Leronlimab Treatment for Multidrug-Resistant HIV-1 (OPTIMIZE): a Randomized, Double-Blind, Placebo-Controlled Trial.

Background: Leronlimab is a humanized κ-IgG4 monoclonal antibody that blocks C-C chemokine receptor type 5 (CCR5). We investigated leronlimab as a treatment option for people living with multidrug-resistant HIV-1.

Setting: and Methods: In a phase 2b/3, multicenter, randomized, double-blind, placebo-controlled study conducted in 21 hospital centers in the United States, treatment-experienced people living with HIV (PLWH) with documented drug resistance were randomly assigned once weekly leronlimab (350 mg subcutaneously) or matching placebo for one week overlapping existing failing antiretroviral treatment (ART), followed by a 24-week single-arm extension with weekly leronlimab combined with a new optimized background treatment (OBT).

SARS-CoV-2 spike antibody levels in lung transplantation recipients versus the spectrum in non-immunocompromised persons.

Lung transplant recipients (LTRs) are immunosuppressed and at high risk from COVID-19, but meaningful quantitative comparisons of their humoral immunity versus non-immunosuppressed persons are scarce. Serum anti-spike receptor binding domain antibodies were quantified in healthy controls after: primary vaccination, mild COVID-19, one vaccination after mild COVID-19, or severe COVID-19. LTRs were assessed after: primary vaccination, a third "booster" vaccination, or severe COVID-19.

Rapid and comprehensive detection of viral antibodies and nucleic acids via an acoustofluidic integrated molecular diagnostics chip: AIMDx.

Precise and rapid disease detection is critical for controlling infectious diseases like COVID-19. Current technologies struggle to simultaneously identify viral RNAs and host immune antibodies due to limited integration of sample preparation and detection. Here, we present acoustofluidic integrated molecular diagnostics (AIMDx) on a chip, a platform enabling high-speed, sensitive detection of viral immunoglobulins [immunoglobulin A (IgA), IgG, and IgM] and nucleic acids.

Direct detection of 4-dimensions of SARS-CoV-2: infection (vRNA), infectivity (antigen), binding antibody, and functional neutralizing antibody in saliva.

We developed a 4-parameter clinical assay using Electric Field Induced Release and Measurement (EFIRM) technology to simultaneously assess SARS-CoV-2 RNA (vRNA), nucleocapsid antigen, host binding (BAb) and neutralizing antibody (NAb) levels from a drop of saliva with performance that equals or surpasses current EUA-approved tests. The vRNA and antigen assays achieved lower limit of detection (LOD) of 100 copies/reaction and 3.5 TCID₅₀/mL, respectively.

A Randomized Placebo-Controlled Trial of Leronlimab in Mild-To-Moderate COVID-19.

Purpose: Early in the course of the SARS-CoV-2 pandemic it was hypothesised that host genetics played a role in the pathophysiology of COVID-19 including a suggestion that the CCR5-Δ32 mutation may be protective in SARS-CoV-2 infection. Leronlimab is an investigational CCR5-specific humanized IgG4 monoclonal antibody currently in development for HIV-1 infection. We aimed to explore the impact of leronlimab on the severity of disease symptoms among participants with mild-to-moderate COVID-19.

Update on Managing the Risks of Exposure to Lentiviral and Retroviral Vectors.

Objective: This paper aims to review the risks associated with using lentiviral and retroviral vectors in research and clinical settings and to propose an update to an effective treatment plan.

Methods: Risks of exposure were evaluated based on vector design, safety features, viral tropism, transgene, and means and modes of transmission. These risks were weighed against the potential risks and benefits of current HIV medications.

NK Cell-Monocyte Cross-talk Underlies NK Cell Activation in Severe COVID-19.

NK cells in the peripheral blood of severe COVID-19 patients exhibit a unique profile characterized by activation and dysfunction. Previous studies have identified soluble factors, including type I IFN and TGF-β, that underlie this dysregulation. However, the role of cell-cell interactions in modulating NK cell function during COVID-19 remains unclear.

