Dominant-negative mutations in human IL6ST underlie hyper-IgE syndrome

Autosomal dominant hyper-IgE syndrome (AD-HIES) is typically caused by dominant-negative (DN) STAT3 mutations. Patients suffer from cold staphylococcal lesions and mucocutaneous candidiasis, severe allergy, and skeletal abnormalities. We report 12 patients from 8 unrelated kindreds with AD-HIES due to DN IL6ST mutations. We identified seven different truncating mutations, one of which was recurrent. The mutant alleles encode GP130 receptors bearing the transmembrane domain but lacking both the recycling motif and all four STAT3-recruiting tyrosine residues. Upon overexpression, the mutant proteins accumulate at the cell surface and are loss of function and DN for cellular responses to IL-6, IL-11, LIF, and OSM. Moreover, the patients’ heterozygous leukocytes and fibroblasts respond poorly to IL-6 and IL-11. Consistently, patients with STAT3 and IL6ST mutations display infectious and allergic manifestations of IL-6R deficiency, and some of the skeletal abnormalities of IL-11R deficiency. DN STAT3 and IL6ST mutations thus appear to underlie clinical phenocopies through impairment of the IL-6 and IL-11 response pathways

Distinct Genetic Loci Control Plasma HIV-RNA and Cellular HIV-DNA Levels in HIV-1 Infection: The ANRS Genome Wide Association 01 Study

Previous studies of the HIV-1 disease have shown that HLA and Chemokine receptor genetic variants influence disease progression and early viral load. We performed a Genome Wide Association study in a cohort of 605 HIV-1-infected seroconverters for detection of novel genetic factors that influence plasma HIV-RNA and cellular HIV-DNA levels. Most of the SNPs strongly associated with HIV-RNA levels were localised in the 6p21 major histocompatibility complex (MHC) region and were in the vicinity of class I and III genes. Moreover, protective alleles for four disease-associated SNPs in the MHC locus (rs2395029, rs13199524, rs12198173 and rs3093662) were strikingly over-represented among forty-five Long Term HIV controllers. Furthermore, we show that the HIV-DNA levels (reflecting the HIV reservoir) are associated with the same four SNPs, but also with two additional SNPs on chromosome 17 (rs6503919; intergenic region flanked by the DDX40 and YPEL2 genes) and chromosome 8 (rs2575735; within the Syndecan 2 gene). Our data provide evidence that the MHC controls both HIV replication and HIV reservoir. They also indicate that two additional genomic loci may influence the HIV reservoir

Antiretroviral-naive and -treated HIV-1 patients can harbour more resistant viruses in CSF than in plasma

Objectives The neurological disorders in HIV-1-infected patients remain prevalent. The HIV-1 resistance in plasma and CSF was compared in patients with neurological disorders in a multicentre study. Methods Blood and CSF samples were collected at time of neurological disorders for 244 patients. The viral loads were >50 copies/mL in both compartments and bulk genotypic tests were realized. Results On 244 patients, 89 and 155 were antiretroviral (ARV) naive and ARV treated, respectively. In ARV-naive patients, detection of mutations in CSF and not in plasma were reported for the reverse transcriptase (RT) gene in 2/89 patients (2.2%) and for the protease gene in 1/89 patients (1.1%). In ARV-treated patients, 19/152 (12.5%) patients had HIV-1 mutations only in the CSF for the RT gene and 30/151 (19.8%) for the protease gene. Two mutations appeared statistically more prevalent in the CSF than in plasma: M41L (P = 0.0455) and T215Y (P = 0.0455). Conclusions In most cases, resistance mutations were present and similar in both studied compartments. However, in 3.4% of ARV-naive and 8.8% of ARV-treated patients, the virus was more resistant in CSF than in plasma. These results support the need for genotypic resistance testing when lumbar puncture is performe

HIV controllers: to treat or not to treat? Is that the right question?

