Christina Psomas

CD32a is a marker of a CD4 T-cell HIV reservoir harbouring replication-competent proviruses

The persistence of the HIV reservoir in infected individuals is a major obstacle to the development of a cure for HIV. Here, using an in vitro model of HIV-infected quiescent CD4 T cells, we reveal a gene expression signature of 103 upregulated genes that are specific for latently infected cells, including genes for 16 transmembrane proteins. In vitro screening for surface expression in HIV-infected quiescent CD4 T cells shows that the low-affinity receptor for the immunoglobulin G Fc fragment, CD32a, is the most highly induced, with no detectable expression in bystander cells. Notably, productive HIV-1 infection of T-cell-receptor-stimulated CD4 T cells is not associated with CD32a expression, suggesting that a quiescence-dependent mechanism is required for its induction. Using blood samples from HIV-1-positive participants receiving suppressive antiretroviral therapy, we identify a subpopulation of 0.012% of CD4 T cells that express CD32a and host up to three copies of HIV DNA per cell. This CD32a+ reservoir was highly enriched in inducible replication-competent proviruses and can be predominant in some participants. Our discovery that CD32a+ lymphocytes represent the elusive HIV-1 reservoir may lead to insights that will facilitate the specific targeting and elimination of this reservoir.

Tubular and glomerular proteinuria in HIV-infected adults with estimated glomerular filtration rate ≥ 60 ml/min per 1.73 m2.

Objective:To assess the frequency of glomerular and tubular proteinuria in a cohort of HIV-infected patients, and to determine the factors associated with each type of injury. Design:Cross-sectional study of 1210 consecutive HIV-infected adults followed in HIV outpatient unit (Montpellier/France). Methods:Spot urine protein to creatinine (uPCR), albumin to creatinine (uACR) and albumin to protein (uAPR) ratios were assessed. Glomerular injury was defined as uACR at least 30 mg/g or uPCR at least 200 mg/g with uAPR at least 0.4. Tubular injury was defined as uPCR 200 mg/g or more with uAPR less than 0.4. Multivariate logistic regression identified independent factors of each type of proteinuria, in the 1158 patients with estimated glomerular filtration rate (eGFR) at least 60 ml/min per 1.73 m2, using re-expressed modification of diet in renal disease equation. Results:Frequency of proteinuria was 18.2% among patients with eGFR at least 60 ml/min per 1.73 m2 consisting in tubular proteinuria for 50.7% of them. Factors associated with glomerular proteinuria were age [OR 1.34/10-year increment (95%CI: 1.08–1.66)], diabetes [OR 3.37 (95%CI: 1.53–7.44)], and arterial hypertension [OR 2.52 (95%CI: 1.36–4.66)]. Factors associated with tubular proteinuria were age [OR 1.43 (95%CI: 1.14–1.79)], current tenofovir use [OR 3.52 (95%CI: 1.86–6.65)], hepatitis C co-infection [OR 1.62 (95%CI: 1.00–2.65)], AIDS stage [OR 1.83 (95%CI: 1.18–2.82)], CD4 cell count less than 200 per &mgr;l [OR 2.48 (95%CI: 1.31–4.70)]. Conclusion:This study distinguished risk factors for tubular injury, mainly related to HIV disease and its treatment (tenofovir), and glomerular injury, linked to non HIV-related variables (age, diabetes, hypertension). Measuring uPCR, uACR and uAPR may help with the detection and specific management of early chronic kidney disease in HIV-infected patients having normal or sub-normal eGFR.

One of the immune activation profiles observed in HIV-1-infected adults with suppressed viremia is linked to metabolic syndrome: The ACTIVIH study☆

Immune activation in HIV-1-infected individuals is reduced under antiretroviral therapies, but persists, resulting in various morbidities. To better characterize this phenomenon, using a panel of 68 soluble and cell surface markers, we measured the level of activation in circulating CD4+ and CD8+ T cells, B cells, monocytes, NK cells, polynuclear and endothelial cells as well as of inflammation and fibrinolysis in 120 virologic responders over 45 years of age. As compared with age- and sex-matched uninfected individuals, we observed a persistence of activation in all the cell subpopulations analyzed, together with marks of inflammation and fibrinolysis. Two independent hierarchical clustering analyses allowed us to identify five clusters of markers that varied concurrently, and five patient groups, each with the same activation profile. The five groups of patients could be characterized by a marker of CD4+ T cell, CD8+ T cell, NK cell, monocyte activation or of inflammation, respectively. One of these profiles was strongly associated with marks of metabolic syndrome, particularly with hyperinsulinemia (OR 12.17 [95% CI 1.79–82.86], p = 0.011). In conclusion, our study unveils biomarkers linked to metabolic syndrome that could be tested as predictive markers, and opens the way to new therapeutic approaches tailored to each patient group.

