Virological pattern of hepatitis B infection in an HIV-positive man with fatal fulminant hepatitis B: a case report

<p>Abstract</p> <p>Introduction</p> <p>There seem to be no published data concerning the clinical impact of populations of hepatitis B virus (HBV) in the hepatic and extrahepatic compartments of HIV-infected people with severe acute hepatitis.</p> <p>Case presentation</p> <p>A 26-year-old Caucasian man presenting to our hospital with clinical symptoms suggesting acute hepatitis was found to have an acute hepatitis B profile upon admission. He developed fatal fulminant hepatitis and was found to be heavily immunocompromised due to HIV-1 infection. He had a high plasma HBV and HIV load, and analysis of the partial pre-S1/pre-S2 domain showed the presence of mixed infection with D and F genotypes. Analysis of the point mutations within this region revealed the presence of HBV strains with amino acid substitutions at the immunodominant epitopes involved in B or T cell recognition. A homogeneous population of a pre-core mutant strain harbouring the A1896G and A1899G affecting HBeAg expression was invariably found in the liver tissue, plasma and peripheral blood mononuclear cells despite active HBeAg secretion; it was the dominant strain in the liver only, and was characterised by the presence of two point mutations in the direct repeat 1 domain involved in HBV replication activity. Taken together, these mutations are indicative of a highly replicative virus capable of evading immune responses.</p> <p>Conclusion</p> <p>This case report provides clinical evidence of a possible association between the rapid spread of highly replicative escape mutants and the development of fulminant hepatitis in a heavily immunocompromised patient. Virological surveillance of severe acute hepatitis B may be important in establishing an early treatment strategy involving antiviral drugs capable of preventing liver failure, especially in individuals for whom liver transplantation is not accepted as a standard indication.</p

Expression of CD4 on human peripheral blood neutrophils

AbstractCD4, the primary receptor for entry of HIV, is known to be expressed on T cells and monocytes/macrophages; healthy natural killer (NK) lymphocytes; in vitro human herpesvirus 6 (HHV6)–infected CD8+, NK, and γδ T lymphocytes; CD34+ progenitor cells; and a subset of eosinophils and basophils. We here report the unconventional expression of CD4 at the surface of peripheral blood neutrophils derived from 4 of 51 (7.8%) HIV-1–infected and 3 of 25 (12%) uninfected donors, with similar frequency within the 2 groups. The percentage of CD4+ neutrophils ranged from 39% to 97% of the total neutrophil population. Both surface and cytoplasmic forms of CD4 were present in neutrophils. Quantitative RNA polymerase chain reaction (PCR) revealed that neutrophils contain levels of CD4 mRNA comparable to those of peripheral blood mononuclear cells derived from the same donor. The conformation of CD4 expressed at the surface of neutrophils was similar to that of CD4 expressed on T lymphocytes as determined by the binding of monoclonal antibodies specific for conformational epitopes and the binding of recombinant HIV-1 gp120. Thus, our data provide evidence that neutrophils express endogenous CD4 and bind HIV. Owing to their abundance in peripheral blood, CD4+ neutrophils may influence significantly the biodistribution of HIV delivering it to sites of inflammation or to additional tissue reservoirs

Characterization of humoral responses to soluble trimeric HIV gp140 from a clade A Ugandan field isolate

Trimeric soluble forms of HIV gp140 envelope glycoproteins represent one of the closest molecular structures compared to native spikes present on intact virus particles. Trimeric soluble gp140 have been generated by several groups and such molecules have been shown to induce antibodies with neutralizing activity against homologous and heterologous viruses. In the present study, we generated a recombinant trimeric soluble gp140, derived from a previously identified Ugandan A-clade HIV field isolate (gp140(94UG018)). Antibodies elicited in immunized rabbits show a broad binding pattern to HIV envelopes of different clades. An epitope mapping analysis reveals that, on average, the binding is mostly focused on the C1, C2, V3, V5 and C5 regions. Immune sera show neutralization activity to Tier 1 isolates of different clades, demonstrating cross clade neutralizing activity which needs to be further broadened by possible structural modifications of the clade A gp140(94UG018). Our results provide a rationale for the design and evaluation of immunogens and the clade A gp140(94UG018) shows promising characteristics for potential involvement in an effective HIV vaccine with broad activity