International audienceThe term HIV controller refers to the small proportion of individuals infected with HIV who can spontaneously control viraemia to maintain very low viral loads. One major unresolved question is whether HIV controllers should receive antiretroviral therapy, given that international guidelines recommend treatment for all individuals who are infected with HIV. Differences in the definitions of a controller (in terms of the viral-load cutoff and the duration of viral control) and contrasting reports on CD4 T-cell decline, chronic immune activation, the cardiovascular risk, and loss of viral control in controllers have prevented the development of a consensus view

Antiretroviral therapy for HIV controllers: Reasons for initiation and outcomes in the French ANRS-CO21 CODEX cohort

International audienceBackground: 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 [235–728]).Interpretation: Only 30% of participants in this large cohort of HIC required ART during a median follow-up of 14.8 years. These results show that HIC status is very stable and vouch for a patient-centered treatment decision based on the individual benefit/risk balance

Immunoblots may not be effective in confirming the recency of HIV-1 infection

International audienc

Immunoblots may not be effective in confirming the recency of HIV-1 infection

International audienceRecently, immunoblots (IBs) have tended to substitute Western blots (WBs) for HIV infection diagnosis. Several studies have confirmed IBs' high sensitivity to confirm HIV infection for every stage. Since the nature and pattern of the antigens of IBs are different from those of WB, the abilities of IBs and WBs to distinguish the stages of recent seroconversion and open-ended chronic infection might differ. We aimed to evaluate the performance of two IBs (INNO-LIA™ HIVI/II, Fujirebio, and Geenius™ HIV1/2 Confirmatory assay, Bio-Rad) to define the stage of infection. We studied 53 patients from the French ANRS CO6 PRIMO cohort. IBs have higher positive rates than WB. However, Geenius was less sensitive than WB and INNO-LIA to detect antibodies to p31 (0% vs 22.6 % and 15.1 %, respectively), so it could wrongly label late Fiebig stage and open-ended chronic infections as recent infections (n = 5/53). For the first time, we provide evidence that centralized WBs associated with an enzyme immunoassay for the identification of recent HIV-1 infection support the establishment of a more accurate diagnosis of primary HIV infection to improve the accuracy of enrollments in cohorts of recent HIV infections useful for epidemiological studies, pathogenesis studies or therapeutic trials

Immunoblots may not be effective in confirming the recency of HIV-1 infection

International audienceRecently, immunoblots (IBs) have tended to substitute Western blots (WBs) for HIV infection diagnosis. Several studies have confirmed IBs' high sensitivity to confirm HIV infection for every stage. Since the nature and pattern of the antigens of IBs are different from those of WB, the abilities of IBs and WBs to distinguish the stages of recent seroconversion and open-ended chronic infection might differ. We aimed to evaluate the performance of two IBs (INNO-LIA™ HIVI/II, Fujirebio, and Geenius™ HIV1/2 Confirmatory assay, Bio-Rad) to define the stage of infection. We studied 53 patients from the French ANRS CO6 PRIMO cohort. IBs have higher positive rates than WB. However, Geenius was less sensitive than WB and INNO-LIA to detect antibodies to p31 (0% vs 22.6 % and 15.1 %, respectively), so it could wrongly label late Fiebig stage and open-ended chronic infections as recent infections (n = 5/53). For the first time, we provide evidence that centralized WBs associated with an enzyme immunoassay for the identification of recent HIV-1 infection support the establishment of a more accurate diagnosis of primary HIV infection to improve the accuracy of enrollments in cohorts of recent HIV infections useful for epidemiological studies, pathogenesis studies or therapeutic trials

Prolonged Antiretroviral Treatment Induces Adipose Tissue Remodelling Associated with Mild Inflammation in SIV-Infected Macaques

During chronic SIV/HIV infection, adipose tissue (AT) is the target of both antiretroviral treatment (ART) and the virus. AT might subsequently contribute to the low-grade systemic inflammation observed in patients on ART. To evaluate the inflammatory profile of AT during chronic SIV/HIV infection, we assayed subcutaneous and visceral abdominal AT from non-infected (SIV&minus;, control), ART-na&iuml;ve SIV-infected (SIV+) and ART-controlled SIV-infected (SIV+ART+) cynomolgus macaques for the mRNA expression of genes coding for factors related to inflammation. Significant differences were observed only when comparing the SIV+ART+ group with the SIV+ and/or SIV&minus; groups. ART-treated infection impacted the metabolic fraction (with elevated expression of PPAR&gamma; and CEBP&alpha;), the extracellular matrix (with elevated expression of COL1A2 and HIF-1&alpha;), and the inflammatory profile. Both pro- and anti-inflammatory signatures were detected in AT, with greater mRNA expression of anti-inflammatory markers (adiponectin and CD163) and markers associated with inflammation (TNF-&alpha;, Mx1, CCL5 and CX3CL1). There were no intergroup differences in other markers (IL-6 and MCP-1). In conclusion, we observed marked differences in the immune and metabolic profiles of AT in the context of an ART-treated, chronic SIV infection; these differences were related more to ART than to SIV infection per se