Virologic effects of broadly neutralizing antibodies VRC01LS and VRC07-523LS on chronic HIV-1 infection.

BACKGROUNDHIV-1-specific broadly neutralizing monoclonal antibodies (bNAbs) have emerged as promising interventions with the potential to effectively treat and prevent HIV-1 infections. We conducted a phase I clinical trial evaluating the potent CD4-binding site-specific (CD4bs-specific) bNAbs VRC01LS and VRC07-523LS in people with HIV-1 (PWH) not receiving antiretroviral therapy (ART).METHODSParticipants received a single intravenous 40 mg/kg dose of either VRC01LS (n = 7) or VRC07-523LS (n = 9) and did not initiate ART for a minimum of 14 days.

Long-term safety of lentiviral or gammaretroviral gene-modified T cell therapies.

Long-term risks of gene therapy are not fully understood. In this study, we evaluated safety outcomes in 783 patients over more than 2,200 total patient-years of observation from 38 T cell therapy trials. The trials employed integrating gammaretroviral or lentiviral vectors to deliver engineered receptors to target HIV-1 infection or cancer.

BACH2-driven tissue resident memory programs promote HIV-1 persistence.

Transcription repressor BACH2 redirects short-lived terminally differentiated effector into long-lived memory cells. We postulate that BACH2-mediated long-lived memory programs promote HIV-1 persistence in gut CD4+ T cells. We coupled single-cell DOGMA-seq and TREK-seq to capture chromatin accessibility, transcriptome, surface proteins, T cell receptor, HIV-1 DNA and HIV-1 RNA in 100,744 gut T cells from ten aviremic HIV-1+ individuals and five HIV-1- donors.

Cognate antigen engagement induces HIV-1 expression in latently infected CD4 T cells from people on long-term antiretroviral therapy.

Despite antiretroviral therapy (ART), HIV-1 persists in latently infected CD4 T cells, preventing a cure. Antigens drive the proliferation of infected cells, precluding latent reservoir decay. However, the relationship between antigen recognition and HIV-1 gene expression is poorly understood because most studies of latency reversal use agents that induce non-specific global T cell activation.

The impact of analytical treatment interruptions and trial interventions on time to viral re-suppression in people living with HIV restarting ART in cure-related clinical studies: a systematic review and meta-analysis.

Introduction: To assess the effectiveness of novel HIV curative strategies, "cure" trials require periods of closely monitored antiretroviral therapy (ART) analytical treatment interruptions (ATIs). We performed a systematic review and meta-analysis to identify the impact of ATI with or without novel therapeutics in cure-related studies on the time to viral re-suppression following ART restart.

Methods: Medline, Embase and Web of Science databases were searched for human studies involving ATIs from 1 January 2015 till 22 April 2024.

Cloning and Functional Characterization of Novel Human Neutralizing Anti-IFN-α and Anti-IFN-β Antibodies.

Type I IFNs play a pivotal role in immune response modulation, yet dysregulation is implicated in various disorders. Therefore, it is crucial to develop tools that facilitate the understanding of their mechanism of action and enable the development of more effective anti-IFN therapeutic strategies. In this study, we isolated, cloned, and characterized anti-IFN-α and anti-IFN-β Abs from PBMCs of individuals treated with IFN-α or IFN-β, harboring confirmed neutralizing Abs.

Implementation of an Approach to Equitable Allocation of SARS-CoV-2 Monoclonal Antibodies for Preexposure Prophylaxis: Experience From a Single Medical Center.

Background: During the COVID-19 pandemic, SARS-CoV-2 monoclonal antibodies for preexposure prophylaxis (SMA-PrEP) offered patients who were immunocompromised another option for protection. However, SMA-PrEP posed administrative, operational, and ethical challenges for health care facilities, resulting in few patients receiving them. Although the first SMA-PrEP medication, tixagevimab and cilgavimab, had its authorization revoked due to compromised in vitro efficacy, new SMA-PrEP medications are currently completing clinical trials.

Cloning and functional characterization of novel human neutralizing anti-interferon-alpha and anti-interferon-beta antibodies.

Type I interferons (IFNs) play a pivotal role in immune response modulation, yet dysregulation is implicated in various disorders. Therefore, it is crucial to develop tools that facilitate the understanding of their mechanism of action and enable the development of more effective anti-IFN therapeutic strategies. In this study, we isolated, cloned, and characterized anti-IFN-α and anti-IFN-β antibodies (Abs) from peripheral blood mononuclear cells of individuals treated with IFN-α or IFN-β, harboring confirmed neutralizing Abs.

Switch to fixed-dose doravirine (100 mg) with islatravir (0·75 mg) once daily in virologically suppressed adults with HIV-1 on antiretroviral therapy: 48-week results of a phase 3, randomised, open-label, non-inferiority trial.

Background: Doravirine and islatravir is an investigational, once-daily, single-tablet regimen with high antiviral potency, favourable safety and tolerability, and low propensity for resistance. We report week 48 results from a phase 3 trial evaluating switch from stable, oral antiretroviral therapy (ART) to the fixed combination of doravirine (100 mg) and islatravir (0·75 mg).

Methods: This phase 3, multicentre, randomised, active-controlled, open-label, non-inferiority trial was conducted at 77 research, community, and hospital-based clinics in 15 countries.

Combination of Extended Antivirals With Antiretrovirals for Severe Mpox in Advanced Human Immunodeficiency Virus Infection: Case Series of 4 Patients.

