Glycan deletions in the HIV-1 gp120 V1/V2 domain compromise viral infectivity, sensitize the mutant virus strains to carbohydrate-binding agents and represent a specific target for therapeutic intervention

AbstractCarbohydrate-binding agents (CBAs), such as the mannose-specific Hippeastrum hybrid agglutinin (HHA) and the GlcNAc-specific Urtica dioica agglutinin (UDA), frequently select for glycan deletions in all different domains of HIV-1 gp120, except in the V1/V2 domain. To reveal the underlying mechanisms, a broad variety of 31 different virus strains containing one or several N-glycan deletions in V1/V2 of the gp120 of the X4-tropic HIV-1NL4.3 were constructed by chimeric virus technology. No co-receptor switch to CCR5 was observed for any of the replication-competent mutant virus strains. With a few exceptions, the more glycans were deleted in the gp120 V1/V2 domain, the more the replication capacity of the mutant viruses became compromised. None of the mutant virus strains showed a markedly decreased sensitivity to the inhibitory activity of HHA and UDA. Instead, an up to 2- to 10-fold higher sensitivity to the inhibitory activity of these CBAs was observed. Our data may provide an explanation why glycan deletions in the gp120 V1/V2 domain rarely occur under CBA pressure and confirm the important functional role of the glycans in the HIV-1 gp120 V1/V2 domain. The gp120 V1/V2 loop glycans of HIV-1 should therefore be considered as a hot spot and novel target for specific therapeutic drug intervention

Lck Availability during Thymic Selection Determines the Recognition Specificity of the T Cell Repertoire

SummaryThymic selection requires signaling by the protein tyrosine kinase Lck to generate T cells expressing αβ T cell antigen receptors (TCR). For reasons not understood, the thymus selects only αβTCR that are restricted by major histocompatibility complex (MHC)-encoded determinants. Here, we report that Lck proteins that were coreceptor associated promoted thymic selection of conventionally MHC-restricted TCR, but Lck proteins that were coreceptor free promoted thymic selection of MHC-independent TCR. Transgenic TCR with MHC-independent specificity for CD155 utilized coreceptor-free Lck to signal thymic selection in the absence of MHC, unlike any transgenic TCR previously described. Thus, the thymus can select either MHC-restricted or MHC-independent αβTCR depending on whether Lck is coreceptor associated or coreceptor free. We conclude that the intracellular state of Lck determines the specificity of thymic selection and that Lck association with coreceptor proteins during thymic selection is the mechanism by which MHC restriction is imposed on a randomly generated αβTCR repertoire

Troponin T in COVID-19 hospitalized patients: Kinetics matter

Background: Coronavirus disease 2019 (COVID-19) emerged as a worldwide health crisis, overwhelming healthcare systems. Elevated cardiac troponin T (cTn T) at admission was associated with increased in-hospital mortality. However, data addressing the role of cTn T in major adverse cardiovascular events (MACE) in COVID-19 are scarce. Therefore, we assessed the role of baseline cTn T and cTn T kinetics for MACE and in-hospital mortality prediction in COVID-19.Methods: Three hundred and ten patients were included prospectively. One hundred and eight patients were excluded due to incomplete records. Patients were divided into three groups according to cTn T kinetics: ascending, descending, and constant. The cTn T slope was defined as the ratio of the cTn T change over time. The primary and secondary endpoints were MACE and in-hospital mortality.Results: Two hundred and two patients were included in the analysis (mean age 64.4 ± 16.7 years, 119 [58.9%] males). Mean duration of hospitalization was 14.0 ± 12.3 days. Sixty (29.7%) patients had MACE, and 40 (19.8%) patients died. Baseline cTn T predicted both endpoints (p = 0.047, hazard ratio [HR] 1.805, 95% confidence interval [CI] 1.009–3.231; p = 0.009, HR 2.322, 95% CI 1.234–4.369). Increased cTn T slope predicted mortality (p = 0.041, HR 1.006, 95% CI 1.000–1.011). Constant cTn T was associated with lower MACE and mortality (p = 0.000, HR 3.080, 95% CI 1.914–4.954, p = 0.000, HR 2.851, 95% CI 1.828–4.447).Conclusions: The present study emphasizes the additional role of cTn T testing in COVID-19 patients for risk stratification and improved diagnostic pathway and management

Coreceptor gene imprinting governs thymocyte lineage fate

Double-positive (CD4+CD8+) thymocytes differentiate into CD4+ helper T cells and CD8+ cytotoxic T cells. A knock-in approach replacing CD8-coding sequences with CD4 cDNA shows that it is the expression kinetics of CD8, and not the identity of the coreceptor, that governs thymocyte-lineage fate

Transmitted drug resistance, selection of resistance mutations and moderate antiretroviral efficacy in HIV-2: Analysis of the HIV-2 Belgium and Luxembourg database