The intracellular detection of MIP-1beta enhances the capacity to detect IFN-gamma mediated HIV-1-specific CD8 T-cell responses in a flow cytometric setting providing a sensitive alternative to the ELISPOT

<p>Abstract</p> <p>Background</p> <p>T-cell mediated immunity likely plays an important role in controlling HIV-1 infection and progression to AIDS. Several candidate vaccines against HIV-1 aim at stimulating cellular immune responses, either alone or together with the induction of neutralizing antibodies, and assays able to measure CD8 and CD4 T-cell responses need to be implemented. At present, the IFN-γ-based ELISPOT assay is considered the gold standard and it is broadly preferred as primary assay for detection of antigen-specific T-cell responses in vaccine trials. However, in spite of its high sensitivity, the measurement of the sole IFN-γ production provides limited information on the quality of the immune response. On the other hand, the introduction of polychromatic flow-cytometry-based assays such as the intracellular cytokine staining (ICS) strongly improved the capacity to detect several markers on a single cell level.</p> <p>Results</p> <p>The cumulative analysis of 275 samples from 31 different HIV-1 infected individuals using an ICS staining procedure optimized by our laboratories revealed that, following antigenic stimulation, IFN-γ producing T-cells were also producing MIP-1β whereas T-cells characterized by the sole production of IFN-γ were rare. Since the analysis of the combination of two functions decreases the background and the measurement of the IFN-γ+ MIP-1β+ T-cells was equivalent to the measurement of the total IFN-γ+ T-cells, we adopted the IFN-γ+ MIP-1β+ data analysis system to evaluate IFN-γ-based, antigen-specific T-cell responses. Comparison of our ICS assay with ELISPOT assays performed in two different experienced laboratories demonstrated that the IFN-γ+ MIP-1β+ data analysis system increased the sensitivity of the ICS up to levels comparable to the sensitivity of the ELISPOT assay.</p> <p>Conclusion</p> <p>The IFN-γ+ MIP-1β+ data evaluation system provides a clear advantage for the detection of low magnitude HIV-1-specific responses. These results are important to guide the choice for suitable highly sensitive immune assays and to build reagent panels able to accurately characterize the phenotype and function of responding T-cells. More importantly, the ICS assay can be used as primary assay to evaluate HIV-1-specific responses without losing sensitivity in comparison to the ELISPOT assay.</p

Nef-specific CD45RA+ CD8+ T cells secreting MIP-1β but not IFN-γ are associated with nonprogressive HIV-1 infection

<p>Abstract</p> <p>Background</p> <p>Long-term survival of HIV-1 infected individuals is usually achieved by continuous administration of combination antiretroviral therapy (ART). An exception to this scenario is represented by HIV-1 infected nonprogressors (NP) which maintain relatively high circulating CD4+ T cells without clinical symptoms for several years in the absence of ART. Several lines of evidence indicate an important role of the T-cell response in the modulation of HIV-1 infection during the acute and chronic phase of the disease.</p> <p>Results</p> <p>We analyzed the functional and the differentiation phenotype of Nef- and Tat-specific CD8+ T cells in a cohort of HIV-1 infected NP in comparison to progressors, ART-treated seropositive individuals and individuals undergoing a single cycle of ART interruption. We observed that a distinctive feature of NP is the presence of Nef-specific CD45RA+ CD8+ T cells secreting MIP-1beta but not IFN-gamma. This population was present in 7 out of 11 NP. CD45RA+ IFN-gamma^negMIP-1beta+ CD8+ T cells were not detected in HIV-1 infected individuals under ART or withdrawing from ART and experiencing a rebounding viral replication. In addition, we detected Nef-specific CD45RA+ IFN-gamma^negMIP-1beta+ CD8+ T cells in only 1 out of 10 HIV-1 infected individuals with untreated progressive disease.</p> <p>Conclusion</p> <p>The novel antigen-specific CD45RA+ IFN-gamma^negMIP-1beta+ CD8+ T cell population represents a new candidate marker of long-term natural control of HIV-1 disease progression and a relevant functional T-cell subset in the evaluation of the immune responses induced by candidate HIV-1 vaccines.</p

Stability and expression levels of HLA-C on the cell membrane modulate HIV-1 infectivity