Direct Detection of 4-Dimensions of SARS-CoV-2: Infection (vRNA), Infectivity (Antigen), Binding Antibody, and Functional Neutralizing Antibody in Saliva.

We developed a 4-parameter clinical assay using Electric Field Induced Release and Measurement (EFIRM) technology to simultaneously assess SARS-CoV-2 RNA (vRNA), nucleocapsid antigen, host binding (BAb) and neutralizing antibody (NAb) levels from a drop of saliva with performance that equals or surpasses current EUA-approved tests. The vRNA and antigen assays achieved lower limit of detection (LOD) of 100 copies/reaction and 3.5 TCID₅₀/mL, respectively.

IFN-γ-mediated control of SARS-CoV-2 infection through nitric oxide.

Introduction: The COVID-19 pandemic has highlighted the need to identify mechanisms of antiviral host defense against SARS-CoV-2. One such mediator is interferon-g (IFN-γ), which, when administered to infected patients, is reported to result in viral clearance and resolution of pulmonary symptoms. IFN-γ treatment of a human lung epithelial cell line triggered an antiviral activity against SARS-CoV-2, yet the mechanism for this antiviral response was not identified.

The role of APOBEC3-induced mutations in the differential evolution of monkeypox virus.

Recent studies show that newly sampled monkeypox virus (MPXV) genomes exhibit mutations consistent with Apolipoprotein B mRNA Editing Catalytic Polypeptide-like3 (APOBEC3)-mediated editing compared to MPXV genomes collected earlier. It is unclear whether these single-nucleotide polymorphisms (SNPs) result from APOBEC3-induced editing or are a consequence of genetic drift within one or more MPXV animal reservoirs. We develop a simple method based on a generalization of the General-Time-Reversible model to show that the observed SNPs are likely the result of APOBEC3-induced editing.

The role of APOBEC3-induced mutations in the differential evolution of monkeypox virus.

Recent studies show that newly sampled monkeypox virus (MPXV) genomes exhibit mutations consistent with Apolipoprotein B mRNA Editing Catalytic Polypeptide-like3 (APOBEC3)-mediated editing, compared to MPXV genomes collected earlier. It is unclear whether these single nucleotide polymorphisms (SNPs) result from APOBEC3-induced editing or are a consequence of genetic drift within one or more MPXV animal reservoirs. We develop a simple method based on a generalization of the General-Time-Reversible (GTR) model to show that the observed SNPs are likely the result of APOBEC3-induced editing.

Vascular and Non-HLA autoantibody profiles in hospitalized patients with COVID-19.

Introduction: Severe COVID-19 illness is characterized by an overwhelming immune hyperactivation. Autoantibodies against vascular, tissue, and cytokine antigens have been detected across the spectrum of COVID-19. How these autoantibodies correlate with COVID-19 severity is not fully defined.

Predominantly defective CD8 T cell immunity to SARS-CoV-2 mRNA vaccination in lung transplant recipients.

Background: Although mRNA vaccines have overall efficacy preventing morbidity/mortality from SARS-CoV-2 infection, immunocompromised persons remain at risk. Antibodies mostly prevent early symptomatic infection, but cellular immunity, particularly the virus-specific CD8 T cell response, is protective against disease. Defects in T cell responses to vaccination have not been well characterized in immunocompromised hosts; persons with lung transplantation are particularly vulnerable to vaccine failure with severe illness.

Persistent memory despite rapid contraction of circulating T Cell responses to SARS-CoV-2 mRNA vaccination.

Introduction: While antibodies raised by SARS-CoV-2 mRNA vaccines have had compromised efficacy to prevent breakthrough infections due to both limited durability and spike sequence variation, the vaccines have remained highly protective against severe illness. This protection is mediated through cellular immunity, particularly CD8+ T cells, and lasts at least a few months. Although several studies have documented rapidly waning levels of vaccine-elicited antibodies, the kinetics of T cell responses have not been well defined.