BACKGROUND: Guidelines established for the treatment of HIV-1 infection and genotype interpretation do not apply for HIV-2. Data about antiretroviral (ARV) drug efficacy and resistance mutations is scarce. METHODS: Clinical data about HIV-2 infected patients in Belgium and Luxembourg were collected and the effect of ARV therapy on plasma viral load and CD4 counts were analysed. Viral RNA encoding for protease (PR) and reverse transcriptase (RT) from ARV-naive and treated patients were sequenced. RESULTS: Sixty-five HIV-2 infected patients were included in this cohort. Twenty patients were treated with 25 different ARV combinations in a total of 34 regimens and six months after the start of ARV therapy, only one third achieved viral load suppression. All of these successful regimens bar one contained protease inhibitors (PIs). Mean CD4 gains in the group of viral load suppressors and the group of patients treated with PI-containing regimens were respectively significantly higher than in the group of non-suppressors and the group of PI-sparing regimens. The most frequent mutations selected under therapy (compared to HIV-2 ROD) were V71I, L90M and I89V within PR. Within RT, they were M184V, Q151M, V111I and K65R. All of these mutations, except K65R and M184V, were also found in variable proportions in ARV-naive patients. CONCLUSION: Despite a high rate of ARV treatment failure, better virological and immunological results were achieved with PI-containing regimens. The analysis of polymorphic positions and HIV-2 specific mutations selected during therapy showed for the first time that transmission of drug resistant viruses has occurred in Belgium and Luxembourg. The high heterogeneity in ARV combinations reflects a lack of guidelines for the treatment of HIV-2 infection

Atténuation des signaux de transduction du récepteurt des lymphocytes T par les glucocorticoïdes

Doctorat en Sciencesinfo:eu-repo/semantics/nonPublishe

Correlation for multi-frequency propagation in urban environments

The multi-frequency propagation in urban environment is investigated in this letter. An experimental measurement campaign is conducted to simultaneously measure the GSM-900, GSM-1800 and UMTS band of a cellular system in a suburban environment. The shadowing and small-scale fading parameters are extracted, and the correlation of these parameters across the different frequency bands is measured. It is shown that shadowing coeffcients are highly correlated, while small-scale fading is completely uncorrelated between different frequency bands.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Targeting CD4 coreceptor expression to postselection thymocytes reveals that CD4/CD8 lineage choice is neither error-prone nor stochastic

The mechanism by which CD4/CD8 lineage choice is coordinated with TCR specificity during positive selection remains an unresolved problem in immunology. The stochastic/selection model proposes that CD4/CD8 lineage choice in TCR-signaled CD4+CD8+ thymocytes occurs randomly and therefore is highly error-prone. This perspective is strongly supported by "coreceptor rescue" experiments in which transgenic CD4 coreceptors were ectopically expressed on thymocytes throughout their development and caused significant numbers of cells bearing MHC-II-specific TCR to differentiate into mature, CD8 lineage T cells. However, it is not known if forced coreceptor expression actually rescued positively selected thymocytes making an incorrect lineage choice or if it influenced developing thymocytes into making an incorrect lineage choice. We have now reassessed coreceptor rescue and the concept that lineage choice is highly error-prone with a novel CD4 transgene (referred to as E8I-CD4) that targets expression of transgenic CD4 coreceptors specifically to thymocytes that have already undergone positive selection and adopted a CD8 lineage fate. Unlike previous CD4 transgenes, the E8I-CD4 transgene has no effect on early thymocyte development and cannot itself influence CD4/CD8 lineage choice. We report that the E8I-CD4 transgene did in fact induce expression of functional CD4 coreceptor proteins on newly arising CD8 lineage thymocytes precisely at the point in thymic development that transgenic CD4 coreceptors would putatively rescue MHC-II-specific thymocytes that incorrectly adopted the CD8 lineage. However, the E8I-CD4 transgene did not reveal any MHC-II-selected thymocytes that adopted the CD8 lineage fate. These results demonstrate that CD4/CD8 lineage choice is neither error-prone nor stochastic

A novel aspect of the anti-inflammatory actions of glucocorticoids: inhibition of proximal steps of signaling cascades in lymphocytes

Glucocorticoid hormones are effective in inhibiting inflammatory responses, but the mechanisms that confer this action have not been completely elucidated. The prevailing view is that these compounds inhibit novel gene transcription regulated by the nuclear factor kappa B and/or activator protein-1 transcription factors. In the last few years, several reports have shown that glucocorticoids can also block signal transduction in lymphocytes at an early, postreceptor step, suggesting novel molecular targets for these hormones. These data will be briefly reviewed and the possible in vivo relevance of these findings discussed, with particular emphasis on T cell development.Journal ArticleResearch Support, Non-U.S. Gov'tReviewinfo:eu-repo/semantics/publishe