HLA-C expression is associated with a differential ability to control HIV-1 infection. Higher HLA-C levels may lead to a better control of HIV-1 infection through both a higher efficiency of antigen presentation to cytotoxic T lymphocytes (CTLs), as well as the triggering of activating Killer Immunoglobulin like receptors (KIR) on NK-cells, whereas lower levels may provide a poor HIV-1 control and a rapid progression toward AIDS.We characterized the relative amount of HLA-C heterotrimers (heavy chain/\u3b22m/peptide) and HLA-C free heavy chains on PBMC from healthy blood donors harboring both alleles with stable or unstable binding to \u3b22m/peptide. We analyzed the stability of HLA-C heterotrimers of different allotypes and the infectivity of HIV-1 virions produced by PBMC with various allotypes.We observed significant differences in HLA-C heterotrimers stability and in expression levels. We found that R5 HIV-1 virions produced by PBMC harboring unstable HLA-C alleles were more infectious than those produced by PBMC carrying the stable variants.We propose that HIV-1 infectivity might depend both on the amounts of HLA-C molecules and on their stability as trimeric complex. According to this model, individuals with low expressed HLA-C alleles and unstable binding to \u3b22m/peptide might have a worse control of HIV-1 infection and an intrinsically higher capacity to support viral replication.IMPORTANCE Following HIV-1 infection, some people advance rapidly toward AIDS while others have a slow disease progression. HLA-C, a molecule involved in immunity, is a key determinant of HIV-1 control.Here we reveal how HLA-C variants contribute to modulate viral infectivity. HLA-C is present on the cell surface in two different conformations: the immunologically active conformation is part of a complex that includes \u3b22-microglobulin/peptide; the other conformation is not bound to \u3b22-microglobulin/peptide and can associate with HIV-1, increasing its infectivity. Individuals with HLA-C variants with a predominance of immunologically active conformations would display a stronger immunity against HIV-1, a reduced viral infectivity and an effective control of HIV-1 infection, while subjects with HLA-C variants that easily dissociate from \u3b22-microglobulin/peptide would have a reduced immunological response to HIV-1 and produce more infectious virions.This study provides new information that could be useful to design novel vaccine strategies and therapeutic approaches against HIV-1

Safety and pharmacokinetics of subcutaneous administration of broadly neutralizing anti-HIV-1 monoclonal antibodies (bNAbs), given to HIV-1 exposed, uninfected neonates and infants : study protocol for a Phase I trial

SUPPLEMENTARY MATERIAL 1 : Appendix 1. Table 1. Changes to the protocol.SUPPLEMENTARY MATERIAL 2 : Appendix 2. PedMAb1_IC_Version 4.0 Dated 15Mar2024_ENGLISH.SUPPLEMENTARY MATERIAL 3 : Appendix 3. PedMAb1_PIS_Version 4.0 Dated 15Mar2024_ENGLISH.SUPPLEMENTARY MATERIAL 4 : Appendix 4.word Table 7: Schedule of sample collection for HIV exposed infants without HIV: ARMS 1 to 5. And Table 8: Schedule of sample collection for HIV exposed infants without HIV: ARMS 6/6b. Schedule for collection of the biological samples of arms 1-5 and arms 6/6b.DATA AVAILABILITY STATEMENT : No datasets were generated or analysed during the current study.BACKGROUND: The ambitious goal to eliminate new pediatric HIV infections by 2030 requires accelerated prevention strategies in high-risk settings such as South Africa. One approach could be pre-exposure prophylaxis (PrEP) with broadly neutralizing anti-HIV-1 monoclonal antibodies (bNAbs). The aim of our study is to define the optimal dose(s), the ideal combination(s) of bNAbs in terms of potency and breadth, and timing of subcutaneous (SC) administration(s) to prevent breast milk transmission of HIV. METHODS: Two bNAbs, CAP256V2LS and VRC07-523LS, will be assessed in a sequential and randomized phase I, single-site, single-blind, dose-finding trial. We aim to investigate the 28-day safety and pharmacokinetics (PK) profile of incrementally higher doses of these bNAbs in breastfeeding HIV-1 exposed born without HIV neonates alongside standard of care antiretroviral (ARV) medication to prevent (infants) or treat (mothers) HIV infection. The trial design includes 3 steps and 7 arms (1, 2, 3, 4, 5, 6 and 6b) with 8 infants in each arm. The first step will evaluate the safety and PK profile of the bNAbs when given alone as a single subcutaneous (SC) administration at increasing mg/kg body weight doses within 96 h of birth: arms 1, 2 and 3 at doses of 5, 10, and 20 mg/kg of CAP256V2LS, respectively; arms 4 and 5 at doses of 20 and 30 mg/kg of VRC07-523LS, respectively. Step two will evaluate the safety and PK profile of a combination of the two bNAbs administered SC at fixed doses within 96 h of birth. Step three will evaluate the safety and PK profile of the two bNAbs administered SC in combination at fixed doses, after 3 months. Arms 1 and 6 will follow sequential recruitment, whereas randomization will occur sequentially between arms (a) 2 & 4 and (b) 3 & 5. Before each randomization, a safety pause will allow review of safety data of the preceding arms. DISCUSSION: The results of this trial will guide further studies on bNAbs to prevent breast milk transmission of HIV. PROTOCOL VERSION: Version 4.0 dated 15 March 2024. TRIAL REGISTRATION: Pan African Clinical Trial Registry (PACTR): PACTR202205715278722, 21 April 2022; South African National Clinical Trial Registry (SANCTR): DOH-27–062022-6058.The European & Developing Countries Clinical Trials Partnership—Research and Innovation Action, the South African Medical Research Council (SAMRC) and the South African Research Chairs Initiative of the Department of Science and Innovation and the National Research Foundation.https://bmcinfectdis.biomedcentral.com/Paediatrics and Child HealthSDG-03:Good heatlh and well-bein