CXCR3 expression on peripheral CD4+ T cells as a predictive marker of response to treatment in chronic hepatitis C

We monitored in fifty individuals with chronic hepatitis C (CHC) the expression of CCR5 and CXCR3, two chemokine receptors involved in the intra-hepatic recruitment of T cells, at the surface of circulating CD4+ T cells. The percentage of CD4+ T cells expressing CCR5 and/or CXCR3 was increased in patients. The increased percentage of CD4+ CXCR3+ T lymphocytes was linked to serum level of aspartate aminotransferase (AST) and to fibrosis METAVIR score. CD4+ T cell surface CCR5 and CXCR3 densities increased after 6 months of treatment with pegylated interferon-alpha and ribavirin. The pre-therapeutic percentage of CD4+ CXCR3+ T cells was correlated with alanine aminotransferase serum level at 12 months, and viral load at 24 months after treatment initiation. Thus, in CHC we observed a high CXCR3 expression on peripheral blood CD4+ T cells which correlates with AST serum level and liver fibrosis, and is predictive of the response to treatment.

Maraviroc-induced decrease in circulating bacterial products is not linked to an increase in immune activation in HIV-infected individuals

To the editor: In an interesting article, Hunt et al described the effect of the addition of the CC chemokine receptor 5 (CCR5) inhibitor maraviroc to the antiretroviral regimen of 23 HIV-1–infected individuals who incompletely restored their CD4 counts under therapy.[1][1] They observed that the

Corrigendum: CD32a is a marker of a CD4 T-cell HIV reservoir harbouring replication-competent proviruses

This corrects the article DOI: 10.1038/nature21710

Corrigendum to “One of the Immune Activation Profiles Observed in HIV-1-Infected Adults with Suppressed Viremia is Linked to Metabolic Syndrome: The ACTIVIH Study” [EBioMedicine 8 (2016) 265–276]

The authors wish to republish high-resolution Figures in this article here. (See Fig. 1, Fig. 2, Fig. 3, Fig. 4, Fig. 5.)

Plasma Level of Soluble ST2 in Chronically Infected HIV-1 Patients with Suppressed Viremia

Introduction: Interleukin-33 (IL-33) is a cell damage-induced alarmin. The plasma concentration of suppression of tumorogenicity (sST2), a surrogate marker of IL-33 production, is a prognostic marker of cardiovascular disease. Observation: Recently, we reported that sST2 plasma levels were elevated in early HIV-1 infection and linked to markers of microbial translocation and of T cell activation. Results: Here we show that it is not the case in patients with suppressed viremia. Thus, IL-33 plays its alarmin role only during the early phase of the infection.

Reversing HIV latency via sphingosine-1-phosphate receptor 1 signaling

Objective: In this study, we looked for a new family of latency reversing agents. Design: We searched for G-protein-coupled receptors (GPCR) coexpressed with the C-C chemokine receptor type 5 (CCR5) in primary CD4+ T cells that activate infected cells and boost HIV production. Methods: GPCR coexpression was unveiled by reverse transcriptase-PCR. We used fluorescence resonance energy transfer to analyze the dimerization with CCR5 of the expressed GPCR. Viral entry was measured by flow cytometry, reverse transcription by quantitative PCR, nuclear factor-kappa B translocation by immunofluorescence, long terminal repeat activation using a gene reporter assay and viral production by p24 quantification. Results: G&agr;i-coupled sphingosine-1-phophate receptor 1 (S1P1) is highly coexpressed with CCR5 on primary CD4+ T cells and dimerizes with it. The presence of S1P1 had major effects neither on viral entry nor on reverse transcription. Yet, S1P1 signaling induced NF&kgr;B activation, boosting the expression of the HIV LTR. Consequently, in culture medium containing sphingosine-1-phophate, the presence of S1P1 enhanced the replication of a CCR5−, but also of a CXCR4-using HIV-1 strain. The S1P1 ligand FTY720, a drug used in multiple sclerosis treatment, inhibited HIV-1 productive infection of monocyte-derived dendritic cells and of severe combined immunodeficiency mice engrafted with human peripheral blood mononuclear cells. Conversely, S1P1 agonists were able to force latently infected peripheral blood mononuclear cells and lymph node cells to produce virions in vitro. Conclusion: Altogether these data indicate that the presence of S1P1 facilitates HIV-1 replicative cycle by boosting viral genome transcription, S1P1 antagonists have anti-HIV effects and S1P1 agonists are HIV latency reversing agents.