To gauge the safety and utility of extended tecovirimat/cidofovir for severe mpox, here we report our experience caring for 4 patients with mpox and advanced human immunodeficiency virus (HIV) at the Hospitals of the University of Pennsylvania during the 2022 global outbreak. Three patients had recurrent courses complicated by superinfections, coinfections and insufficient nutrition/housing, requiring extended tecovirimat (5-16 weeks) and cidofovir (1-12 doses) with probenecid and fluids. At follow-up, patients had undetectable HIV RNA on antiretrovirals, improved ulcers and stable renal function on antivirals.

The immunogenicity of an HIV-1 Gag conserved element DNA vaccine in people with HIV and receiving antiretroviral therapy.

Objective: The primary objective of the study was to assess the immunogenicity of an HIV-1 Gag conserved element DNA vaccine (p24CE DNA) in people with HIV (PWH) receiving suppressive antiretroviral therapy (ART).

Design: AIDS Clinical Trials Group A5369 was a phase I/IIa, randomized, double-blind, placebo-controlled study of PWH receiving ART with plasma HIV-1 RNA less than 50 copies/ml, current CD4 + T-cell counts greater than 500 cells/μl, and nadir CD4 + T-cell counts greater than 350 cells/μl.

Methods: The study enrolled 45 participants randomized 2 : 1 : 1 to receive p24CE DNA vaccine at weeks 0 and 4, followed by p24CE DNA admixed with full-length p55 Gag DNA vaccine at weeks 12 and 24 (arm A); full-length p55 Gag DNA vaccine at weeks 0, 4, 12, and 24 (arm B); or placebo at weeks 0, 4, 12, and 24 (arm C).

Participant experiences in HIV cure-directed trial with an extended analytical treatment interruption in Philadelphia, United States.

Background: A feature of HIV cure trials is the need to interrupt treatment to test the efficacy of experimental interventions-a process known as analytical treatment interruptions (ATIs).

Objectives: We report the experiences of participants after they completed an extended ATI.

Methods: From April to November 2022, we conducted post-ATI in-depth interviews with BEAT2 clinical trial (NCT03588715) participants who stopped ART while receiving an immunotherapy regimen.

The Penn Medicine COVID-19 Therapeutics Committee-Reflections on a Model for Rapid Evidence Review and Dynamic Practice Recommendations During a Public Health Emergency.

The Penn Medicine COVID-19 Therapeutics Committee-an interspecialty, clinician-pharmacist, and specialist-front line primary care collaboration-has served as a forum for rapid evidence review and the production of dynamic practice recommendations during the 3-year coronavirus disease 2019 public health emergency. We describe the process by which the committee went about its work and how it navigated specific challenging scenarios. Our target audiences are clinicians, hospital leaders, public health officials, and researchers invested in preparedness for inevitable future threats.

The latent reservoir of inducible, infectious HIV-1 does not decrease despite decades of antiretroviral therapy.

HIV-1 persists in a latent reservoir in resting CD4+ T cells despite antiretroviral therapy (ART). The reservoir decays slowly over the first 7 years of ART (t1/2 = 44 months). However, whether decay continues with long-term ART is unclear.

Susceptibility to 3BNC117 and 10-1074 in ART suppressed chronically infected persons.

Objective: The aim of this study was to assess the susceptibility of HIV to two HIV monoclonal antibodies (bnAbs), 3BNC117 and 10-1074, in individuals with chronically antiretroviral therapy (ART) suppressed HIV infection.

Design: The susceptibility of bnAbs was determined using the PhenoSense mAb Assay, which is a cell-based infectivity assay designed to assess the susceptibility of luciferase-reporter pseudovirions. This assay is the only Clinical Laboratory Improvement Ammendment (CLIA)/College of American Pathologist (CAP) compliant screening test specifically developed for evaluating bnAb susceptibility in people with HIV infection.

A prospective 18 F-fluorodeoxyglucose positron emission tomography/computed tomography study of the neurometabolic effects in cocaine use and HIV infection.

Objectives: HIV affects 36 million people globally with prevalence decreasing due to antiretroviral therapy (ART) and social awareness; transmission occurs during substance use. Cocaine usage independently affects brain activity and may result in reduced ART adherence. This study evaluates brain glucose metabolism measured by 18 F-fluorodeoxyglucose positron emission tomography/computed tomography ( 18 F-FDG PET/CT) in cocaine users with HIV infection.

Profound phenotypic and epigenetic heterogeneity of the HIV-1-infected CD4 T cell reservoir.

Understanding the complexity of the long-lived HIV reservoir during antiretroviral therapy (ART) remains a considerable impediment in research towards a cure for HIV. To address this, we developed a single-cell strategy to precisely define the unperturbed peripheral blood HIV-infected memory CD4 T cell reservoir from ART-treated people living with HIV (ART-PLWH) via the presence of integrated accessible proviral DNA in concert with epigenetic and cell surface protein profiling. We identified profound reservoir heterogeneity within and between ART-PLWH, characterized by new and known surface markers within total and individual memory CD4 T cell subsets.

Nucleocapsid-specific antibody function is associated with therapeutic benefits from COVID-19 convalescent plasma therapy.

Coronavirus disease 2019 (COVID-19) convalescent plasma (CCP), a passive polyclonal antibody therapeutic agent, has had mixed clinical results. Although antibody neutralization is the predominant approach to benchmarking CCP efficacy, CCP may also influence the evolution of the endogenous antibody response. Using systems serology to comprehensively profile severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) functional antibodies of hospitalized people with COVID-19 enrolled in a randomized controlled trial of CCP (ClinicalTrials.