Report from Working Group 3: Beyond the standard model physics at the HL-LHC and HE-LHC

This is the third out of five chapters of the final report [1] of the Workshop on Physics at HL-LHC, and perspectives on HE-LHC [2]. It is devoted to the study of the potential, in the search for Beyond the Standard Model (BSM) physics, of the High Luminosity (HL) phase of the LHC, defined as $3$ ab$^{-1}$ of data taken at a centre-of-mass energy of 14 TeV, and of a possible future upgrade, the High Energy (HE) LHC, defined as $15$ ab$^{-1}$ of data at a centre-of-mass energy of 27 TeV. We consider a large variety of new physics models, both in a simplified model fashion and in a more model-dependent one. A long list of contributions from the theory and experimental (ATLAS, CMS, LHCb) communities have been collected and merged together to give a complete, wide, and consistent view of future prospects for BSM physics at the considered colliders. On top of the usual standard candles, such as supersymmetric simplified models and resonances, considered for the evaluation of future collider potentials, this report contains results on dark matter and dark sectors, long lived particles, leptoquarks, sterile neutrinos, axion-like particles, heavy scalars, vector-like quarks, and more. Particular attention is placed, especially in the study of the HL-LHC prospects, to the detector upgrades, the assessment of the future systematic uncertainties, and new experimental techniques. The general conclusion is that the HL-LHC, on top of allowing to extend the present LHC mass and coupling reach by $20-50\%$ on most new physics scenarios, will also be able to constrain, and potentially discover, new physics that is presently unconstrained. Moreover, compared to the HL-LHC, the reach in most observables will, generally more than double at the HE-LHC, which may represent a good candidate future facility for a final test of TeV-scale new physics

Health, education, and social care provision after diagnosis of childhood visual disability

Aim: To investigate the health, education, and social care provision for children newly diagnosed with visual disability.Method: This was a national prospective study, the British Childhood Visual Impairment and Blindness Study 2 (BCVIS2), ascertaining new diagnoses of visual impairment or severe visual impairment and blindness (SVIBL), or equivalent vi-sion. Data collection was performed by managing clinicians up to 1-year follow-up, and included health and developmental needs, and health, education, and social care provision.Results: BCVIS2 identified 784 children newly diagnosed with visual impairment/SVIBL (313 with visual impairment, 471 with SVIBL). Most children had associated systemic disorders (559 [71%], 167 [54%] with visual impairment, and 392 [84%] with SVIBL). Care from multidisciplinary teams was provided for 549 children (70%). Two-thirds (515) had not received an Education, Health, and Care Plan (EHCP). Fewer children with visual impairment had seen a specialist teacher (SVIBL 35%, visual impairment 28%, χ2p < 0.001), or had an EHCP (11% vs 7%, χ2p < 0 . 01).Interpretation: Families need additional support from managing clinicians to access recommended complex interventions such as the use of multidisciplinary teams and educational support. This need is pressing, as the population of children with visual impairment/SVIBL is expected to grow in size and complexity.This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited