HIV-1 Residual Viremia Correlates with Persistent T-Cell Activation in Poor Immunological Responders to Combination Antiretroviral Therapy

BACKGROUND:The clinical significance and cellular sources of residual human immunodeficiency virus type 1 (HIV-1) production despite suppressive combination antiretroviral therapy (cART) remain unclear and the effect of low-level viremia on T-cell homeostasis is still debated. METHODOLOGY/PRINCIPAL FINDINGS:We characterized the recently produced residual viruses in the plasma and short-lived blood monocytes of 23 patients with various immunological responses to sustained suppressive cART. We quantified the residual HIV-1 in the plasma below 50 copies/ml, and in the CD14(high) CD16(-) and CD16+ monocyte subsets sorted by flow cytometry, and predicted coreceptor usage by genotyping V3 env sequences. We detected residual viremia in the plasma of 8 of 10 patients with poor CD4+ T-cell reconstitution in response to cART and in only 5 of 13 patients with good CD4+ T-cell reconstitution. CXCR4-using viruses were frequent among the recently produced viruses in the plasma and in the main CD14(high) CD16(-) monocyte subset. Finally, the residual viremia was correlated with persistent CD4+ and CD8+ T-cell activation in patients with poor immune reconstitution. CONCLUSIONS:Low-level viremia could result from the release of archived viruses from cellular reservoirs and/or from ongoing virus replication in some patients. The compartmentalization of the viruses between the plasma and the blood monocytes suggests at least two origins of residual virus production during effective cART. CXCR4-using viruses might be produced preferentially in patients on cART. Our results also suggest that low-level HIV-1 production in some patients may contribute to persistent immune dysfunction despite cART

Modélisation cellulaire de la dégénérescence neurofibrillaire (étude du rôle et des modifications des protéines Tau)

LILLE2-BU Santé-Recherche (593502101) / SudocPARIS-BIUP (751062107) / SudocSudocFranceF

Detection of filamentous tau inclusions by the fluorescent Congo red derivative FSB [(trans,trans)-1-fluoro-2,5-bis(3-hydroxycarbonyl-4-hydroxy)styrylbenzene]

Filamentous inclusions made of the microtubule-associated protein tau in a hyperphosphorylated state are a defining feature of a large number of human neurodegenerative diseases. Here we show that (trans,trans)-1-fluoro-2,5-bis(3-hydroxycarbonyl-4-hydroxy)styrylbenzene (FSB), a fluorescent Congo red derivative, labels tau inclusions in tissue sections from a mouse line transgenic for human P301S tau and in cases of familial frontotemporal dementia and sporadic Pick’s disease. Labelling by FSB required the presence of tau filaments. More importantly, tau inclusions in the spinal cord of human P301S tau transgenic mice were labelled following a single intravenous injection of FSB. These findings indicate that FSB can be used to detect filamentous tau in vivo

Experiences of HIV postexposure prophylaxis (PEP) among highly exposed men who have sex with men (MSM)

International audienc

Tau story : des démences fronto-temporales aux autres tauopathies

Les protéines tau sont des protéines associées aux microtubules. Elles sont principalement exprimées dans les neurones. Il existe six isoformes de protéines tau dans le cerveau humain adulte générées par épissage alternatif à partir d’un gène unique situé sur le chromosome 17. Ces protéines jouent un rôle dans la polymérisation et la stabilité des microtubules. Cette fonction est régulée par l’état de phosphorylation des protéines tau. Dans de nombreuses maladies neurodégénératives regroupées sous le terme tauopathies, des formes anormalement phosphorvlées d’isoformes de protéines tau s’agrègent en filaments. La phosphorylation anormale et le rapport entre les différentes isoformes de protéines tau sont primordiaux dans l’étiopathogenèse de la dégénérescence neurofibrillaire. Ces facteurs peuvent être modulés de façon directe (ululations sur le gène de tau dans certaines formes familiales de démence fronto-temporale avec syndrome parkinsonien) ou indirecte (répétitions de triplets CTG dans la dystrophie myotonique de Steinert)

Population-Based Sequencing of the V3 Region of env for Predicting the Coreceptor Usage of Human Immunodeficiency Virus Type 1 Quasispecies

