact proviral DNA assay, at 27 months. HIV-1-specific CD4 and CD8 T-cell responses have remained absent at 27 months. Low-avidity Env antibodies have continued to decline. Mathematical modelling suggests that the probability of remission for life (cure) is 98% in the context of 80% donor chimerism in total HIV target cells and greater than 99% probability of remission for life with 90% donor chimerism. The London patient has been in HIV-1 remission for 30 months with no detectable replication-competent virus in blood, CSF, intestinal tissue, or lymphoid tissue. Donor chimerism has been maintained at 99% in peripheral T cells. We propose that these findings represent HIV-1 cure. Wellcome Trust and amfAR (American Foundation for AIDS Research)

Pasado y futuro de la infección por VIH. Un documento basado en la opinión de expertos

[EN] HIV infection is now almost 40 years old. In this time, along with the catastrophe and tragedy that it has entailed, it has also represented the capacity of modern society to take on a challenge of this magnitude and to transform an almost uniformly lethal disease into a chronic illness, compatible with a practically normal personal and relationship life. This anniversary seemed an ideal moment to pause and reflect on the future of HIV infection, the challenges that remain to be addressed and the prospects for the immediate future. This reflection has to go beyond merely technical approaches, by specialized professionals, to also address social and ethical aspects. For this reason, the Health Sciences Foundation convened a group of experts in different aspects of this disease to discuss a series of questions that seemed pertinent to all those present. Each question was presented by one of the participants and discussed by the group. The document we offer is the result of this reflection.[ES] La infección por VIH cumple ahora casi 40 años de existencia. En este tiempo, junto a la catástrofe y la tragedia que ha supuesto, ha representado también la capacidad de la sociedad moderna de asumir un reto de esta magnitud y de transformar, gracias al tratamiento antirretroviral, una enfermedad mayoritariamente letal en una enfermedad crónica, compatible con una vida personal y de relación prácticamente normales. Este aniversario parecía un momento idóneo para pararse a reflexionar sobre el futuro de la infección VIH, los retos que todavía quedan por abordar y las perspectivas para el inmediato futuro. Esa reflexión tiene que ir más allá de planteamientos meramente técnicos, de profesionales especializados, para abordar aspectos sociales y éticos. Por este motivo, la Fundación de Ciencias de la Salud convocó a un grupo de expertos en distintos aspectos de esta infección para discutir una serie de preguntas que parecieron pertinentes a todos los convocados. Cada pregunta era expuesta por uno de los participantes y discutida por el grupo. El documento que ofrecemos es el resultado de esa reflexión.For transparency purposes, we would like to inform you that GSK has contributed to the funding of this publicationPeer reviewe

Phase I clinical trial of an intranodally administered mRNA-based therapeutic vaccine against HIV-1 infection

OBJECTIVE: The efficacy of therapeutic vaccines against HIV-1 infection has been modest. New inerts to redirect responses to vulnerable sites are urgently needed to improve these results.DESIGN: We performed the first-in-human clinical trial with naked mRNA (iHIVARNA) combining a dendritic cell activation strategy (TriMix:CD40L+CD70+caTLR4 RNA) with a novel HIV immunogen sequences (HTI immunogen).METHODS: A dose escalation, phase I clinical trial was performed in 21 chronic HIV-1-infected patients under ART who received three intranodal doses of mRNA (weeks 0, 2 and 4

Short-course antibiotic regimen compared to conventional antibiotic treatment for gram-positive cocci infective endocarditis: randomized clinical trial (SATIE).

Most serious complications of infective endocarditis (IE) appear in the so-called "critical phase" of the disease, which represents the first days after diagnosis. The majority of patients overcoming the acute phase has a favorable outcome, yet they remain hospitalized for a long period of time mainly to complete antibiotic therapy. The major hypothesis of this trial is that in patients with clinically stable IE and adequate response to antibiotic treatment, without signs of persistent infection, periannular complications or metastatic foci, a shorter antibiotic time period would be as efficient and safe as the classic 4 to 6 weeks antibiotic regimen. Multicenter, prospective, randomized, controlled open-label, phase IV clinical trial with a non-inferiority design to evaluate the efficacy of a short course (2 weeks) of parenteral antibiotic therapy compared with conventional antibiotic therapy (4-6 weeks). patients with IE caused by gram-positive cocci, having received at least 10 days of conventional antibiotic treatment, and at least 7 days after surgery when indicated, without clinical, analytical, microbiological or echocardiographic signs of persistent infection. Estimated sample size: 298 patients. Control group: standard duration antibiotic therapy, (4 to 6 weeks) according to ESC guidelines recommendations. Experimental group: short-course antibiotic therapy for 2 weeks. The incidence of the primary composite endpoint of all-cause mortality, unplanned cardiac surgery, symptomatic embolisms and relapses within 6 months after the inclusion in the study will be prospectively registered and compared. SATIE will investigate whether a two weeks short-course of intravenous antibiotics in patients with IE caused by gram-positive cocci, without signs of persistent infection, is not inferior in safety and efficacy to conventional antibiotic treatment (4-6 weeks). ClinicalTrials.gov Identifier: NCT04222257 (January 7, 2020). EudraCT 2019-003358-10

Identification of Siglec-1 null individuals infected with HIV-1

Altres ajudes: Gilead Fellowship Program GLD1400271; Mathilde Krim Fellowship in basic biomedical research 10867; SHCS Project number 717; Swiss National Science Foundation (Grant Number 148522); NIAID U01-AI35042, U01-AI35039, U01-AI35040, U01-AI35041 i UM1-AI3504; Frederick National Laboratory for Cancer Research contract HHSN261200800001ESiglec-1/CD169 is a myeloid-cell surface receptor critical for HIV-1 capture and infection of bystander target cells. To dissect the role of SIGLEC1 in natura, we scan a large population genetic database and identify a loss-of-function variant (Glu88Ter) that is found in ∼1% of healthy people. Exome analysis and direct genotyping of 4,233 HIV-1-infected individuals reveals two Glu88Ter homozygous and 97 heterozygous subjects, allowing the analysis of ex vivo and in vivo consequences of SIGLEC1 loss-of-function. Cells from these individuals are functionally null or haploinsufficient for Siglec-1 activity in HIV-1 capture and trans-infection ex vivo. However, Siglec-1 protein truncation does not have a measurable impact on HIV-1 acquisition or AIDS outcomes in vivo. This result contrasts with the known in vitro functional role of Siglec-1 in HIV-1 trans-infection. Thus, it provides evidence that the classical HIV-1 infectious routes may compensate for the lack of Siglec-1 in fuelling HIV-1 dissemination within infected individuals

Different Plasma Markers of Inflammation Are Influenced by Immune Recovery and cART Composition or Intensification in Treated HIV Infected Individuals

BACKGROUND: HIV-1 infection increases plasma levels of inflammatory markers. Combination antiretroviral therapy (cART) does not restore inflammatory markers to normal levels. Since intensification of cART with raltegravir reduced CD8 T-cell activation in the Discor-Ral and IntegRal studies, we have evaluated the effect of raltegravir intensification on several soluble inflammation markers in these studies. METHODS: Longitudinal plasma samples (0-48 weeks) from the IntegRal (n = 67, 22 control and 45 intensified individuals) and the Discor-Ral studies (44 individuals with CD4 T-cell counts<350 cells/µl, 14 control and 30 intensified) were assayed for 25 markers. Mann-Whitney, Wilcoxon, Spearman test and linear mixed models were used for analysis. RESULTS: At baseline, different inflammatory markers were strongly associated with HCV co-infection, lower CD4 counts and with cART regimens (being higher in PI-treated individuals), but poorly correlated with detection of markers of residual viral replication. Although raltegravir intensification reduced inflammation in individuals with lower CD4 T-cell counts, no effect of intensification was observed on plasma markers of inflammation in a global analysis. An association was found, however, between reductions in immune activation and plasma levels of the coagulation marker D-dimer, which exclusively decreased in intensified patients on protease inhibitor (PI)-based cART regimens (P = 0.040). CONCLUSIONS: The inflammatory profile in treated HIV-infected individuals showed a complex association with HCV co-infection, the levels of CD4 T cells and the cART regimen. Raltegravir intensification specifically reduced D-dimer levels in PI-treated patients, highlighting the link between cART composition and residual viral replication; however, raltegravir had little effect on other inflammatory markers