Autophagy inducer rapamycin treatment reduces IFN-I-mediated Inflammation and improves anti-HIV-1 T cell response in vivo.

A hallmark of HIV-1 infection is chronic inflammation, even in patients treated with antiretroviral therapy (ART). Chronic inflammation drives HIV-1 pathogenesis, leading to loss of CD4+ T cells and exhaustion of antiviral immunity. Therefore, strategies to safely reduce systematic inflammation are needed to halt disease progression and restore defective immune responses.

Early SARS-CoV-2 dynamics and immune responses in unvaccinated participants of an intensely sampled longitudinal surveillance study.

Background: A comprehensive understanding of the SARS-CoV-2 infection dynamics and the ensuing host immune responses is needed to explain the pathogenesis as it relates to viral transmission. Knowledge gaps exist surrounding SARS-CoV-2 in vivo kinetics, particularly in the earliest stages after exposure.

Methods: An ongoing, workplace clinical surveillance study was used to intensely sample a small cohort longitudinally.

Longitudinal Evaluation of Antibody Persistence in Mother-Infant Dyads After Severe Acute Respiratory Syndrome Coronavirus 2 Infection in Pregnancy.

Background: There are limited data on how coronavirus disease 2019 (COVID-19) severity, timing of infection, and subsequent vaccination impact transplacental transfer and persistence of maternal and infant antibodies.

Methods: In a longitudinal cohort of pregnant women with polymerase chain reaction-confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, maternal/infant sera were collected at enrollment, delivery/birth, and 6 months. Anti-SARS-CoV-2 spike immunoglobulin (Ig)G, IgM, and IgA were measured by enzyme-linked immunosorbent assay.

Machine learning prediction of COVID-19 severity levels from salivaomics data.

The clinical spectrum of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the strain of coronavirus that caused the COVID-19 pandemic, is broad, extending from asymptomatic infection to severe immunopulmonary reactions that, if not categorized properly, may be life-threatening. Researchers rate COVID-19 patients on a scale from 1 to 8 according to the severity level of COVID-19, 1 being healthy and 8 being extremely sick, based on a multitude of factors including number of clinic visits, days since the first sign of symptoms, and more. However, there are two issues with the current state of severity level designation.

Coronavirus Disease 2019 Vaccine Dosage in Children, Adolescents, and Young Adults: Is Less More?

The lower efficacy of the COVID-19 mRNA vaccines in 5-11 year old children was unexpected. Neutralizing antibody titers elicited by the vaccines in children, adolescents, and young adults suggest that the lower efficacy is not due to the lower dosage. Confirming the efficacy of these vaccines in children, determining if mRNA vaccination strategies are less effective in younger children, as well as optimizing the dosage, dosing intervals, and number of doses needed in children, adolescents, and young adults are critical to improve vaccination strategies for these populations going forward.

Baricitinib versus dexamethasone for adults hospitalised with COVID-19 (ACTT-4): a randomised, double-blind, double placebo-controlled trial.

Background: Baricitinib and dexamethasone have randomised trials supporting their use for the treatment of patients with COVID-19. We assessed the combination of baricitinib plus remdesivir versus dexamethasone plus remdesivir in preventing progression to mechanical ventilation or death in hospitalised patients with COVID-19.

Methods: In this randomised, double-blind, double placebo-controlled trial, patients were enrolled at 67 trial sites in the USA (60 sites), South Korea (two sites), Mexico (two sites), Singapore (two sites), and Japan (one site).

Reduced Cell Surface Levels of C-C Chemokine Receptor 5 and Immunosuppression in Long Coronavirus Disease 2019 Syndrome.

In an exploratory trial treating "long COVID" with the CCR5-binding antibody leronlimab, we observed significantly increased blood cell surface CCR5 in treated symptomatic responders but not in nonresponders or placebo-treated participants. These findings suggest an unexpected mechanism of abnormal immune downmodulation in some persons that is normalized by leronlimab. Clinical Trials Registration.