Genotypic population-based methods could be faster and less expensive than phenotypic recombinant assays for determining human immunodeficiency virus type 1 (HIV-1) coreceptor usage in patient samples, but their clinical use requires good genotype-phenotype correlation and concordance with clonal analyses. We have assessed these requirements by clonal analysis of the V1 to V3 env PCR products of 26 patients infected with subtype B HIV-1. We used the resulting set of molecular clones, all sequenced and characterized using a single-cycle recombinant virus phenotypic entry assay, to reevaluate genotype-phenotype correlations. Combining the previously described 11/25 and net charge rules for the V3 genotype improved the prediction of HIV-1 coreceptor usage. We also evaluated the concordance of population-based and clonal analyses for predicting the coreceptor usage of HIV-1 quasispecies. Our population-based recombinant phenotypic assay and direct sequencing of V3 were similarly sensitive for detecting the presence of minor species in the virus population, and both correlated well with clonal analysis. The improved genotype-phenotype correlation obtained by combining two simple genotypic rules and the good concordance with clonal analyses suggest that direct sequencing of V3 is a valuable alternative to population-based recombinant phenotypic assays

Toxoplasmic encephalitis IRIS in HIV-infected patients: a case series and review of the literature

International audienceBackground: Toxoplasmic encephalitis associated with immune reconstitution inflammatory syndrome (TE-IRIS) is rarely described. Methods: To identify TE-IRIS cases, we performed a retrospective study of all HIV-infected patients diagnosed with TE in our unit between January 2000 and June 2009, and a review of published cases. Results: Three patients out of our 65 TE cases, together with six from the literature, fulfilled unmasking TE-IRIS definition. None fulfilled paradoxical TE-IRIS definition. TE occurred within a median time of 48.5 days [IQ25-75 21-56] after starting antiretroviral therapy. Cases did not have distinctive clinical nor neuroimaging features from TE occurring without immune reconstitution. However: i) Cases occurred at a median CD4 lymphocytes count of 222/µL [IQ25-75 160-280], ii) TE occurred in five patients who were supposed to take an effective chemoprophylaxis, iii) Two patients had a brain biopsy showing an intense angiocentric inflammatory infiltrates with predominantly CD8 lymphocytes, iv) In one patient, the abnormal length of evolution under treatment might be due to the heightened immune response. Conclusion: Although rare, unmasking TE-IRIS exists and might occur despite effective prophylaxis and an unusually high CD4 lymphocytes count. IRIS does not modify TE diagnosis and treatment but might extend its clinical course

Genotypic prediction of HIV-1 subtype D tropism.

International audienceUNLABELLED: ABSTRACT: BACKGROUND: HIV-1 subtype D infections have been associated with rapid disease progression and phenotypic assays have shown that CXCR4-using viruses are very prevalent. Recent studies indicate that the genotypic algorithms used routinely to assess HIV-1 tropism may lack accuracy for non-B subtypes. Little is known about the genotypic determinants of HIV-1 subtype D tropism. RESULTS: We determined the HIV-1 coreceptor usage for 32 patients infected with subtype D by both a recombinant virus phenotypic entry assay and V3-loop sequencing to determine the correlation between them. The sensitivity of the Geno2pheno10 genotypic algorithm was 75% and that of the combined 11/25 and net charge rule was 100% for predicting subtype D CXCR4 usage, but their specificities were poor (54% and 68%). We have identified subtype D determinants in the V3 region associated with CXCR4 use and built a new simple genotypic rule for optimizing the genotypic prediction of HIV-1 subtype D tropism. We validated this algorithm using an independent GenBank data set of 67 subtype D V3 sequences of viruses of known phenotype. The subtype D genotypic algorithm was 68% sensitive and 95% specific for predicting X4 viruses in this data set, approaching the performance of genotypic prediction of HIV-1 subtype B tropism. CONCLUSION: The genotypic determinants of HIV-1 subtype D coreceptor usage are slightly different from those for subtype B viruses. Genotypic predictions based on a subtype D-specific algorithm appear to be preferable for characterizing coreceptor usage in epidemiological and pathophysiological studies

Genotypic Prediction of Human Immunodeficiency Virus Type 1 CRF02-AG Tropism▿

We assessed the performance of genotypic algorithms for predicting the tropism of human immunodeficiency virus type 1 coreceptor usage in 52 patients infected with the CRF02-AG subtype. The combined criteria of the 11/25 and net charge rules accurately detected CXCR4-using CRF02-AG viruses, whereas the Geno2pheno tool lacked sensitivity and the position-specific scoring matrix (PSSM) tool WebPSSM lacked specificity